自噬和病原微生物的攻坚战

A dynamically evolving war between autophagy and pathogenic microorganisms 自噬和病原微生物的攻坚战 1 2 equal first-author https://orcid.org/0000-0002-1760-4906 1 2 equal https://orcid.org/0000-0001-9728-3251 1 2 1 2 1 2 1 2 corresp Hui WANG, wanghui@xxmu.edu.cn Hui WANG, wanghui@xxmu.edu.cn wanghui@xxmu.edu.cn https://orcid.org/0000-0002-2454-3814 Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang453003, China Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang453003, China Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang453003, China Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang453003, China Autophagy is an intracellular degradation process that maintains cellular homeostasis. It is essential for protecting organisms from environmental stress. Autophagy can help the host to eliminate invading pathogens, including bacteria, viruses, fungi, and parasites. However, pathogens have evolved multiple strategies to interfere with autophagic signaling pathways or inhibit the fusion of autophagosomes with lysosomes to form autolysosomes. Moreover, host cell matrix degradation by different types of autophagy can be used for the proliferation and reproduction of pathogens. Thus, determining the roles and mechanisms of autophagy during pathogen infections will promote understanding of the mechanisms of pathogen‍‒‍host interactions and provide new strategies for the treatment of infectious diseases. 自噬是机体一种主动的细胞防御系统，可积极应对病原微生物感染，如细菌、病毒、真菌和寄生虫，直接清除它们或通过调节固有免疫和适应性免疫反应来杀灭它们。同时，当细胞自噬被触发时，病原体也可通过逃避或利用自噬来促进自身的生存。本文对病原微生物改变自噬信号通路的多种策略进行了介绍；总结了关于细菌、病毒、真菌和寄生虫等病原微生物与宿主细胞内自噬发生复杂相互作用的最新研究进展；探讨了自噬在病原性感染过程中的作用和机制。自噬在病原感染中的作用特点在于：自噬不仅在病原体与机体抗感染相互作用方面存在着双重调节作用，而且自噬的效果取决于细胞类型、病原体特征和所处的微环境。病原感染过程中自噬作用和机制的阐明将促进人们对病原体-宿主相互作用机制的深入理解，并可进一步为传染病的防治提供新策略。 Autophagy Pathogenic microorganism Bacteria Virus Fungi Parasite 自噬 病原微生物 细菌 病毒 真菌 寄生虫 1 Introduction 1 Cellular autophagy is a type of subcellular degradation pathway that is vital to maintain the health of eukaryotes ( Chun and Kim, 2018 Chun and Kim, 2018 ; Schille et al., 2018 Schille et al., 2018 ; Allen et al., 2020 Allen et al., 2020 ; Andriantsitohaina and Papon, 2020 Andriantsitohaina and Papon, 2020 ). Cellular autophagy refers broadly to the process of lysosome-mediated cytoplasmic degradation ( Wang and Qin, 2013 Wang and Qin, 2013 ). Compared with the proteasome, the lysosome has a more powerful degradation ability. Therefore, the cellular autophagy pathway can degrade intracellular substances from soluble proteins to intact organelles in large quantities, and has advantages for the degradation of long-lived macromolecules and damaged organelles ( Chang et al., 2013 Chang et al., 2013 ; Chen G et al., 2014 Chen G et al., 2014 ; Kocaturk and Gozuacik, 2018 Kocaturk and Gozuacik, 2018 ). Cellular autophagy has important roles in growth and development, immune defense, programmed cell death, tumor suppression, and neuropathological inhibition ( Mestre and Colombo, 2012 Mestre and Colombo, 2012 ; Chew et al., 2015 Chew et al., 2015 ; Tian et al., 2015 Tian et al., 2015 ; Yin et al., 2016 Yin et al., 2016 ; Dai and Zhu, 2020 Dai and Zhu, 2020 ; Wen et al., 2020 Wen et al., 2020 ). Depending on the method of wrapping the intracellular material and the mode of delivery, cellular autophagy can be classified into macro-autophagy, micro-autophagy, and chaperone-mediated autophagy ( Glick et al., 2010 Glick et al., 2010 ; Feng et al., 2014 Feng et al., 2014 ; Farré and Subramani, 2016 Farré and Subramani, 2016 ). Macro-autophagy wraps intracellular material by forming an autophagosome with a bilayer membrane structure, which eventually fuses with a lysosome ( Feng et al., 2014 Feng et al., 2014 ; Fujioka et al., 2020 Fujioka et al., 2020 ). Micro-autophagy directly engulfs specific organelles through deformation of the lysosome or vesicle surface ( Mijaljica et al., 2011 Mijaljica et al., 2011 ; Schuck, 2020 Schuck, 2020 ). Chaperone-mediated autophagy introduces cytoplasmic or organelle proteins into the lysosome lumen through unfolding via molecular chaperones ( Kaushik and Cuervo, 2018 Kaushik and Cuervo, 2018 ; Tekirdag and Cuervo, 2018 Tekirdag and Cuervo, 2018 ). This review focuses on macro-autophagy (referred to hereafter as autophagy). Autophagy is a complex process. First, the Unc-51-like autophagy activating kinase 1 (ULK1) complex mediates the initiation of autophagy ( Zachari and Ganley, 2017 Zachari and Ganley, 2017 ). When cells are in a normal physiological state, intracellular energy is sufficient, and the mammalian target of rapamycin complex 1 (mTORC1) is in an activated state to promote the phosphorylation of autophagy-related 13 (ATG13) and ULK1 to inactivate the ULK1 complex, but when cells are under starvation conditions, mTORC1 activity is inhibited ( Li and Yan, 2019 Li and Yan, 2019 ). Intermolecular interactions, such as dephosphorylation of ATG13 and ULK1, promote the formation of the active ULK1 complex and initiate autophagy ( Joo et al., 2011 Joo et al., 2011 ; Richards and Jackson, 2012 Richards and Jackson, 2012 ; Kamber et al., 2015 Kamber et al., 2015 ; Kandul et al., 2016 Kandul et al., 2016 ). Second, the activated ULK1 complex phosphorylates the phosphatidylinositol 3-kinase catalytic subunit type 3 (PI3KC3) complex to mediate the formation of the pre-autophagosome structure (PAS) of the endoplasmic reticulum, Golgi apparatus, and other membranous organelles ( Kim et al., 2011 Kim et al., 2011 ; Kato et al., 2019 Kato et al., 2019 ; Kawabata and Yoshimori, 2020 Kawabata and Yoshimori, 2020 ). The PI3KC3 complex further recruits the ATG16L1 complex, and both are co-located on the outer membrane surface of the PAS and promote its expansion ( Kirkin and Rogov, 2019 Kirkin and Rogov, 2019 ). Then, ATG4 cleaves the microtubule-associated protein 1 light chain 3 ‍α (LC3) precursor to form LC3-I, which is delivered to the autophagic vesicles, under the action of E1-like enzyme ATG7 and E2 - like enzyme ATG3, by covalent conjugation of phosphatidylethanolamine (PE) into LC3-Ⅱ ( Tanida et al., 2008 Tanida et al., 2008 ; Kourtis and Tavernarakis, 2009 Kourtis and Tavernarakis, 2009 ; Kobayashi et al., 2015 Kobayashi et al., 2015 ) . LC3-‍Ⅱ then participates in the extension of the membrane of the autophagosome. LC3-Ⅱ can further combine with the newly formed autophagic membrane to promote the fusion and expansion of autophagosomes ( Lee and Lee, 2016 Lee and Lee, 2016 ). Finally, the endosomal sorting complex required for transport (ESCRT) complex, soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, and Rab guanosine triphosphatases (GTPases) mediate the movement of autophagosomes along the microtubule framework. The autophagosomes then fuse with lysosomes to form autophagolysosomes, whose contents and inner membrane are degraded by lysosomal enzymes ( Towers and Thorburn, 2016 Towers and Thorburn, 2016 ; Kumsta et al., 2017 Kumsta et al., 2017 ). Autophagy plays an important role in the regulation of physiological activities, such as the reconstruction of cell structures and the maintenance of normal growth and differentiation, as well as the process of resisting adverse external environments ( Mizushima and Komatsu, 2011 Mizushima and Komatsu, 2011 ; Cardenal-Muñoz et al., 2017 Cardenal-Muñoz et al., 2017 ). It was believed that autophagy did not selectively degrade substrates ( Reggiori et al., 2012 Reggiori et al., 2012 ). However, increasing autophagy-related research has shown that under certain circumstances, autophagy can specifically degrade certain types of macromolecules or organelles in a process known as selective autophagy ( Farré and Subramani, 2016 Farré and Subramani, 2016 ). The pathways of selective autophagy include the cytoplasm-to-vacuole targeting (Cvt) pathway, mitochondrial autophagy, endoplasmic reticulum autophagy, peroxisomal autophagy, ribosomal autophagy, and lipid autophagy ( Yuan et al., 1999 Yuan et al., 1999 ; Kamada et al., 2000 Kamada et al., 2000 ; Shintani and Klionsky, 2004b Shintani and Klionsky, 2004b ; Narendra et al., 2008 Narendra et al., 2008 ). In essence, cellular autophagy comprises type II programmed cell death. The reasons that cells are selected as targets for autophagy vary, and include cellular senescence and invading exogenous pathogens. Numerous studies have shown that selective autophagic pathways can also destroy these invading pathogens ( Deretic and Levine, 2009 Deretic and Levine, 2009 ). These processes are known as xenophagy ( Bauckman et al., 2015 Bauckman et al., 2015 ). Xenophagy is closely related to innate immunity and its receptor is typified by sequestosome-1/p62-like receptors (SLRs) ( Deretic, 2012 Deretic, 2012 ). These act as pattern recognition receptors (PRRs) and usually have one or more LC3-interacting region (LIR) structural domains, including sequestosome-1 (SQSTM1, also known as p62), optineurin (OPTN), neighbor of BRCA1 gene l (NBR1), and nuclear dot protein 52 (NDP52) ( Levine, 2005 Levine, 2005 ; Deretic, 2012 Deretic, 2012 ). These proteins function as autophagy adaptor proteins, which are capable of directly capturing bacteria, producing and transporting antimicrobial peptides, and acting as inflammatory signals to promote autophagy, thereby clearing pathogens from invading cells. In virophagy (a form of xenophagy), the pathogen-associated molecular pattern (PAMP) of the virus is recognized by intracellular PRRs, including retinoic acid-inducible gene I (RIG-I) like receptors (RLRs), nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), and Toll-like receptors (TLRs) ( Cadwell, 2016 Cadwell, 2016 ; Choi et al., 2018 Choi et al., 2018 ). After pathogen recognition and binding, they induce apoptosis or autophagy, modulate and regulate inflammatory responses, and activate specific signaling pathways ( Cadwell, 2016 Cadwell, 2016 ). When cells are invaded by various microbial pathogens (mainly bacteria, viruses, fungi, or parasites), intracellular pathogens are usually endocytosed by host cells and then enter the cytoplasm. There, the host cells initiate the autophagic pathway, and autophagic vesicles wrap pathogens and transport them to lysosomes for degradation ( Lin et al., 2021 Lin et al., 2021 ). However, recent studies have revealed that certain pathogenic factors have evolved multiple strategies to interfere with the autophagic signaling pathway, enabling or inhibiting the fusion of autophagosomes with lysosomes to form autophagolysosomes to evade autophagic degradation, or even using autophagy to promote their own replication ( Kimmey and Stallings, 2016 Kimmey and Stallings, 2016 ; Coppens, 2017 Coppens, 2017 ; Abdoli et al., 2018 Abdoli et al., 2018 ; Xiong et al., 2019 Xiong et al., 2019 ; Hu et al., 2020 Hu et al., 2020 ). Therefore, it is important to determine the relationship between host cell autophagy and various pathogenic factors to clarify the pathogenic mechanisms of pathogens. In this review, we focus on important progress in research on the interaction between autophagy and pathogenic microorganisms, and describe the direct scavenging effect of various regulations of autophagic signaling pathways on pathogenic factors. In addition, we provide an overview of the mechanisms used by pathogenic microorganisms to evade or use autophagy for themselves, thereby promoting their own survival. These could provide a reference for autophagy research and reveal new routes for effective anti-infective therapies targeting autophagy. 2 Bacteria and autophagy 1 Autophagy can act as an innate immune mechanism against bacterial infection ( Ogawa et al., 2011 Ogawa et al., 2011 ; Hu et al., 2020 Hu et al., 2020 ). For healthy cell growth, invading bacteria are recognized by the SLRs and the selective autophagy pathway (xenophagy) removes invading extracellular bacteria, as well as bacteria colonized in the cytoplasm, phagosomes, or vesicles. However, this method of killing bacteria is not perfect. By interfering with the processes associated with autophagy, the bacteria's innate aim to survive can be achieved. This interference process can begin with the fusion of pathogenic bacteria-infested autophagosomes with lysosomes. Maturation of the autophagosomes to autophagic lysosomes is then delayed by the secretion of associated proteins, which remain in the vesicles of autophagosome-like structures as a resource for bacterial proliferation or survival. Alternatively, in macrophages, bacterially secreted proteins promote the formation of autophagosome-like structures or interfere with the maturation of autophagosomes, which in turn allows the pathogens themselves to survive ( Deretic, 2010 Deretic, 2010 ; Bah and Vergne, 2017 Bah and Vergne, 2017 ; Sudhakar et al., 2019 Sudhakar et al., 2019 ; Hu et al., 2020 Hu et al., 2020 ). Autophagy plays an important role in the interaction between pathogenic bacteria and host cells. After bacterial infection of host cells, the results of the interaction between autophagy and bacteria include preventing bacterial proliferation or autophagy interacting with other immune factors (such as inflammatory factors and interferon-γ (IFN-γ)) to control bacterial infection ( Desai et al., 2015 Desai et al., 2015 ). Bacteria use their virulence factors, synthesize messenger RNA (mRNA), or secrete certain proteins and lipids to block the autophagy process or induce incomplete autophagy processes, thereby evading the killing effect of autophagy. 2.1 Gram-positive bacterial infection and autophagy 2 Current research has focused mainly on pathogenic Gram-positive bacteria, such as Staphylococcus aureus , group A Streptococcus (GAS), and Listeria monocytogenes . S. aureus infection can cause septic and toxic diseases ( Otto, 2014 Otto, 2014 ). S. aureus is rapidly ubiquitinated upon invasion of human cervical cancer (HeLa) cells and induces cellular autophagy by binding to the autophagy receptor proteins SQSTM1, NDP52, and OPTN, which are marked by the formation of an apparent co-localization of S. aureus with LC3. However, the fusion of autophagosomes and lysosomes is blocked and complete autophagic flux cannot be performed ( Schnaith et al., 2007 Schnaith et al., 2007 ). S. aureus can evade autophagy by activating certain proteins or signaling pathways. After infection of murine fibroblasts and human keratinocytes, it activates mitogen-activated protein kinase 14 (MAPK14), which then phosphorylates autophagy-related 5 (ATG5) to inhibit the fusion of autophagosomes and lysosomes to avoid autophagic degradation ( Keil et al., 2013 Keil et al., 2013 ; Neumann et al., 2016 Neumann et al., 2016 ) ( Fig. 1 Fig. 1 ). In addition, the autophagy caused by S. aureus infection of the mouse macrophage cell line RAW264.7 is closely related to the PI3K/protein kinase B (AKT)-Beclin1 signaling pathway ( Lv et al., 2019 Lv et al., 2019 ). After inhibiting this signaling pathway, the level of S. aureus -induced autophagy is significantly downregulated ( Lv et al., 2019 Lv et al., 2019 ). These observations have shown that because the autophagosomes that occur in S. aureus -infected cells cannot fuse with lysosomes, incomplete autophagy is triggered. This prevents the autophagosomes from being acidified, thereby allowing S. aureus to proliferate in the autophagosome without being degraded ( Schnaith et al., 2007 Schnaith et al., 2007 ) ( Fig. 1 Fig. 1 ). The manipulation of autophagy by S. aureus to avoid being killed is well documented. S. aureus secretes the virulence factor pore-forming toxin α‍-hemolysin (Hla), which activates autophagy in a different way. This leads to a decrease in intracellular cyclic adenosine monophosphate (cAMP) levels and promotes a non-classical autophagic pathway. This autophagic pathway requires the involvement of ATG5, which is essential for the development of autophagosomal membranes. S. aureus can be present in the autophagosome, preventing its maturation and fusion with the lysosome. Subsequently, S. aureus escapes from autophagosomes and enters the cytoplasm where it replicates prolifically, leading to the death of the host cell and the infection of neighboring cells ( Mestre et al., 2010 Mestre et al., 2010 ). GAS are pathogenic bacteria that exist widely in nature ( Okamoto and Nagase, 2018 Okamoto and Nagase, 2018 ). After GAS invade a host cell, most of the GAS in the cytoplasm are encapsulated in GAS-containing autophagosome-like vacuoles (GcAVs) and degraded through the autophagy pathway ( Nakagawa et al., 2004 Nakagawa et al., 2004 ). In Atg5 -/- mouse embryo fibroblasts (MEFs), which cannot form autophagosomes, GAS can survive, proliferate, and be released from the cells ( Nakagawa et al., 2004 Nakagawa et al., 2004 ). Autophagy can inhibit the growth and proliferation of GAS. To survive in the cell for a long time, GAS have evolved a variety of strategies to evade autophagy. For example, they use certain virulence factors to avoid autophagy degradation. Streptococcus pyrogenic exotoxin B (SpeB) is a cysteine protease secreted by Streptococcus ( Hytönen et al., 2001 Hytönen et al., 2001 ). The M1T1 serotype GAS use SpeB to degrade SQSTM1, NDP52, and NBR1 proteins in the host cell cytoplasm and prevent recognition of host cell autophagy-related proteins ( Barnett et al., 2013 Barnett et al., 2013 ). Streptolysin O (SLO) is a member of the cholesterol-dependent pore-forming cytolysin conserved family ( Vita et al., 2020 Vita et al., 2020 ). GAS use SLO to form pores in the newly formed endosomal membrane to help them escape into the cytoplasm ( Sakurai et al., 2010 Sakurai et al., 2010 ). By activating β1 integrin, SLO recruits nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), produces reactive oxygen species (ROS), and induces ineffective LC3-related phagocytosis (LAP), leading to insufficient acidification to evade host autophagic clearance and promoting the proliferation of GAS ( Lu et al., 2015 Lu et al., 2015 ; Cheng et al., 2019 Cheng et al., 2019 ). L. monocytogenes is a zoonotic pathogen and a facultative intracellular bacterium, which is used as a model intracellular parasite ( Lecuit, 2020 Lecuit, 2020 ). Upon infection with L. monocytogenes , host cells activate autophagy through their own recognition receptors. β2 integrin/macrophage-1 antigen (MAC-1) is a receptor expressed by macrophages that recognizes a variety of microbial ligands ( Ehlers, 2000 Ehlers, 2000 ). Host cell MAC-1 induces LAP by activating acid sphingomyelinase (ASMase) and NADPH oxidase Nox2 to generate ROS ( Gluschko et al., 2018 Gluschko et al., 2018 ). In addition, LAP promotes the fusion of Listeria -containing phagosomes and lysosomes, thereby enhancing the anti-bacterial ability of macrophages and the host's immune response ( Gluschko et al., 2018 Gluschko et al., 2018 ). TLR2 is involved in the auto phagy process produced by Listeria . In Tlr2 -/- macrophages, Listeria and LC3 cannot co-localize, and further studies have shown that TLR2 participates in this autophagy process through its downstream extracellular signal-regulated kinase (ERK) signaling pathway ( Anand et al., 2011 Anand et al., 2011 ). After invading the host cell, L. monocytogenes , like GAS, is able to use its virulence factors to assist its escape from the autophagosome, and then enters the cytoplasm to continue its proliferation. Its virulence factor, L. monocytogenes Lysin O (LLO), is a cholesterol-dependent pore-forming cytolysin ( Anand et al., 2011 Anand et al., 2011 ). In the early stages of infection, Listeria enters macrophages but its replication is inhibited by autophagy induced by LLO ( Birmingham et al., 2007 Birmingham et al., 2007 ; Py et al., 2007 Py et al., 2007 ). For a period of time after infection, with the help of two bacterial phospholipases C (PLCs), a phosphatidylinositol-specific PLC (PI-PLC, encoded by plcA ) and a broad-range PLC (PC-PLC, encoded by plcB ), Listeria escapes from the autophagosome ( Birmingham et al., 2007 Birmingham et al., 2007 ). LLO binds to cholesterol, inserts into the host cell membrane, and aggregates to form pores to facilitate the escape of Listeria from the cell. Therefore, the autophagy response induced by LLO exhibits dynamic changes over time during Listeria infection. Actin assembly-inducing protein A (ActA) is also a virulence factor of Listeria , and plays an important role in autophagy escape. ActA shields bacteria from recognition by autophagy by recruiting the actin-related protein 2/3 (Arp2/3) complex and the extractable nuclear antigen/vasodilator-stimulated phosphoprotein (Ena/VASP) to the bacterial surface to form an artifact. The camouflage provided by these proteins prevents bacteria from being recognized by autophagy ( Yoshikawa et al., 2009 Yoshikawa et al., 2009 ; Cheng et al., 2018 Cheng et al., 2018 ). Listeria evades autophagy mainly through PlcA and ActA ( Rudnicka et al., 1997 Rudnicka et al., 1997 ; Mitchell et al., 2015 Mitchell et al., 2015 ). PlcA blocks the binding of PE to LC3 and presumably acts by preventing the formation of PI3P ( Mitchell et al., 2015 Mitchell et al., 2015 ). The internalin K (InlK) is recognized by decorating the bacterial surface with the major vault protein (MVP) to escape autophagy. The InlK-MVP interaction is a two-part process along the same pathway as actin polymerization. InlK recruits MVP to the bacterial surface, followed by ActA replacing InlK, and actin replaces MVP to modify the bacterium, preventing the recruitment of ubiquitin (Ub), the recognition of p62, and the recruitment of LC3 as a means of evading cellular autophagy ( Dortet et al., 2011 Dortet et al., 2011 ). Mycobacterium tuberculosis (MTB) is an intracellular parasitic bacterium ( Yi et al., 2020 Yi et al., 2020 ). Cellular autophagy of MTB is an important anti-MTB response mechanism, operating either directly through the formation of autophagic lysosomes or indirectly through the upregulation of intrinsic immunity ( Zhai et al., 2019 Zhai et al., 2019 ). MTB infection-induced autophagy in macrophages enhances the acidification and maturation of Mycobacterium -containing phagosomes, thereby inhibiting the survival of intracellular MTB ( Queval et al., 2017 Queval et al., 2017 ). There is also a mechanism by which MTB inhibits autophagy in macrophages, thereby avoiding being killed ( Maphasa et al., 2021 Maphasa et al., 2021 ). MTB can inhibit the maturation and acidification of autophagosomes and thus avoid clearance via autophagy. Inhibition of macrophage phagosome and lysosome binding is one of the main mechanisms by which MTB inhibits the maturation of phagosomes ( Zhai et al., 2019 Zhai et al., 2019 ). After capturing MTB, autophagic vesicles fuse with lysosomes to transport the bacteria into an acidic environment filled with hydrolytic enzymes and free radicals. Impaired lysosome function increases susceptibility to MTB infection by inhibiting macrophage autophagy and the ability to migrate directionally. The killing of MTB by autophagic lysosomes is associated with p62, which transports ribosomal precursors and other ubiquitinated proteins from the cytoplasm into autophagic lysosomes for degradation to produce new antimicrobial peptides ( Deretic, 2012 Deretic, 2012 ). 2.2 Gram-negative bacterial infection and autophagy 2 Current studies have focused mainly on the Gram-negative pathogen Salmonella , which causes mainly gastroenteritis in humans and mammals and contains two Type III secretion systems (T3SSs), Salmonella virulence island 1 (SPI-1) and SPI-2 ( Kim et al., 2018 Kim et al., 2018 ). SPI-1 is essential for invasion by Salmonella , and SPI-2 promotes its survival in the host cell ( Jennings et al., 2017 Jennings et al., 2017 ). Phagocytic vesicles inhibited by Salmonella are called Salmonella -containing vacuoles (SCVs) ( Stévenin et al., 2019 Stévenin et al., 2019 ). Most Salmonella strains exist in SCVs, and only a fraction escapes from SCVs to replicate in the cytoplasm. Autophagy acts on Salmonella in two ways. First, Salmonella escaped from SCVs are ubiquitinated. Ubiquitination modification recruits a variety of autophagy adaptor proteins, including SQSTM1/p62, NDP52, and OPTN ( Kishi-Itakura et al., 2020 Kishi-Itakura et al., 2020 ). These proteins bind to ubiquitinated bacteria through their Ub-binding domains. Then, new autophagosomes are attached through interactions with the ATG8 family members anchored in the autophagosome membrane. Salmonella -containing autophagosomes are fused with lysosomes and Salmonella is then killed in a hydrolytic environment ( Mostowy, 2013 Mostowy, 2013 ). Second, SCVs are punctured via SPI-1, causing the damaged SCVs to be recognized by the autophagy machinery. In this case, Salmonella does not need to enter the cytoplasm to be captured by autophagy ( Birmingham et al., 2006 Birmingham et al., 2006 ). The formation of pores in SCVs by SPI-1 leads to the accumulation of multiple cytoplasmic galectins, such as galectin-8, which monitors the integrity of intracellular lysosomes ( Thurston et al., 2012 Thurston et al., 2012 ). SCV is modified by galectin-8 to recruit Ub ligases and NDP52 to the cell membrane, leading to SCV components being cleared via autophagy ( Ravenhill et al., 2019 Ravenhill et al., 2019 ). Autophagic recognition of bacteria is usually associated with ubiquitination, and the E3 ligase could play a significant role in cellular autophagy by mediating ubiquitination. Human leucine-enriched sterile α motif containing 1 (LRSAM1) recognizes and ubiquitinates Salmonella typhimurium in the cytoplasm of HeLa cells through its leucine-rich repeat (LRR) domain and really interesting new gene (RING) domain, respectively, and initiates Ub-dependent autophagy, thereby restricting S. typhimurium infection ( Huett et al., 2012 Huett et al., 2012 ). In addition, the E3 ligase linear ubiquitin chain assembly complex (LUBAC) produces linear polyubiquitin chains on the surface of S. typhimurium , recruiting receptors OPTN, NDP52, and SQSTM1/p62, thereby limiting its proliferation ( Noad et al., 2017 Noad et al., 2017 ). Besides, the RING-between-RING E3 ligase Ariadne-1 homolog (ARIH1) can directly target S. typhimurium to autophagosomes ( Polajnar et al., 2017 Polajnar et al., 2017 ). Depletion of LRSAM1 and ARIH1 after S. typhimurium infection leads to enhanced LUBAC-dependent ubiquitination. However, this does not inhibit its growth in the cytoplasm ( Polajnar et al., 2017 Polajnar et al., 2017 ). These findings highlight that host cells can initiate autophagy by recruiting different E3 Ub ligases on the surface of bacteria to prevent the cellular proliferation of S. typhimurium . Legionella pneumophila is a Gram-negative pathogen that can cause lethal pneumonia or influenza-like symptoms in humans ( Huss et al., 2020 Huss et al., 2020 ). Immediately upon entry into the host cell phagosome, ATG7 binds to the bacteria and then to ATG8 to form Legionella -containing vacuoles (LCVs). LCVs can fuse with endoplasmic reticulum-derived vesicles, facilitating the replication of L. pneumophila within them, a process that requires the involvement of Ras-related proteins Rab1 and Sec22b ( Kagan et al., 2004 Kagan et al., 2004 ). The SNARE protein Syntaxin 17 plays an important role in autophagosome membrane formation by recruiting ATG14L to the endoplasmic reticulum-mitochondrial binding site to aid in the formation of autophagosomes ( Hamasaki et al., 2013 Hamasaki et al., 2013 ). In addition, Syntaxin 17 is essential for the fusion of autophagosomes and lysosomes, and its function is dependent on its C-terminal hairpin structure ( Itakura et al., 2012 Itakura et al., 2012 ). The effector protein of L. pneumophila , Lpg1137, is a serine protease that cleaves Syntaxin 17, thereby blocking autophagy from occurring ( Arasaki et al., 2017 Arasaki et al., 2017 ). In addition, the RavZ protein blocks the binding of the ATG8 (LC3) protein to PE on the autophagosome membrane by hydrolyzing the amide bond between the glycine residue at the ATG8 C-terminus and the adjacent aromatic residue ( Choy et al., 2012 Choy et al., 2012 ). This prevents ATG from lipidating and forming an LC3-PE form to aggregate in the vesicle, thereby blocking autophagosome formation ( Xie et al., 2008 Xie et al., 2008 ). 3 Viruses and autophagy 1 Viruses are an important class of pathogens that are unique in that once they leave the host cell, they have no replication, transcription, or translation functions. Autophagy plays a key role in viral infections, first as an antiviral process, and second in the possible radicalization of the virus when antiviral methods fail. Some viruses hijack the autophagic machinery to survive within the cell, while others express specific proteins to evade autophagy and multiply within the host cell ( Orvedahl and Levine, 2008 Orvedahl and Levine, 2008 ; Ploen and Hildt, 2015 Ploen and Hildt, 2015 ; Zhao et al., 2020 Zhao et al., 2020 ). In short, viruses in host cells need to avoid the negative effects of apoptosis and autophagy as far as possible to prolong their life activities, such as replication and spread. 3.1 Antiviral effects of autophagy 2 Autophagy acts not only as a metabolic pathway to maintain intracellular homeostasis, but also as part of the body's immune defense against viruses. After a virus has invaded a cell, the cell transports the virus proteins, nucleic acids, and viral particles through autophagy to the lysosome for degradation, thereby maintaining the health of the body. This involves both innate and adaptive immunity ( Choi et al., 2018 Choi et al., 2018 ). Innate immunity is the body's first line of defense against invasion by exogenous microorganisms and is achieved through the recognition and binding of specific molecular structures of pathogenic microorganisms by membrane-bound PRRs and cytoplasmic PRRs. This activates downstream signaling pathways to produce type I IFN, type III IFN, pro-inflammatory cytokines, and chemokines, enabling the body to establish an antiviral state ( Mogensen and Paludan, 2001 Mogensen and Paludan, 2001 ; Farag et al., 2020 Farag et al., 2020 ). TLRs are classical PRRs that recognize a wide range of viral nucleic acids and transmit signals to myeloid differentiation factors 88 (MyD88) by recruiting Toll/interleukin-1 receptor domain-containing adapter protein inducing IFN-‍β (TRIF) or MyD88, signaling to the downstream nuclear factor-‍κB (NF-κB) signaling pathway, and synthesizing inflammatory factors and IFN regulatory factors (IRFs) to promote IFN production. In this process, TLRs can induce TRIF or MyD88 to interact with Beclin1, which disrupts the binding of Beclin1 to B-cell lymphoma 2 (BCL-2) and thus promotes autophagy ( Shi and Kehrl, 2008 Shi and Kehrl, 2008 ). Autophagy can also be activated directly by PAMPs and transmit PAMP signals to TLRs to induce an immune response. RLRs are located in the cytoplasm and are responsible for the recognition of specific structures not found in normal cellular RNA, such as the 5'- end triphosphate of viral double-stranded RNA (dsRNA). The RLRs, upon sensing the presence of a virus, can interact with the mitochondrial antiviral signal (MAVS) through the caspase recruitment domain (CARD), which in turn activates the IRF3 and IRF7 and the NF-‍κB signaling pathway. A number of receptor molecules in cells that sense DNA virus invasion can also interact with the autophagic pathway. Cyclic guanosine monophosphate (GMP)‍-AMP (cGAMP) synthase (cGAS) recognizes DNA viruses and synthesizes cGAMP. Stimulator of IFN response cGAMP interactor 1 (STING) then binds to cGAMP to activate downstream related regulatory factors and induce NF-‍κB activation. In addition, the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), containing STING, can provide a membrane source for lipidation of LC3, thereby facilitating the clearance of cytoplasmic DNA viruses via autophagy. By contrast, during herpes simplex virus 1 (HSV-1) infection, Beclin1 interacts with cGAS to inhibit cGAMP synthesis and IFN production. This enhances autophagy-mediated degradation of cytoplasmic pathogen DNA to prevent excessive activation of cGAS and sustained immune stimulation. Thus, in addition to being regulated by signals such as cGAS-STING, autophagy or autophagy-related proteins can in turn negatively regulate related signaling pathways ( Gui et al., 2019 Gui et al., 2019 ; Liu et al., 2019 Liu et al., 2019 ; Zhang et al., 2020 Zhang et al., 2020 ). Antigen delivery is a transitional phase in the shift from innate to adaptive immunity, which is activated by peptide fragments on the major histocompatibility complex (MHC) on antigen-presenting cells (APCs), followed by recognition of antigens by T cells ( Wieczorek et al., 2017 Wieczorek et al., 2017 ). It is expressed in all nucleated cells, and viral proteins can be delivered to cluster of differentiation 8-positive (CD8 + ) T cells via MHC-I-like molecules after being degraded by the proteasome into immunogenic peptides. Autophagy limits the delivery of MHC-I-like molecules by mediating their internalization and degradation. Inactivation of the autophagy factors ATG5 and ATG7 in dendritic cells (DCs) can lead to an increase in the expression of MHC-I on the cell surface, making the body more susceptible to the expression of MHC-I in influenza A virus (IAV) and lymphocytic choriomeningitis virus (LCMV) infection to induce a more intense CD8 + T cell immune response ( Loi et al., 2016 Loi et al., 2016 ). In contrast, autophagosomes are constitutively formed in MHC-II-positive APCs, such as DCs, B cells, and epithelial cells. They capture extracellular antigens and deliver them to autophagosomes, which deliver antigens from the cytoplasm to MHC by fusing with MHC-II-containing intranuclear body compartment (MIIC)‍-like molecules. These in turn are then delivered to CD4 + T cells. Studies have shown that human immunodeficiency virus (HIV)-infected DCs can use LC3 fusion proteins to specifically target HIV antigens to autophagosomes, effectively enhancing and broadening the immune response of CD4 + T cells, thereby facilitating an endogenous MHC-II-restricted presentation ( Coulon et al., 2016 Coulon et al., 2016 ). In addition, autophagy mediates cross-antigen presentation of MHC-I and MHC-II types in APCs, facilitating the exchange of information between cells to generate effective immune responses against endogenous and exogenous antigens ( Ghislat and Lawrence, 2018 Ghislat and Lawrence, 2018 ). 3.2 Viral hijacking and evasion of autophagy 2 The life cycle of a virus generally includes the processes of virus adsorption and invasion, intracellular replication, transcription and translation, assembly, and release ( Duan et al., 2020 Duan et al., 2020 ). In the case of cellular autophagy, viruses hijack the autophagy machinery throughout their life cycle to survive within the cell, and express specific proteins to escape autophagy and multiply within the host cell ( Ahmad et al., 2018 Ahmad et al., 2018 ). The key problem of coronaviruses using autophagy to promote their own replication lies in determining whether the replication of the virus requires the assistance of autophagy, as illustrated by studies of mouse hepatitis virus (MHV). In mouse Atg5 knockout embryonic stem cells (ESCs), Prentice et al. (2004a) Prentice et al. (2004a) found that both MHV replication and double-membrane vesicle (DMV) formation were impaired and that viral reverse transcription complexes (RTCs) co-localized with endogenous LC3. This suggests that autophagy occurrence and DMV formation are associated with MHV replication. Similarly, the same group observed co-localization of viral RTCs with endogenous LC3 in another severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related study ( Prentice et al., 2004b Prentice et al., 2004b ). However, this conclusion has been disputed by Zhao et al. (2007), who also observed co-localization of viral RTCs with endogenous LC3, but did not find any effect on the MHV life cycle in bone marrow macrophages (BMMs) or mouse embryonic fibroblasts (MEFs) deficient in Atg5 . In contrast, Snijder et al. (2006) failed to detect co-localization of LC3 or green fluorescent protein (GFP)-LC3 with viral RTCs of SARS-CoV in SARS-CoV-infected African green monkey kidney (Vero) cells. A related study showed that knockdown of Atg5 did not affect SARS-CoV replication ( Schneider et al., 2012 Schneider et al., 2012 ). Contradictory results were also seen in studies of infectious bronchitis virus (IBV). On the one hand, it has been shown that IBV-induced autophagy is dependent on ATG5, and that the endoplasmic reticulum stress sensor inositol-requiring enzyme 1 (IRE1) and mitogen activated protein (MAP) kinase ERK1/2 are required for IBV-induced autophagy and play a survival-promoting role in the late stages of IBV infection ( Fung and Liu, 2019 Fung and Liu, 2019 ). On the other hand, Maier et al. (2013) found that although overexpression of IBV's nonstructural protein 6 (NSP6) induced autophagic signaling, induction or inhibition of autophagy did not affect IBV replication, suggesting that classical autophagy might not be important for viral replication. Thus, there is no definitive answer as to whether autophagy is required for coronavirus replication. However, results so far suggest that the effect of autophagy on coronavirus might vary considerably depending on the origin of the cells, as several of the above studies used cells sourced from different tissues of the same species or of different species. In addition, these results suggest that the "need" for autophagy might not be the same in different cells, and that in addition to ATG5, important autophagy proteins, such as LC3 and Beclin1, might play an important role in viral replication. Furthermore, whether coronaviruses can use autophagy to promote their own replication, or whether induced autophagy can enhance viral proliferation, is unclear. Some studies have provided positive evidence. Guo et al. (2017) Guo et al. (2017) found that in Vero cells, porcine epidemic disease virus (PEDV) was able to induce autophagy to promote its own replication. Also, reduced production of infectious viral particles was found in cells deficient in Beclin1 or ATG5 or in cells treated with 3-methyladenine, suggesting that autophagy induced during PEDV infection was beneficial to the virus. Zhu et al. (2016) Zhu et al. (2016) found that the transmissible gastroenteritis coronavirus (TGEV) nucleocapsid protein (N) and GFP-LC3 were localized to mitochondria. The induction of mitochondrial autophagy using carbonyl cyanide 3-chlorophenylhydrazone (CCCP) depolarized mitochondria and increased viral titers, suggesting that this pathway might facilitate viral replication. Human coronavirus (HCoV)‍-OC43 infection increased autophagic flux in human lung fibroblast MRC-5 cells. Treatment of the cells with kurarinone reduced virus-induced autophagic flux and thus inhibited viral replication ( Min et al., 2020 Min et al., 2020 ). These results suggest that autophagy can be beneficial for coronaviruses, promoting their proliferation by enhancing the autophagic pathway. Conversely, disruption of the autophagic pathway can reduce viral replication. Notably, coronaviruses might also hijack a component of autophagy for the purpose of aiding or facilitating replication, and this activity is not dependent on the classical autophagic pathway. For example, it has been found that although the autophagic pathway is not essential for MHV infection, the non-lipidated form of LC3-I is closely associated with coronavirus-induced DMV and is required for MHV replication ( Reggiori et al., 2010 Reggiori et al., 2010 ). Middle East respiratory syndrome-coronavirus (MERS-CoV) is able to reduce Beclin1 activity by activating S-phase kinase-associated protein 2 (SKP2), which inhibits the fusion of autophagosomes with lysosomes, thereby blocking the destructive effects of autophagy on the virus ( Gassen et al., 2019 Gassen et al., 2019 ). The membrane-associated papain-like protease 2 (PLP2-TM) of various coronaviruses induces incomplete autophagy and inhibits the natural immune response by interacting with Beclin1 and promoting the interaction between Beclin1 and STING. Knockdown of Beclin1 partially reverses the inhibitory effect of PLP2-TM, leading to a reduction in viral replication ( Chen XJ et al., 2014 Chen XJ et al., 2014 ). From these results, it is clear that coronaviruses have diverse strategies to resist autophagy. The structural similarities between the coronavirus replication site DMV and autophagosomes allow some coronaviruses to induce the production of autophagosomes to assist their own proliferation. In addition, to avoid damage to the virus by autophagic degradation, coronaviruses often block subsequent steps of the autophagic pathway, such as preventing the expansion of autophagosomes or blocking the fusion between autophagosomes and lysosomes. Autophagy is also involved in the body's immune response ( Channappanavar et al., 2014 Channappanavar et al., 2014 ). Therefore, coronaviruses can also escape from natural immune "supervision" by inducing autophagy, allowing some autophagic proteins to interact with relevant immune signaling pathways, thereby inhibiting the IFN signaling pathway. 4 Fungi and cellular autophagy 1 4.1 Autophagy mechanism of Saccharomyces cerevisiae 2 In the early 1990s, a group of cell biologists, represented by Daniel J. KLIONSKY and Yoshinori OHSUMI, started the screening and cell biology of autophagy-related genes using Saccharomyces cerevisiae as a model organism. To date, over 40 autophagy-related genes have been identified in yeast ( Yu et al., 2020 Yu et al., 2020 ). More than two decades later, S. cerevisiae has become the most commonly used model organism in the study of the molecular mechanisms of cellular autophagy ( Feng et al., 2014 Feng et al., 2014 ; Yin et al., 2019 Yin et al., 2019 ). The macro-autophagy occurring in S. cerevisiae is of significant interest. This process occurs at the PAS, where the phagophore/isolation membrane expands and grows into an autophagosome with a bilayer membrane structure by the regulation of related proteins. At the same time, the cytoplasmic matrix is encapsulated into the autophagosomal lumen. Subsequently, the outer membrane of the autophagosome fuses with the vesicle, and the inner membrane and contents are degraded by hydrolytic enzymes into small molecules, such as amino acids, which are reused by the cell to help it survive in adverse conditions ( Yang et al., 2019 Yang et al., 2019 ). The whole process of cellular autophagy can be divided conceptually into the following aspects: (1) regulation of cellular autophagy, (2) formation of autophagosomes in the PAS, (3) fusion of autophagosomes with vesicles, and (4) degradation and recycling of inclusions ( Levine and Klionsky, 2004 Levine and Klionsky, 2004 ) (Fig. 2). Under physiological conditions, cellular autophagy is tightly regulated. Two main pathways are known to regulate autophagy: the TOR and PI3K pathways ( Yin et al., 2019 Yin et al., 2019 ). In yeast, TOR has two homologs, Tor1 and Tor2, which can form two protein complexes, TORC1 (containing either Tor1 or Tor2) and TORC2 (containing only Tor2) ( Raught et al., 2001 Raught et al., 2001 ). Both complexes are involved in the regulation of cell growth and intracellular metabolism, but TORC1 is more sensitive to rapamycin ( Loewith et al., 2002 Loewith et al., 2002 ). In addition, TORC1 can sense extracellular nutrient conditions. When cells are in starvation conditions, TORC1 is inhibited and the level of cellular autophagy increases, thus being the main regulator of cellular autophagy ( Yorimitsu and Klionsky, 2005 Yorimitsu and Klionsky, 2005 ; González and Hall, 2017 González and Hall, 2017 ). In cellular autophagy, the formation of autophagosomes is a key step, and the size and number of autophagosomes also reflect the level of cellular autophagy. Here, we focus on the core systems involved in this step, including the assembly of the backbone of the PAS, the PI3K signaling system, and the Atg9 recycling system ( Li et al., 2020 Li et al., 2020 ). 4.1.1　Assembly of the PAS backbone 3 The PAS is the site of autophagosome formation, and is usually found close to the vesicles. Under fluorescence microscopy, most Atg proteins can be seen to co-localize to the PAS. So far, localization of the PAS appears to be a yeast-specific phenomenon, because the sites of autophagosome production in other species are spread throughout the cytoplasm, rather than being confined to a few sites ( Cheng et al., 2014 Cheng et al., 2014 ). It is generally believed that the assembly of Atg proteins in the PAS initiates from several important backbone proteins, and the specific process depends on the conditions of regulatory induction of cellular autophagy. In the Cvt pathway, which occurs under eutrophic growth conditions, the PAS assembly signal is derived from the Cvt complex transport. The main components of the Cvt complex are precursor Ape1 multimer and its receptor Atg19 ( Scott et al., 2001 Scott et al., 2001 ; Yamasaki et al., 2016 Yamasaki et al., 2016 ). Atg19 binds to Atg11, which then recruits other related proteins and gradually forms specialized autophagosome-Cvt vesicles around the Cvt complex. In this process, Atg11 plays the role of an assembly protein in PAS formation ( Zientara-Rytter and Subramani, 2020 Zientara-Rytter and Subramani, 2020 ). By contrast, Atg17 plays a major role when cells are under starvation conditions and non-selective autophagy is significantly enhanced ( Matscheko et al., 2019 Matscheko et al., 2019 ). Atg17 is also involved in various aspects of autophagosome formation, including the regulation of Atg1 activity and the transport of Atg9 to the PAS ( Kamada et al., 2000 Kamada et al., 2000 ; Sekito et al., 2009 Sekito et al., 2009 ) (Fig. 2b). 4.1.2　PI3K complex signaling system 3 PI3K is an important class of intracellular signaling regulatory molecules that control physiological processes, such as cell growth, differentiation, and transport of intracellular substances, through phosphorylation modification of phosphatidylinositol on the membrane. Class III PI3K is the oldest class and phosphorylates phosphatidylinositol to phosphatidylinositol 3-phosphate (PI3P). The yeast genome contains only one gene encoding PI3K, namely type III PI3K-Vps34 ( Jaber and Zong, 2013 Jaber and Zong, 2013 ). Vps34 is involved in the formation of at least two types of complexes. Class I complexes contain Atg14 and are involved in cellular autophagy. Class II complexes contain Vps38 and are involved in the vacuolar protein sorting (VPS) pathway, which is responsible for the translocation of proteins to vesicles via the Golgi apparatus ( Kihara et al., 2001 Kihara et al., 2001 ). Both complexes contain Vps34, Vps15, and Vps30/Atg6 ( Kihara et al., 2001 Kihara et al., 2001 ). Vps15 is a protein kinase that forms the regulatory subunit of Vps34. Atg14 links Vps30/Atg6 to Vps34-Vps15 to form a complex. The coiled-coil domain (CCD) at the N-terminus of Atg14 executes this function ( Matsunaga et al., 2010 Matsunaga et al., 2010 ). In cellular autophagy, Atg14 localizes the PI3K complex to the PAS site and recruits downstream proteins through the PI3P product of the later ( Matsunaga et al., 2010 Matsunaga et al., 2010 ; Obara and Ohsumi, 2011 Obara and Ohsumi, 2011 ; Harada et al., 2019 Harada et al., 2019 ) (Fig. 2a). 4.1.3　Cyclic transport of Atg9 3 Atg9 is the only transmembrane protein of the core autophagy machinery and might be the key to the origin of autophagosomal membranes ( Yamamoto et al., 2012 Yamamoto et al., 2012 ; Kirkin and Rogov, 2019 Kirkin and Rogov, 2019 ). Atg9 is an integral membrane protein containing six highly conserved transmembrane domains as well as N-terminal and C-terminal domains located in the cytoplasm ( Guardia et al., 2020 Guardia et al., 2020 ). It participates in the formation of autophagosomes by cycling between the PAS and peripheral structures (e.g., mitochondria, endoplasmic reticulum, and Golgi apparatus) with the assistance of related proteins. Thus, Atg9 is considered to be a "membrane carrier" for vesicle formation ( He et al., 2006 He et al., 2006 ). In yeast, the majority of Atg9 is located on the surface of mitochondrial membranes or on components attached to mitochondria ( Reggiori et al., 2005b Reggiori et al., 2005b ) (Fig. 2). The transport of Atg9 from peripheral structures to the PAS is accomplished with the assistance of other proteins, and different assisting proteins are required under different conditions. In the selective cellular autophagic Cvt pathway, the transport of Atg9 from peri pheral structures to the PAS is blocked when any of the components of Atg11, the Cvt complex, or the actin cytoskeleton are missing ( Shintani and Klionsky, 2004a Shintani and Klionsky, 2004a ; Reggiori et al., 2005a Reggiori et al., 2005a ; He et al., 2006 He et al., 2006 ). The actin-related protein Arp2 interacts with Atg9 and directly regulates the transport of Atg9 from peripheral structures to the PAS. As a subunit of the Arp2-Arp3 complex, Arp2 likely facilitates the movement of Atg9 and remodels the actin structure to facilitate Atg9 transport ( Reggiori et al., 2005a Reggiori et al., 2005a ). In starvation-induced non-selective cellular autophagy, this transport requires Atg17 ( Sekito et al., 2009 Sekito et al., 2009 ). Atg17 helps Atg9 localize to the PAS and complete membrane assembly ( Kawamata et al., 2008 Kawamata et al., 2008 ; Sekito et al., 2009 Sekito et al., 2009 ). The Atg1-Atg13 complex and the PI3K complex I are required for retrograde transport of Atg9 from the PAS. However, this process does not require the kinase activity of Atg1 ( Reggiori et al., 2004 Reggiori et al., 2004 ). The role of Atg1 in this process is most likely to regulate the balance between Atg9 assembly and retrieval at the PAS site ( Reggiori et al., 2004 Reggiori et al., 2004 ). In addition, anterograde transport of Atg9 requires Atg23 and Atg27, which, like Atg9, are localized to the PAS and some other scattered membrane structures in the cytoplasm ( Backues et al., 2015 Backues et al., 2015 ). During transport, the three are transferred together as a complex ( Backues et al., 2015 Backues et al., 2015 ) (Fig. 2). When the autophagosome is completed, Atg9 does not remain on the autophagosomal membrane, but returns from the PAS to peripheral structures in the cytoplasm. This retrograde transport relies on the Atg1-Atg13 complex ( Reggiori et al., 2004 Reggiori et al., 2004 ), the Atg2-Atg18 complex ( Kotani et al., 2018 Kotani et al., 2018 ), and the Vps34 complex I ( Reggiori et al., 2004 Reggiori et al., 2004 ). One widely accepted model is that once the Atg1-Atg13 complex is recruited to the Atg9-located PAS, Atg1-Atg13 drives Atg9 to interact with Atg2-Atg18 and the subsequent formation of a large multiprotein complex drives Atg9 from the PAS back to the peripheral structures (Fig. 2). 4.2 Fungal infection of host cells triggers autophagy 2 In phagocytic cells, PRR- or Fc-‍γ receptors (FcγR)-mediated phagocytosis-related autophagy-related molecules, such as LC3, Beclin1, PI3KC3, and ATG12-ATG5 complexes, can decorate on the phagosome membrane, promoting phagosome fusion with lysosomes and the formation of a monolayer membrane structure. However, this process does not induce cell autophagy and is defined as LAP ( Schille et al., 2018 Schille et al., 2018 ; Heckmann and Green, 2019 Heckmann and Green, 2019 ). The occurrence of LAP is independent of the induction of the ULK1 complex (Martinez et al., 2011). Rubicon and NOX2 act on class III PI3K complexes and promote phagocytosis with the participation of the ATG16L complex (Martinez et al., 2015). The formation of LAP can promote the presentation of fungal antigens by MHC-II molecules ( Ma et al., 2012 Ma et al., 2012 ). In addition, the occurrence of LAP requires the productions of NADPH oxidase and ROS ( Heckmann et al., 2017 Heckmann et al., 2017 ). How ROS induces the recruitment of LC3 to the phagosome surface and why autophagy-related molecules are involved in the aggregation of phagosomes and lysosomes remain unclear ( Pauwels et al., 2017 Pauwels et al., 2017 ). However, it is certain that LAP plays an important role in controlling pathogen infections ( Upadhyay and Philips, 2019 Upadhyay and Philips, 2019 ). LAP also participates in the process of promoting phagocyte maturation. These findings link two conserved biological behaviors, autophagy and phagocytosis, to a synergistic mechanism that promotes the elimination of fungal pathogens. When yeast cells invade an organism, they can form a vacuole that is not recognized by the host's lysosome. The vacuole acts as a barrier to protect the yeast cells from lysosomal action. However, when yeast cells invade macrophages that are activated by IFN-‍γ, the vacuolar membrane of yeast is disrupted, and the bare yeast cells are wrapped in autophagic vesicles, which are sent to the lysosome for degrad‍ation via autophagy, so as to clear the yeast cells from the organism. However, autophagy is not always good for the host, and might also be a necessary condition for the growth and infection of certain fungi. Studies have found that the Magnaporthe oryzae genome encodes Atg proteins that have been classified into four major groups, namely an Atg1-Atg13-Atg17 complex, an Atg9 trafficking system, a PI3K complex, and two Ub-like conjugation systems ( Zhu et al., 2019 Zhu et al., 2019 ). MoAtg2-MoAtg10, MoAtg12, MoAtg14-MoAtg16, and MoAtg18 have been shown to play an important role in M. oryzae -induced cell autophagy ( Dong et al., 2009 Dong et al., 2009 ; Liu et al., 2010, Liu et al., 2010, 2012 2012 , 2017 2017 ; Zhu et al., 2019 Zhu et al., 2019 ; Li et al., 2021 Li et al., 2021 ). Host cell autophagy can provide nourishment for the development and infection of M. oryzae by degrading organelles and senescent proteins. Therefore, autophagy plays an important role in the whole development and infection cycle of M. oryzae ( Liu and Lin, 2008 Liu and Lin, 2008 ). Furthermore, studies have shown that IFN-γ activates autophagy in human macrophages, leading to an increase in anti-fungal host defense against M. oryzae infection. Other studies have reported that activation of macro-autophagy can promote phagosomal acidification and anti-fungal responses in murine and human macrophages, suggesting that autophagy might represent a promising host-targeting therapeutic strategy against M. oryzae infection. Macrophages are an important population of cells involved in mediating the innate immunity of the host. Phagocytosis is the most important characteristic of macrophages, and plays an important role in killing and clearing fungal pathogens, as well as initiating and interaction with host cell autophagy ( Ma and Underhill, 2013 Ma and Underhill, 2013 ; Wu and Lu, 2019 Wu and Lu, 2019 ). The occurrence of autophagy depends on autophagy-related receptors on the cell surface, mainly PRRs, FcγRs, complement receptors (CRs), such as C-type lectin receptors (like Dectin-1), mannose receptors (MRs), and TLRs (Öhman et al., 2014). The receptors bind to the corresponding ligand and activate autophagy-related proteins, thereby mediating cell autophagy. Dectin-1 receptor-mediated autophagy is an important part of the host's defense against fungal infection (Öhman et al., 2014; Kanayama and Shinohara, 2016 Kanayama and Shinohara, 2016 ; Tang et al., 2018 Tang et al., 2018 ). The recognition of fungal β-glucan by its receptor Dectin-1 triggers downstream signaling via spleen tyrosine kinase (SyK)-dependent and Raf-1-dependent pathways to mediate antifungal immunity, including CARD-containing protein 9 (CARD9)–BCL-10–mucosa-associated translocation lymphoma 1 (MALT1) signaling ( Ruland and Hartjes, 2019 Ruland and Hartjes, 2019 ) and Raf-1 signaling pathways ( Tang et al., 2018 Tang et al., 2018 ), which mediate the host's innate immune response to fungi ( Salazar and Brown, 2018 Salazar and Brown, 2018 ). The immune response can induce cell autophagy by producing ROS and secreting pro-inflammatory factors. Studies have found that the Dectin-1/Syk pathway mediates the occurrence of autophagy via ROS production, LC3-lipidation, and so on ( Ma et al., 2012 Ma et al., 2012 ; Kyrmizi et al., 2013 Kyrmizi et al., 2013 ; Tam et al., 2014 Tam et al., 2014 ), which plays an important role in resisting fungal infection ( Smeekens et al., 2014 Smeekens et al., 2014 ; Kanayama et al., 2015 Kanayama et al., 2015 ). Candida albicans is one of the most common pathogenic Candida ( Duhring et al., 2015 Duhring et al., 2015 ). After infection, it can be swallowed into the cell by phagocytes (mainly macrophages and neutrophils) to induce an inflammatory response and affect the biological function of host cells ( Miramón et al., 2012 Miramón et al., 2012 ; Rudkin et al., 2013 Rudkin et al., 2013 ). The cell wall component, β-1,3-glucan, of C. albicans is considered to be a major PAMP and can be recognized by the Dectin-1 receptor ( Bain et al., 2014 Bain et al., 2014 ). Because of the dysfunction of the autophagy process in mice with Atg5 knockout in vaginal cells, the secretion of anti- C. albicans cytokines was significantly reduced, as was the recruitment of neutrophils, ultimately leading to a decreased ability to clear C. albicans ( Shroff et al., 2018 Shroff et al., 2018 ). However, mice with Atg5 selectively knocked out in myeloid cells showed increased susceptibility and decreased survival ( Nicola et al., 2012 Nicola et al., 2012 ). Accumulating evidence showed that fungal microorganisms have evolved various ways to avoid the influence of autophagy, including blocking the signal pathway of autophagy, disturbing organelles, blocking the fusion of autophagosomes and lysosomes, and even using autophagy to evade recognition and relying on autophagosomes to survive in the cell for a long time. 5 Parasites and autophagy 1 5.1 Autophagy eliminates parasites 2 Parasites are an important class of pathogens. The worms stimulate host cells to maintain a balance between inducing and evading the host immune response, and host cells also maintain a balance between infection and elimination. Research on the interaction between autophagy and parasitic infections has focused mostly on serious intracellular parasitic protozoa, such as Toxoplasma gondii ( Attias et al., 2020 Attias et al., 2020 ). The protozoa of the T. gondii class comprise a group of parasites that cause serious infections, and their process of invasion of host cells includes adhesion, invasion, and the formation of parasitophorous vacuoles ( Portes et al., 2020 Portes et al., 2020 ). Such parasites can prevent the killing effect of lysosomes because of the protective effect of parasitophorous vacuoles, thus creating an autophagy evasion effect ( Coppens et al., 2006 Coppens et al., 2006 ). As a part of natural immunity, when foreign parasites enter the body, autophagy can encapsulate the invading parasites, mainly through PRRs in the cytoplasm and on membranes to sense the invading pathogens, thereby triggering innate immune signaling to form the first defense barrier ( Sasai and Yamamoto, 2019 Sasai and Yamamoto, 2019 ). In this process, TLR4 initiates recognition, activates MyD88- and TRIF-dependent signaling pathways, and initiates the activation of the inhibitor of NF-‍κB kinase α (IKKα)‍-IKKβ‍-NF-‍κB essential modulator (NEMO) complex and the IKKi complex to regulate nuclear transcription factors NF-‍κB and IRF3. These in turn induce the transcription of inflammatory factors and type I IFNs, thereby activating the IFN-mediated cellular anti-pathogen response ( Zare-Bidaki et al., 2014 Zare-Bidaki et al., 2014 ). Research has also revealed that in the RAW macrophage cell line, TLR2 signaling triggers the autophagosome marker LC3 to be rapidly recruited to the phagosome, which then fuses with lysosomes to destruct and digest engulfed organisms ( Sanjuan et al., 2007 Sanjuan et al., 2007 ). Type II IFN (IFN-‍γ) promotes autophagy by inducing GTPases to participate in autophagy formation. T. gondii enters host cells to form parasitophorous vacuoles, which have no receptors that can be recognized and captured by lysosomes. Thus, they can successfully escape lysosome-mediated phagocytosis ( Fig. 3 Fig. 3 ). T. gondii infection of activated macrophages induces the expression of the autophagy-related molecule ATG5, and then recruits IFN-γ to induce p47 GTPase IIGP1 (also known as Irga6) to the parasitophorous vacuole membrane. Macrophage GTPases are activated to damage the parasitophorous vacuole ( Zhao et al., 2008 Zhao et al., 2008 ). The vacuole membrane is disrupted, the plasma membrane of the worm body is stripped, and autophagic vacuoles in the cell then wrap the naked parasite, which is subsequently transported to the lysosome for degradation of the worm body ( Zhao et al., 2008 Zhao et al., 2008 ). Conversely, if autophagy is inhibited by regulating the PI3K signaling pathway, the ability of host cells to degrade T. gondii will be impaired, indicating that autophagy is necessary for the degradation of T. gondii ( Subauste, 2019 Subauste, 2019 ). One group studied a culture of T. gondii tachyzoites in skeletal muscle cells (SkMCs) and found that after increasing the level of SkMC autophagy, ultrastructural observations showed that many autophagosome-like structures were distributed near the parasitophorous vacuole membrane of the worm, which contains parts of the parasites to be degraded. This suggests that an increase in the level of SkMC autophagy has a certain clearance effect on the infection and development of T. gondii tachyzoites. Besides the participation of ATG5, Ohshima et al. (2014) Ohshima et al. (2014) found that human ATG16L1 and mouse Atg7 and Atg16L1 are involved in the recruitment reaction mediated by IFN-γ to complete the elimination of T. gondii . In addition to its important role in natural immunity, autophagy regulates the body's adaptive immune response and plays an important role by participating in antigen processing and presentation of MHC molecules ( Fig. 3 Fig. 3 ). Different groups found that during autophagic killing of T. gondii , IFN-‍γ stimulates astrocytes and macrophages to recruit to p47 GTPases to the parasitophorous vacuole, disintegrating the parasite into fragments ( Halonen et al., 2001 Halonen et al., 2001 ; Martens et al., 2005; Ling et al., 2006 Ling et al., 2006 ; Melzer et al., 2008 Melzer et al., 2008 ). Autophagy then regulates the antigen presentation pathway of MHC class II molecules and transports the worm antigens from the cytoplasm to the lysosome to complete phagocytosis and removal of the worm debris. When cellular autophagy is inhibited or interfered with, the ability to eliminate parasites is significantly reduced ( Subauste, 2019 Subauste, 2019 ) ( Fig. 3 Fig. 3 ). 5.2 Parasites use autophagy to help their own development 2 In the long-term evolutionary process, some parasites have formed specific mechanisms to induce incomplete cell autophagy, and the recycled materials produced by autophagy provide favorable conditions for parasite replication and development, thereby achieving intracellular proliferation and growth ( Salassa and Romano, 2019 Salassa and Romano, 2019 ). Alvarez et al. (2008) Alvarez et al. (2008) showed that during the development cycle of Trypanosoma cruzi , the process of proliferation and differentiation from epimastigotes to the formation of trypanosomes requires many amino acids. Under nutrient deficiency conditions, T. cruzi can use TcAtg4 and TcAtg8 to induce host cells to degrade cytoplasm and organelles via the autophagy pathway to provide a source of nutrients for their own differentiation and development ( Fig. 3 Fig. 3 ). Although host cell autophagy plays a certain role in the elimination of T. gondii , it has been shown that T. cruzi can mediate the degree of host cell autophagy and provide biological energy for the development of the parasite by inducing host cell autophagy ( Alvarez et al., 2008 Alvarez et al., 2008 ; Romano et al., 2009 Romano et al., 2009 ). In cells deficient in ATG5, a crucial molecule of autophagy, the growth of T. gondii is markedly restricted ( Wang et al., 2009 Wang et al., 2009 ). It was speculated that the reason for this is that the autophagy mediated by T. gondii is closely related to the accumulation of calcium. In the absence of nutritional conditions, Toxoplasma cannot be controlled by the traditional mTOR pathway, but competes with host cells for the material resources needed for anabolism via calcium regulation, and uses the nutrients obtained by the autophagic degradation of host cells to provide energy for Toxoplasma development ( Wang et al., 2009 Wang et al., 2009 ) ( Fig. 3 Fig. 3 ). Normally, the occurrence of calcium regulation events in infected cells is accompanied by high levels of PI3P, and Toxoplasma infection can independently regulate calcium signals. The restriction of PI3P distribution in the vicinity of the vacuole membrane of the worm is not necessary as it can be relocated with Beclin1 and LC3. This process is controlled by the worm. That is, T. gondii can control the location of host cell autophagy in a purposeful manner, instead of extensively and blindly inducing host cell autophagy. This, to some extent, enhances the ability of the parasite to capture and use host cell biological energy. Gao et al. (2014) Gao et al. (2014) found that the invasion of T. gondii tachyzoites can cause human embryonic fibroblasts (HEFs) to produce significant amounts of autophagy. When the autophagy inhibitors chloroquine and bafilomycin were used to treat HEF cells, the invasion rate of T. gondii was lower than that of the untreated control group. The results indicated that invasion of host cells by T. gondii promotes its own proliferation and development by causing an increase in the level of host cell autophagy. Based on current findings, there are two recognized outcomes of cellular autophagy and intracellular parasite interactions during parasite infection of host cells. One is that autophagy successfully reduces the parasite invasion rate, and the other is that the parasite uses the formation of autophagic vesicles to provide substrates for its own energy metabolism, thus promoting its own reproductive development (Ghartey-Kwansah et al., 2020a, (Ghartey-Kwansah et al., 2020a, 2020b 2020b ). 6 Conclusions 1 Autophagy is an automatic cellular defense system that can actively respond to the invasion of pathogenic microbes, such as bacteria, viruses, fungi, and parasites, by directly removing them or modulating innate adaptive immune responses to destroy them. At the same time, when cellular autophagy is triggered, pathogens can also escape or use autophagy to promote their own survival. The regulatory role of autophagy in pathogen infections has several characteristics. First, there is a dual regulatory role between microbial pathogens and the body's defenses against infections. Second, the effect of autophagy depends on the cell type, pathogen characteristics, and the microenvironment in which pathogens are located. Therefore, in order to treat infectious diseases, autophagy should be induced or inhibited in a reasonable manner to play an appropriate role, considering the characteristics of pathogenic microorganisms and their infections, to achieve the goal of inhibiting pathogen infections without damaging the organism. At the same time, regulating autophagy to keep the organism in a good metabolic state might be an effective strategy to proactively prevent pathogenic infections. Notably, deletion of different autophagy-related genes sometimes produces different symptomatic manifestations. In conclusion, much work is still needed to explore the dynamic regulatory roles of autophagy in pathogen infections, and the fine tuning of these mechanisms could provide a new theoretical basis and clinical drug targets for novel antimicrobial and anti-infective research. References Abdoli A , Alirezaei M , Mehrbod P , et al. , 2018 . Autophagy: the multi-purpose bridge in viral infections and host cells . Rev Med Virol , 28 ( 4 ): e1973 . https://doi.org/10.1002/rmv.1973 https://doi.org/10.1002/rmv.1973 Autophagy: the multi-purpose bridge in viral infections and host cells Ahmad L , Mostowy S , Sancho-Shimizu V , 2018 . Autophagy-virus interplay: from cell biology to human disease . Front Cell Dev Biol , 6 : 155 . https://doi.org/10.3389/fcell.2018.00155 https://doi.org/10.3389/fcell.2018.00155 Autophagy-virus interplay: from cell biology to human disease Allen EA , Amato C , Fortier TM , et al. , 2020 . A conserved myotubularin-related phosphatase regulates autophagy by maintaining autophagic flux . J Cell Biol , 219 ( 11 ): e201909073 . https://doi.org/10.1083/jcb.201909073 https://doi.org/10.1083/jcb.201909073 A conserved myotubularin-related phosphatase regulates autophagy by maintaining autophagic flux Alvarez VE , Kosec G , Sant'Anna C , et al. , 2008 . Autophagy is involved in nutritional stress response and differentiation in Trypanosoma cruzi . J Biol Chem , 283 ( 6 ): 3454 - 3464 . https://doi.org/10.1074/jbc.M708474200 https://doi.org/10.1074/jbc.M708474200 Autophagy is involved in nutritional stress response and differentiation in Trypanosoma cruzi Anand PK , Tait SWG , Lamkanfi M , et al. , 2011 . TLR2 and RIP2 pathways mediate autophagy of Listeria monocytogenes via extracellular signal-regulated kinase (ERK) activation . J Biol Chem , 286 ( 50 ): 42981 - 42991 . https://doi.org/10.1074/jbc.M111.310599 https://doi.org/10.1074/jbc.M111.310599 TLR2 and RIP2 pathways mediate autophagy of Listeria monocytogenes via extracellular signal-regulated kinase (ERK) activation Andriantsitohaina R , Papon N , 2020 . Extracellular vesicles: new bullets to fight fungal infections . Trends Cell Biol , 30 ( 8 ): 589 - 590 . https://doi.org/10.1016/j.tcb.2020.05.008 https://doi.org/10.1016/j.tcb.2020.05.008 Extracellular vesicles: new bullets to fight fungal infections Arasaki K , Mikami Y , Shames SR , et al. , 2017 . Legionella effector Lpg1137 shuts down ER-mitochondria communication through cleavage of syntaxin 17 . Nat Commun , 8 : 15406 . https://doi.org/10.1038/ncomms15406 https://doi.org/10.1038/ncomms15406 Legionella effector Lpg1137 shuts down ER-mitochondria communication through cleavage of syntaxin 17 Attias M , Teixeira DE , Benchimol M , et al. , 2020 . The life-cycle of Toxoplasma gondii reviewed using animations . Parasit Vectors , 13 : 588 . https://doi.org/10.1186/s13071-020-04445-z https://doi.org/10.1186/s13071-020-04445-z The life-cycle of Toxoplasma gondii reviewed using animations Backues SK , Orban DP , Bernard A , et al. , 2015 . Atg23 and Atg27 act at the early stages of Atg9 trafficking in S . cerevisiae. Traffic , 16 ( 2 ): 172 - 190 . https://doi.org/10.1111/tra.12240 https://doi.org/10.1111/tra.12240 Atg23 and Atg27 act at the early stages of Atg9 trafficking in S Bah A , Vergne I , 2017 . Macrophage autophagy and bacterial infections . Front Immunol , 8 : 1483 . https://doi.org/10.3389/fimmu.2017.01483 https://doi.org/10.3389/fimmu.2017.01483 Macrophage autophagy and bacterial infections Bain JM , Louw J , Lewis LE , et al. , 2014 . Candida albicans hypha formation and mannan masking of β-glucan inhibit macrophage phagosome maturation . mBio , 5 ( 6 ): e01874-14 . https://doi.org/10.1128/mBio.01874-14 https://doi.org/10.1128/mBio.01874-14 Candida albicans hypha formation and mannan masking of β-glucan inhibit macrophage phagosome maturation Barnett TC , Liebl D , Seymour LM , et al. , 2013 . The globally disseminated M1T1 clone of group A Streptococcus evades autophagy for intracellular replication . Cell Host Microbe , 14 ( 6 ): 675 - 682 . https://doi.org/10.1016/j.chom.2013.11.003 https://doi.org/10.1016/j.chom.2013.11.003 The globally disseminated M1T1 clone of group A Streptococcus evades autophagy for intracellular replication Bauckman KA , Owusu-Boaitey N , Mysorekar IU , 2015 . Selective autophagy: xenophagy . Methods , 75 : 120 - 127 . https://doi.org/10.1016/j.ymeth.2014.12.005 https://doi.org/10.1016/j.ymeth.2014.12.005 Selective autophagy: xenophagy Birmingham CL , Smith AC , Bakowski MA , et al. , 2006 . Autophagy controls Salmonella infection in response to damage to the Salmonella -containing vacuole . J Biol Chem , 281 ( 16 ): 11374 - 11383 . https://doi.org/10.1074/jbc.M509157200 https://doi.org/10.1074/jbc.M509157200 Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole Birmingham CL , Canadien V , Gouin E , et al. , 2007 . Listeria monocytogenes evades killing by autophagy during colonization of host cells . Autophagy , 3 ( 5 ): 442 - 451 . https://doi.org/10.4161/auto.4450 https://doi.org/10.4161/auto.4450 Listeria monocytogenes evades killing by autophagy during colonization of host cells Cadwell K , 2016 . Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis . Nat Rev Immunol , 16 ( 11 ): 661 - 675 . https://doi.org/10.1038/nri.2016.100 https://doi.org/10.1038/nri.2016.100 Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis Cardenal-Muñoz E , Arafah S , López-Jiménez AT , et al. , 2017 . Mycobacterium marinum antagonistically induces an autophagic response while repressing the autophagic flux in a TORC1- and ESX-1-dependent manner . PLoS Pathog , 13 ( 4 ): e1006344 . https://doi.org/10.1371/journal.ppat.1006344 https://doi.org/10.1371/journal.ppat.1006344 Mycobacterium marinum antagonistically induces an autophagic response while repressing the autophagic flux in a TORC1- and ESX-1-dependent manner Chang TK , Shravage BV , Hayes SD , et al. , 2013 . Uba1 functions in Atg7- and Atg3-independent autophagy . Nat Cell Biol , 15 ( 9 ): 1067 - 1078 . https://doi.org/10.1038/ncb2804 https://doi.org/10.1038/ncb2804 Uba1 functions in Atg7- and Atg3-independent autophagy Channappanavar R , Zhao JC , Perlman S , 2014 . T cell-mediated immune response to respiratory coronaviruses . Immunol Res , 59 : 118 - 128 . https://doi.org/10.1007/s12026-014-8534-z https://doi.org/10.1007/s12026-014-8534-z T cell-mediated immune response to respiratory coronaviruses Chen G , Han Z , Feng D , et al. , 2014 . A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy . Mol Cell , 54 ( 3 ): 362 - 377 . https://doi.org/10.1016/j.molcel.2014.02.034 https://doi.org/10.1016/j.molcel.2014.02.034 A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy Chen XJ , Wang K , Xing YL , et al. , 2014 . Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclin1 to negatively regulate antiviral innate immunity . Protein Cell , 5 ( 12 ): 912 - 927 . https://doi.org/10.1007/s13238-014-0104-6 https://doi.org/10.1007/s13238-014-0104-6 Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclin1 to negatively regulate antiviral innate immunity Cheng JL , Fujita A , Yamamoto H , et al. , 2014 . Yeast and mammalian autophagosomes exhibit distinct phosphatidylinositol 3-phosphate asymmetries . Nat Commun , 5 : 3207 . https://doi.org/10.1038/ncomms4207 https://doi.org/10.1038/ncomms4207 Yeast and mammalian autophagosomes exhibit distinct phosphatidylinositol 3-phosphate asymmetries Cheng MI , Chen C , Engström P , et al. , 2018 . Actin-based motility allows Listeria monocytogenes to avoid autophagy in the macrophage cytosol . Cell Microbiol , 20 ( 9 ): e12854 . https://doi.org/10.1111/cmi.12854 https://doi.org/10.1111/cmi.12854 Actin-based motility allows Listeria monocytogenes to avoid autophagy in the macrophage cytosol Cheng YL , Kuo CF , Lu SL , et al. , 2019 . Group A streptococcus induces LAPosomes via SLO/β1 integrin/NOX2/ROS pathway in endothelial cells that are ineffective in bacterial killing and suppress xenophagy . mBio , 10 ( 5 ): e02148-19 . https://doi.org/10.1128/mBio.02148-19 https://doi.org/10.1128/mBio.02148-19 Group A streptococcus induces LAPosomes via SLO/β1 integrin/NOX2/ROS pathway in endothelial cells that are ineffective in bacterial killing and suppress xenophagy Chew LH , Lu S , Liu X , et al. , 2015 . Molecular interactions of the Saccharomyces cerevisiae Atg1 complex provide insights into assembly and regulatory mechanisms . Autophagy , 11 ( 6 ): 891 - 905 . https://doi.org/10.1080/15548627.2015.1040972 https://doi.org/10.1080/15548627.2015.1040972 Molecular interactions of the Saccharomyces cerevisiae Atg1 complex provide insights into assembly and regulatory mechanisms Choi Y , Bowman JW , Jung JU , 2018 . Autophagy during viral infection—a double-edged sword . Nat Rev Microbiol , 16 ( 6 ): 341 - 354 . https://doi.org/10.1038/s41579-018-0003-6 https://doi.org/10.1038/s41579-018-0003-6 Autophagy during viral infection—a double-edged sword Choy A , Dancourt J , Mugo B , et al. , 2012 . The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation . Science , 338 ( 6110 ): 1072 - 1076 . https://doi.org/10.1126/science.1227026 https://doi.org/10.1126/science.1227026 The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation Chun Y , Kim J , 2018 . Autophagy: an essential degradation program for cellular homeostasis and life . Cells , 7 ( 12 ): 278 . https://doi.org/10.3390/cells7120278 https://doi.org/10.3390/cells7120278 Autophagy: an essential degradation program for cellular homeostasis and life Coppens I , 2017 . How Toxoplasma and malaria parasites defy first, then exploit host autophagic and endocytic pathways for growth . Curr Opin Microbiol , 40 : 32 - 39 . https://doi.org/10.1016/j.mib.2017.10.009 https://doi.org/10.1016/j.mib.2017.10.009 How Toxoplasma and malaria parasites defy first, then exploit host autophagic and endocytic pathways for growth Coppens I , dan Dunn J , Romano JD , et al. , 2006 . Toxoplasma gondii sequesters lysosomes from mammalian hosts in the vacuolar space . Cell , 125 ( 2 ): 261 - 274 . https://doi.org/10.1016/j.cell.2006.01.056 https://doi.org/10.1016/j.cell.2006.01.056 Toxoplasma gondii sequesters lysosomes from mammalian hosts in the vacuolar space Coulon PG , Richetta C , Rouers A , et al. , 2016 . HIV-infected dendritic cells present endogenous MHC class II-restricted antigens to HIV-specific CD4 + T cells . J Immunol , 197 ( 2 ): 517 - 532 . https://doi.org/10.4049/jimmunol.1600286 https://doi.org/10.4049/jimmunol.1600286 HIV-infected dendritic cells present endogenous MHC class II-restricted antigens to HIV-specific CD4+ T cells Dai XF , Zhu ML , 2020 . Coupling of ribosome synthesis and translational capacity with cell growth . Trends Biochem Sci , 45 ( 8 ): 681 - 692 . https://doi.org/10.1016/j.tibs.2020.04.010 https://doi.org/10.1016/j.tibs.2020.04.010 Coupling of ribosome synthesis and translational capacity with cell growth Deretic V , 2010 . Autophagy in infection . Curr Opin Cell Biol , 22 ( 2 ): 252 - 262 . https://doi.org/10.1016/j.ceb.2009.12.009 https://doi.org/10.1016/j.ceb.2009.12.009 Autophagy in infection Deretic V , 2012 . Autophagy as an innate immunity paradigm: expanding the scope and repertoire of pattern recognition receptors . Curr Opin Immunol , 24 ( 1 ): 21 - 31 . https://doi.org/10.1016/j.coi.2011.10.006 https://doi.org/10.1016/j.coi.2011.10.006 Autophagy as an innate immunity paradigm: expanding the scope and repertoire of pattern recognition receptors Deretic V , Levine B , 2009 . Autophagy, immunity, and microbial adaptations . Cell Host Microbe , 5 ( 6 ): 527 - 549 . https://doi.org/10.1016/j.chom.2009.05.016 https://doi.org/10.1016/j.chom.2009.05.016 Autophagy, immunity, and microbial adaptations Desai M , Fang R , Sun JR , 2015 . The role of autophagy in microbial infection and immunity . Immunotargets Ther , 4 : 13 - 26 . https://doi.org/10.2147/ITT.S76720 https://doi.org/10.2147/ITT.S76720 The role of autophagy in microbial infection and immunity Dong B , Liu XH , Lu JP , et al. , 2009 . MgAtg9 trafficking in Magnaporthe oryzae . Autophagy , 5 ( 7 ): 946 - 953 . https://doi.org/10.4161/auto.5.7.9161 https://doi.org/10.4161/auto.5.7.9161 MgAtg9 trafficking in Magnaporthe oryzae Dortet L , Mostowy S , Louaka AS , et al. , 2011 . Recruitment of the major vault protein by InlK: a Listeria monocytogenes strategy to avoid autophagy . PLoS Pathog , 7 ( 8 ): e1002168 . https://doi.org/10.1371/journal.ppat.1002168 https://doi.org/10.1371/journal.ppat.1002168 Recruitment of the major vault protein by InlK: a Listeria monocytogenes strategy to avoid autophagy Duan LW , Zheng QQ , Zhang HX , et al. , 2020 . The SARS-CoV-2 spike glycoprotein biosynthesis, structure, function, and antigenicity: implications for the design of spike-based vaccine immunogens . Front Immunol , 11 : 576622 . https://doi.org/10.3389/fimmu.2020.576622 https://doi.org/10.3389/fimmu.2020.576622 The SARS-CoV-2 spike glycoprotein biosynthesis, structure, function, and antigenicity: implications for the design of spike-based vaccine immunogens Duhring S , Germerodt S , Skerka C , et al. , 2015 . Host-pathogen interactions between the human innate immune system and Candida albicans —understanding and modeling defense and evasion strategies . Front Microbiol , 6 : 625 . https://doi.org/10.3389/fmicb.2015.00625 https://doi.org/10.3389/fmicb.2015.00625 Host-pathogen interactions between the human innate immune system and Candida albicans—understanding and modeling defense and evasion strategies Ehlers MRW , 2000 . CR3: a general purpose adhesion-recognition receptor essential for innate immunity . Microbes Infect , 2 ( 3 ): 289 - 294 . https://doi.org/10.1016/s1286-4579(00)00299-9 https://doi.org/10.1016/s1286-4579(00)00299-9 CR3: a general purpose adhesion-recognition receptor essential for innate immunity Farag NS , Breitinger U , Breitinger HG , et al. , 2020 . Viroporins and inflammasomes: a key to understand virus-induced inflammation . Int J Biochem Cell Biol , 122 : 105738 . https://doi.org/10.1016/j.biocel.2020.105738 https://doi.org/10.1016/j.biocel.2020.105738 Viroporins and inflammasomes: a key to understand virus-induced inflammation Farré JC , Subramani S , 2016 . Mechanistic insights into selective autophagy pathways: lessons from yeast . Nat Rev Mol Cell Biol , 17 ( 9 ): 537 - 552 . https://doi.org/10.1038/nrm.2016.74 https://doi.org/10.1038/nrm.2016.74 Mechanistic insights into selective autophagy pathways: lessons from yeast Feng YC , He D , Yao ZY , et al. , 2014 . The machinery of macroautophagy . Cell Res , 24 ( 1 ): 24 - 41 . https://doi.org/10.1038/cr.2013.168 https://doi.org/10.1038/cr.2013.168 The machinery of macroautophagy Fujioka Y , Alam JM , Noshiro D , et al. , 2020 . Phase separation organizes the site of autophagosome formation . Nature , 578 ( 7794 ): 301 - 305 . https://doi.org/10.1038/s41586-020-1977-6 https://doi.org/10.1038/s41586-020-1977-6 Phase separation organizes the site of autophagosome formation Fung TS , Liu DX , 2019 . The ER stress sensor IRE1 and MAP kinase ERK modulate autophagy induction in cells infected with coronavirus infectious bronchitis virus . Virology , 533 : 34 - 44 . https://doi.org/10.1016/j.virol.2019.05.002 https://doi.org/10.1016/j.virol.2019.05.002 The ER stress sensor IRE1 and MAP kinase ERK modulate autophagy induction in cells infected with coronavirus infectious bronchitis virus Gao DM , Zhang J , Zhao J , et al. , 2014 . Autophagy activated by Toxoplasma gondii infection in turn facilitates Toxoplasma gondii proliferation . Parasitol Res , 113 ( 6 ): 2053 - 2058 . https://doi.org/10.1007/s00436-014-3853-5 https://doi.org/10.1007/s00436-014-3853-5 Autophagy activated by Toxoplasma gondii infection in turn facilitates Toxoplasma gondii proliferation Gassen NC , Niemeyer D , Muth D , et al. , 2019 . SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-coronavirus infection . Nat Commun , 10 : 5770 . https://doi.org/10.1038/s41467-019-13659-4 https://doi.org/10.1038/s41467-019-13659-4 SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-coronavirus infection Ghartey-Kwansah G , Adu-Nti F , Aboagye B , et al. , 2020a . Autophagy in the control and pathogenesis of parasitic infections . Cell Biosci , 10 : 101 . https://doi.org/10.1186/s13578-020-00464-6 https://doi.org/10.1186/s13578-020-00464-6 Autophagy in the control and pathogenesis of parasitic infections Ghartey-Kwansah G , Aboagye B , Adu-Nti F , et al. , 2020b . Clearing or subverting the enemy: role of autophagy in protozoan infections . Life Sci , 247 : 117453 . https://doi.org/10.1016/j.lfs.2020.117453 https://doi.org/10.1016/j.lfs.2020.117453 Clearing or subverting the enemy: role of autophagy in protozoan infections Ghislat G , Lawrence T , 2018 . Autophagy in dendritic cells . Cell Mol Immunol , 15 ( 11 ): 944 - 952 . https://doi.org/10.1038/cmi.2018.2 https://doi.org/10.1038/cmi.2018.2 Autophagy in dendritic cells Glick D , Barth S , Macleod KF , 2010 . Autophagy: cellular and molecular mechanisms . J Pathol , 221 ( 1 ): 3 - 12 . https://doi.org/10.1002/path.2697 https://doi.org/10.1002/path.2697 Autophagy: cellular and molecular mechanisms Gluschko A , Herb M , Wiegmann K , et al. , 2018 . The β2 integrin Mac-1 induces protective LC3-associated phagocytosis of Listeria monocytogenes . Cell Host Microbe , 23 ( 3 ): 324 - 337.e5 . https://doi.org/10.1016/j.chom.2018.01.018 https://doi.org/10.1016/j.chom.2018.01.018 The β2 integrin Mac-1 induces protective LC3-associated phagocytosis of Listeria monocytogenes González A , Hall MN , 2017 . Nutrient sensing and TOR signaling in yeast and mammals . EMBO J , 36 ( 4 ): 397 - 408 . https://doi.org/10.15252/embj.201696010 https://doi.org/10.15252/embj.201696010 Nutrient sensing and TOR signaling in yeast and mammals Guardia CM , Tan XF , Lian TF , et al. , 2020 . Structure of human ATG9A, the only transmembrane protein of the core autophagy machinery . Cell Rep , 31 ( 13 ): 107837 . https://doi.org/10.1016/j.celrep.2020.107837 https://doi.org/10.1016/j.celrep.2020.107837 Structure of human ATG9A, the only transmembrane protein of the core autophagy machinery Gui X , Yang H , Li T , et al. , 2019 . Autophagy induction via STING trafficking is a primordial function of the cGAS pathway . Nature , 567 ( 7747 ): 262 - 266 . https://doi.org/10.1038/s41586-019-1006-9 https://doi.org/10.1038/s41586-019-1006-9 Autophagy induction via STING trafficking is a primordial function of the cGAS pathway Guo XZ , Zhang MJ , Zhang XQ , et al. , 2017 . Porcine epidemic diarrhea virus induces autophagy to benefit its replication . Viruses , 9 ( 3 ): 53 . https://doi.org/10.3390/v9030053 https://doi.org/10.3390/v9030053 Porcine epidemic diarrhea virus induces autophagy to benefit its replication Halonen SK , Taylor GA , Weiss LM , 2001 . Gamma interferon-induced inhibition of Toxoplasma gondii in astrocytes is mediated by IGTP . Infect Immun , 69 ( 9 ): 5573 - 5576 . https://doi.org/10.1128/IAI.69.9.5573-5576.2001 https://doi.org/10.1128/IAI.69.9.5573-5576.2001 Gamma interferon-induced inhibition of Toxoplasma gondii in astrocytes is mediated by IGTP Hamasaki M , Furuta N , Matsuda A , et al. , 2013 . Autophagosomes form at ER-mitochondria contact sites . Nature , 495 ( 7441 ): 389 - 393 . https://doi.org/10.1038/nature11910 https://doi.org/10.1038/nature11910 Autophagosomes form at ER-mitochondria contact sites Harada K , Kotani T , Kirisako H , et al. , 2019 . Two distinct mechanisms target the autophagy-related E3 complex to the pre-autophagosomal structure . eLife , 8 : e43088 . https://doi.org/10.7554/eLife.43088 https://doi.org/10.7554/eLife.43088 Two distinct mechanisms target the autophagy-related E3 complex to the pre-autophagosomal structure He CC , Song H , Yorimitsu T , et al. , 2006 . Recruitment of Atg9 to the preautophagosomal structure by Atg11 is essential for selective autophagy in budding yeast . J Cell Biol , 175 ( 6 ): 925 - 935 . https://doi.org/10.1083/jcb.200606084 https://doi.org/10.1083/jcb.200606084 Recruitment of Atg9 to the preautophagosomal structure by Atg11 is essential for selective autophagy in budding yeast Heckmann BL , Green DR , 2019 . LC3-associated phagocytosis at a glance . J Cell Sci , 132 ( 5 ): jcs222984 . https://doi.org/10.1242/jcs.222984 https://doi.org/10.1242/jcs.222984 LC3-associated phagocytosis at a glance Heckmann BL , Boada-Romero E , Cunha LD , et al. , 2017 . LC3-associated phagocytosis and inflammation . J Mol Biol , 429 ( 23 ): 3561 - 3576 . https://doi.org/10.1016/j.jmb.2017.08.012 https://doi.org/10.1016/j.jmb.2017.08.012 LC3-associated phagocytosis and inflammation Hu W , Chan H , Lu L , et al. , 2020 . Autophagy in intracellular bacterial infection . Semin Cell Dev Biol , 101 : 41 - 50 . https://doi.org/10.1016/j.semcdb.2019.07.014 https://doi.org/10.1016/j.semcdb.2019.07.014 Autophagy in intracellular bacterial infection Huett A , Heath RJ , Begun J , et al. , 2012 . The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella typhimurium . Cell Host Microbe , 12 ( 6 ): 778 - 790 . https://doi.org/10.1016/j.chom.2012.10.019 https://doi.org/10.1016/j.chom.2012.10.019 The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella typhimurium Huss A , Derks LAN , Heederik DJJ , et al. , 2020 . Green waste compost as potential reservoirs of Legionella in the Netherlands . Clin Microbiol Infec , 26 ( 9 ): 1259.e1 - 1259.e3 . https://doi.org/10.1016/j.cmi.2020.05.018 https://doi.org/10.1016/j.cmi.2020.05.018 Green waste compost as potential reservoirs of Legionella in the Netherlands Hytönen J , Haataja S , Gerlach D , et al. , 2001 . The SpeB virulence factor of Streptococcus pyogenes , a multifunctional secreted and cell surface molecule with strepadhesin, laminin-binding and cysteine protease activity . Mol Microbiol , 39 ( 2 ): 512 - 519 . https://doi.org/10.1046/j.1365-2958.2001.02269.x https://doi.org/10.1046/j.1365-2958.2001.02269.x The SpeB virulence factor of Streptococcus pyogenes, a multifunctional secreted and cell surface molecule with strepadhesin, laminin-binding and cysteine protease activity Itakura E , Kishi-Itakura C , Mizushima N , 2012 . The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes . Cell , 151 ( 6 ): 1256 - 1269 . https://doi.org/10.1016/j.cell.2012.11.001 https://doi.org/10.1016/j.cell.2012.11.001 The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes Jaber N , Zong WX , 2013 . Class III PI3K Vps34: essential roles in autophagy, endocytosis, and heart and liver function . Ann N Y Acad Sci , 1280 ( 1 ): 48 - 51 . https://doi.org/10.1111/nyas.12026 https://doi.org/10.1111/nyas.12026 Class III PI3K Vps34: essential roles in autophagy, endocytosis, and heart and liver function Jennings E , Thurston TLM , Holden DW , 2017 . Salmonella SPI-2 type III secretion system effectors: molecular mechanisms and physiological consequences . Cell Host Microbe , 22 ( 2 ): 217 - 231 . https://doi.org/10.1016/j.chom.2017.07.009 https://doi.org/10.1016/j.chom.2017.07.009 Salmonella SPI-2 type III secretion system effectors: molecular mechanisms and physiological consequences Joo JH , Dorsey FC , Joshi A , et al. , 2011 . Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy . Mol Cell , 43 ( 4 ): 572 - 585 . https://doi.org/10.1016/j.molcel.2011.06.018 https://doi.org/10.1016/j.molcel.2011.06.018 Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy Kagan JC , Stein MP , Pypaert M , et al. , 2004 . Legionella subvert the functions of Rab1 and Sec22b to create a replicative organelle . J Exp Med , 199 ( 9 ): 1201 - 1211 . https://doi.org/10.1084/jem.20031706 https://doi.org/10.1084/jem.20031706 Legionella subvert the functions of Rab1 and Sec22b to create a replicative organelle Kamada Y , Funakoshi T , Shintani T , et al. , 2000 . Tor-mediated induction of autophagy via an Apg1 protein kinase complex . J Cell Biol , 150 ( 6 ): 1507 - 1513 . https://doi.org/10.1083/jcb.150.6.1507 https://doi.org/10.1083/jcb.150.6.1507 Tor-mediated induction of autophagy via an Apg1 protein kinase complex Kamber RA , Shoemaker CJ , Denic V , 2015 . Receptor-bound targets of selective autophagy use a scaffold protein to activate the Atg1 kinase . Mol Cell , 59 ( 3 ): 372 - 381 . https://doi.org/10.1016/j.molcel.2015.06.009 https://doi.org/10.1016/j.molcel.2015.06.009 Receptor-bound targets of selective autophagy use a scaffold protein to activate the Atg1 kinase Kanayama M , Shinohara ML , 2016 . Roles of autophagy and autophagy-related proteins in antifungal immunity . Front Immunol , 7 : 47 . https://doi.org/10.3389/fimmu.2016.00047 https://doi.org/10.3389/fimmu.2016.00047 Roles of autophagy and autophagy-related proteins in antifungal immunity Kanayama M , Inoue M , Danzaki K , et al. , 2015 . Autophagy enhances NFκB activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity . Nat Commun , 6 : 5779 . https://doi.org/10.1038/ncomms6779 https://doi.org/10.1038/ncomms6779 Autophagy enhances NFκB activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity Kandul NP , Zhang T , Hay BA , et al. , 2016 . Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila . Nat Commun , 7 : 13100 . https://doi.org/10.1038/ncomms13100 https://doi.org/10.1038/ncomms13100 Selective removal of deletion-bearing mitochondrial DNA in heteroplasmic Drosophila Kato M , Yang YS , Sutter BM , et al. , 2019 . Redox state controls phase separation of the yeast ataxin-2 protein via reversible oxidation of its methionine-rich low-complexity domain . Cell , 177 ( 3 ): 711 - 721.e8 . https://doi.org/10.1016/j.cell.2019.02.044 https://doi.org/10.1016/j.cell.2019.02.044 Redox state controls phase separation of the yeast ataxin-2 protein via reversible oxidation of its methionine-rich low-complexity domain Kaushik S , Cuervo AM , 2018 . The coming of age of chaperone-mediated autophagy . Nat Rev Mol Cell Biol , 19 ( 6 ): 365 - 381 . https://doi.org/10.1038/s41580-018-0001-6 https://doi.org/10.1038/s41580-018-0001-6 The coming of age of chaperone-mediated autophagy Kawabata T , Yoshimori T , 2020 . Autophagosome biogenesis and human health . Cell Discov , 6 : 33 . https://doi.org/10.1038/s41421-020-0166-y https://doi.org/10.1038/s41421-020-0166-y Autophagosome biogenesis and human health Kawamata T , Kamada Y , Kabeya Y , et al. , 2008 . Organization of the pre-autophagosomal structure responsible for autophagosome formation . Mol Biol Cell , 19 ( 5 ): 2039 - 2050 . https://doi.org/10.1091/mbc.E07-10-1048 https://doi.org/10.1091/mbc.E07-10-1048 Organization of the pre-autophagosomal structure responsible for autophagosome formation Keil E , Höcker R , Schuster M , et al. , 2013 . Phosphorylation of Atg5 by the Gadd45 β‍‍ ‒‍MEKK4-p38 pathway inhibits autopha gy. Cell Death Differ, 20 ( 2 ): 321 - 332 .https://doi.org/10.1038/cdd.2012.12 .https://doi.org/10.1038/cdd.2012.12 9 Phosphorylation of Atg5 by the Gadd45β‍‍‒‍MEKK4-p38 pathway inhibits autopha Kihara A , Noda T , Ishihara N , et al. , 2001 . Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae . J Cell Biol , 152 ( 3 ): 519 - 530 . https://doi.org/10.1083/jcb.152.3.519 https://doi.org/10.1083/jcb.152.3.519 Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae Kim J , Kundu M , Viollet B , et al. , 2011 . AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 . Nat Cell Biol , 13 ( 2 ): 132 - 141 . https://doi.org/10.1038/ncb2152 https://doi.org/10.1038/ncb2152 AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 Kim SI , Kim S , Kim E , et al. , 2018 . Secretion of Salmonella pathogenicity island 1-encoded type III secretion system effectors by outer membrane vesicles in Salmonella enterica serovar typhimurium . Front Microbiol , 9 : 2810 . https://doi.org/10.3389/fmicb.2018.02810 https://doi.org/10.3389/fmicb.2018.02810 Secretion of Salmonella pathogenicity island 1-encoded type III secretion system effectors by outer membrane vesicles in Salmonella enterica serovar typhimurium Kimmey JM , Stallings CL , 2016 . Bacterial pathogens versus autophagy: implications for therapeutic interventions . Trends Mol Med , 22 ( 12 ): 1060 - 1076 . https://doi.org/10.1016/j.molmed.2016.10.008 https://doi.org/10.1016/j.molmed.2016.10.008 Bacterial pathogens versus autophagy: implications for therapeutic interventions Kirkin V , Rogov VV , 2019 . A diversity of selective autophagy receptors determines the specificity of the autophagy pathway . Mol Cell , 76 ( 2 ): 268 - 285 . https://doi.org/10.1016/j.molcel.2019.09.005 https://doi.org/10.1016/j.molcel.2019.09.005 A diversity of selective autophagy receptors determines the specificity of the autophagy pathway Kishi-Itakura C , Ktistakis NT , Buss F , 2020 . Ultrastructural insights into pathogen clearance by autophagy . Traffic , 21 ( 4 ): 310 - 323 . https://doi.org/10.1111/tra.12723 https://doi.org/10.1111/tra.12723 Ultrastructural insights into pathogen clearance by autophagy Kobayashi S , Koujin T , Kojidani T , et al. , 2015 . BAF is a cytosolic DNA sensor that leads to exogenous DNA avoiding autophagy . Proc Natl Acad Sci USA , 112 ( 22 ): 7027 - 7032 . https://doi.org/10.1073/pnas.1501235112 https://doi.org/10.1073/pnas.1501235112 BAF is a cytosolic DNA sensor that leads to exogenous DNA avoiding autophagy Kocaturk NM , Gozuacik D , 2018 . Crosstalk between mammalian autophagy and the ubiquitin-proteasome system . Front Cell Dev Biol , 6 : 128 . https://doi.org/10.3389/fcell.2018.00128 https://doi.org/10.3389/fcell.2018.00128 Crosstalk between mammalian autophagy and the ubiquitin-proteasome system Kotani T , Kirisako H , Koizumi M , et al. , 2018 . The Atg2-Atg18 complex tethers pre-autophagosomal membranes to the endoplasmic reticulum for autophagosome formation . Proc Natl Acad Sci USA , 115 ( 41 ): 10363 - 10368 . https://doi.org/10.1073/pnas.1806727115 https://doi.org/10.1073/pnas.1806727115 The Atg2-Atg18 complex tethers pre-autophagosomal membranes to the endoplasmic reticulum for autophagosome formation Kourtis N , Tavernarakis N , 2009 . Autophagy and cell death in model organisms . Cell Death Differ , 16 ( 1 ): 21 - 30 . https://doi.org/10.1038/cdd.2008.120 https://doi.org/10.1038/cdd.2008.120 Autophagy and cell death in model organisms Kumsta C , Chang JT , Schmalz J , et al. , 2017 . Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C . elegans. Nat Commun , 8 : 14337 . https://doi.org/10.1038/ncomms14337 https://doi.org/10.1038/ncomms14337 Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C Kyrmizi I , Gresnigt MS , Akoumianaki T , et al. , 2013 . Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling . J Immunol , 191 ( 3 ): 1287 - 1299 . https://doi.org/10.4049/jimmunol.1300132 https://doi.org/10.4049/jimmunol.1300132 Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling Lecuit M , 2020 . Listeria monocytogenes , a model in infection biology . Cell Microbiol , 22 ( 4 ): e13186 . https://doi.org/10.1111/cmi.13186 https://doi.org/10.1111/cmi.13186 Listeria monocytogenes, a model in infection biology Lee YK , Lee JA , 2016 . Role of the mammalian ATG8/LC3 family in autophagy: differential and compensatory roles in the spatiotemporal regulation of autophagy . BMB Rep , 49 ( 8 ): 424 - 430 . https://doi.org/10.5483/bmbrep.2016.49.8.081 https://doi.org/10.5483/bmbrep.2016.49.8.081 Role of the mammalian ATG8/LC3 family in autophagy: differential and compensatory roles in the spatiotemporal regulation of autophagy Levine B , 2005 . Eating oneself and uninvited guests: autophagy-related pathways in cellular defense . Cell , 120 ( 2 ): 159 - 162 . https://doi.org/10.1016/j.cell.2005.01.005 https://doi.org/10.1016/j.cell.2005.01.005 Eating oneself and uninvited guests: autophagy-related pathways in cellular defense Levine B , Klionsky DJ , 2004 . Development by self-digestion: molecular mechanisms and biological functions of autophagy . Dev Cell , 6 ( 4 ): 463 - 477 . https://doi.org/10.1016/s1534-5807(04)00099-1 https://doi.org/10.1016/s1534-5807(04)00099-1 Development by self-digestion: molecular mechanisms and biological functions of autophagy Li L , Zhu XM , Su ZZ , et al. , 2021 . Insights of roles played by septins in pathogenic fungi . Virulence , 12 ( 1 ): 1550 - 1562 . https://doi.org/10.1080/21505594.2021.1933370 https://doi.org/10.1080/21505594.2021.1933370 Insights of roles played by septins in pathogenic fungi Li XH , He SK , Ma BY , 2020 . Autophagy and autophagy-related proteins in cancer . Mol Cancer , 19 : 12 . https://doi.org/10.1186/s12943-020-1138-4 https://doi.org/10.1186/s12943-020-1138-4 Autophagy and autophagy-related proteins in cancer Li XZ , Yan XH , 2019 . Sensors for the mTORC1 pathway regulated by amino acids . J Zhejiang Univ-Sci B (Biomed & Biotechnol) , 20 ( 9 ): 699 - 712 . https://doi.org/10.1631/jzus.B1900181 https://doi.org/10.1631/jzus.B1900181 Sensors for the mTORC1 pathway regulated by amino acids Lin PW , Chu ML , Liu HS , 2021 . Autophagy and metabolism . Kaohsiung J Med Sci , 37 ( 1 ): 12 - 19 . https://doi.org/10.1002/kjm2.12299 https://doi.org/10.1002/kjm2.12299 Autophagy and metabolism Ling YM , Shaw MH , Ayala C , et al. , 2006 . Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages . J Exp Med , 203 ( 9 ): 2063 - 2071 . https://doi.org/10.1084/jem.20061318 https://doi.org/10.1084/jem.20061318 Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages Liu D , Wu H , Wang CG , et al. , 2019 . STING directly activates autophagy to tune the innate immune response . Cell Death Differ , 26 ( 9 ): 1735 - 1749 . https://doi.org/10.1038/s41418-018-0251-z https://doi.org/10.1038/s41418-018-0251-z STING directly activates autophagy to tune the innate immune response Liu TB , Liu XH , Lu JP , et al. , 2010 . The cysteine protease MoAtg4 interacts with MoAtg8 and is required for differentiation and pathogenesis in Magnaporthe oryzae . Autophagy , 6 ( 1 ): 74 - 85 . https://doi.org/10.4161/auto.6.1.10438 https://doi.org/10.4161/auto.6.1.10438 The cysteine protease MoAtg4 interacts with MoAtg8 and is required for differentiation and pathogenesis in Magnaporthe oryzae Liu XH , Lin FC , 2008 . Investigation of the biological roles of autophagy in appressorium morphogenesis in Magnaporthe oryzae . J Zhejiang Univ-Sci B (Biomed & Biotechnol) , 9 ( 10 ): 793 - 796 . https://doi.org/10.1631/jzus.B0860013 https://doi.org/10.1631/jzus.B0860013 Investigation of the biological roles of autophagy in appressorium morphogenesis in Magnaporthe oryzae Liu XH , Gao HM , Xu F , et al. , 2012 . Autophagy vitalizes the pathogenicity of pathogenic fungi . Autophagy , 8 ( 10 ): 1415 - 1425 . https://doi.org/10.4161/auto.21274 https://doi.org/10.4161/auto.21274 Autophagy vitalizes the pathogenicity of pathogenic fungi Liu XH , Zhao YH , Zhu XM , et al. , 2017 . Autophagy-related protein MoAtg14 is involved in differentiation, development and pathogenicity in the rice blast fungus Magnaporthe oryzae . Sci Rep , 7 : 40018 . https://doi.org/10.1038/srep40018 https://doi.org/10.1038/srep40018 Autophagy-related protein MoAtg14 is involved in differentiation, development and pathogenicity in the rice blast fungus Magnaporthe oryzae Loewith R , Jacinto E , Wullschleger S , et al. , 2002 . Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control . Mol Cell , 10 ( 3 ): 457 - 468 . https://doi.org/10.1016/s1097-2765(02)00636-6 https://doi.org/10.1016/s1097-2765(02)00636-6 Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control Loi M , Müller A , Steinbach K , et al. , 2016 . Macroautophagy proteins control MHC class I levels on dendritic cells and shape anti-viral CD8 + T cell responses . Cell Rep , 15 ( 5 ): 1076 - 1087 . https://doi.org/10.1016/j.celrep.2016.04.002 https://doi.org/10.1016/j.celrep.2016.04.002 Macroautophagy proteins control MHC class I levels on dendritic cells and shape anti-viral CD8+ T cell responses Lu SL , Kuo CF , Chen HW , et al. , 2015 . Insufficient acidification of autophagosomes facilitates group A streptococcus survival and growth in endothelial cells . mBio , 6 ( 5 ): e01435-15 . https://doi.org/10.1128/mBio.01435-15 https://doi.org/10.1128/mBio.01435-15 Insufficient acidification of autophagosomes facilitates group A streptococcus survival and growth in endothelial cells Lv YX , Fang L , Ding PS , et al. , 2019 . PI3K/Akt-Beclin1 signaling pathway positively regulates phagocytosis and negatively mediates NF-‍κB-dependent inflammation in Staphylococcus aureus -infected macrophages . Biochem Biophys Res Commun , 510 ( 2 ): 284 - 289 . https://doi.org/10.1016/j.bbrc.2019.01.091 https://doi.org/10.1016/j.bbrc.2019.01.091 PI3K/Akt-Beclin1 signaling pathway positively regulates phagocytosis and negatively mediates NF-‍κB-dependent inflammation in Staphylococcus aureus-infected macrophages Ma J , Underhill DM , 2013 . β‍-glucan signaling connects phagocytosis to autophagy . Glycobiology , 23 ( 9 ): 1047 - 1051 . https://doi.org/10.1093/glycob/cwt046 https://doi.org/10.1093/glycob/cwt046 β‍-glucan signaling connects phagocytosis to autophagy Ma J , Becker C , Lowell CA , et al. , 2012 . Dectin-1-triggered recruitment of light chain 3 protein to phagosomes facilitates major histocompatibility complex class II presentation of fungal-derived antigens . J Biol Chem , 287 ( 41 ): 34149 - 34156 . https://doi.org/10.1074/jbc.M112.382812 https://doi.org/10.1074/jbc.M112.382812 Dectin-1-triggered recruitment of light chain 3 protein to phagosomes facilitates major histocompatibility complex class II presentation of fungal-derived antigens Maier HJ , Cottam EM , Stevenson-Leggett P , et al. , 2013 . Visualizing the autophagy pathway in avian cells and its application to studying infectious bronchitis virus . Autophagy , 9 ( 4 ): 496 - 509 . https://doi.org/10.4161/auto.23465 https://doi.org/10.4161/auto.23465 Visualizing the autophagy pathway in avian cells and its application to studying infectious bronchitis virus Maphasa RE , Meyer M , Dube A , 2021 . The macrophage response to Mycobacterium tuberculosis and opportunities for autophagy inducing nanomedicines for tuberculosis therapy . Front Cell Infect Microbiol , 10 : 618414 . https://doi.org/10.3389/fcimb.2020.618414 https://doi.org/10.3389/fcimb.2020.618414 The macrophage response to Mycobacterium tuberculosis and opportunities for autophagy inducing nanomedicines for tuberculosis therapy Martens S , Parvanova I , Zerrahn J , et al. , 2005 . Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p47-resistance GTPases . PLoS Pathog , 1 ( 3 ): e24 . https://doi.org/10.1371/journal.ppat.0010024 https://doi.org/10.1371/journal.ppat.0010024 Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p47-resistance GTPases Martinez J , Almendinger J , Oberst A , et al. , 2011 . Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells . Proc Natl Acad Sci USA , 108 ( 42 ): 17396 - 17401 . https://doi.org/10.1073/pnas.1113421108 https://doi.org/10.1073/pnas.1113421108 Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells Martinez J , Malireddi RKS , Lu Q , et al. , 2015 . Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins . Nat Cell Biol , 17 ( 7 ): 893 - 906 . https://doi.org/10.1038/ncb3192 https://doi.org/10.1038/ncb3192 Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins Matscheko N , Mayrhofer P , Rao YJ , et al. , 2019 . Atg11 tethers Atg9 vesicles to initiate selective autophagy . PLoS Biol , 17 ( 7 ): e3000377 . https://doi.org/10.1371/journal.pbio.3000377 https://doi.org/10.1371/journal.pbio.3000377 Atg11 tethers Atg9 vesicles to initiate selective autophagy Matsunaga K , Morita E , Saitoh T , et al. , 2010 . Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L . J Cell Biol , 190 ( 4 ): 511 - 521 . https://doi.org/10.1083/jcb.200911141 https://doi.org/10.1083/jcb.200911141 Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L Melzer T , Duffy A , Weiss LM , et al. , 2008 . The gamma interferon (IFN-γ)-inducible GTP-binding protein IGTP is necessary for Toxoplasma vacuolar disruption and induces parasite egression in IFN-‍γ‍-stimulated astrocytes . Infect Immun , 76 ( 11 ): 4883 - 4894 . https://doi.org/10.1128/IAI.01288-07 https://doi.org/10.1128/IAI.01288-07 The gamma interferon (IFN-γ)-inducible GTP-binding protein IGTP is necessary for Toxoplasma vacuolar disruption and induces parasite egression in IFN-‍γ‍-stimulated astrocytes Mestre MB , Colombo MI , 2012 . cAMP and EPAC are key players in the regulation of the signal transduction pathway involved in the α-hemolysin autophagic response . PLoS Pathog , 8 ( 5 ): e1002664 . https://doi.org/10.1371/journal.ppat.1002664 https://doi.org/10.1371/journal.ppat.1002664 cAMP and EPAC are key players in the regulation of the signal transduction pathway involved in the α-hemolysin autophagic response Mestre MB , Fader CM , Sola C , et al. , 2010 . α‍-Hemolysin is required for the activation of the autophagic pathway in Staphylococcus aureus infected cells . Autophagy , 6 ( 1 ): 110 - 125 . https://doi.org/10.4161/auto.6.1.10698 https://doi.org/10.4161/auto.6.1.10698 α‍-Hemolysin is required for the activation of the autophagic pathway in Staphylococcus aureus infected cells Mijaljica D , Prescott M , Devenish RJ , 2011 . Microautophagy in mammalian cells: revisiting a 40-year-old conundrum . Autophagy , 7 ( 7 ): 673 - 682 . https://doi.org/10.4161/auto.7.7.14733 https://doi.org/10.4161/auto.7.7.14733 Microautophagy in mammalian cells: revisiting a 40-year-old conundrum Min JS , Kim DE , Jin YH , et al. , 2020 . Kurarinone inhibits HCoV-OC43 infection by impairing the virus-induced autophagic flux in MRC-5 human lung cells . J Clin Med , 9 ( 7 ): 2230 . https://doi.org/10.3390/jcm9072230 https://doi.org/10.3390/jcm9072230 Kurarinone inhibits HCoV-OC43 infection by impairing the virus-induced autophagic flux in MRC-5 human lung cells Miramón P , Dunker C , Windecker H , et al. , 2012 . Cellular responses of Candida albicans to phagocytosis and the extracellular activities of neutrophils are critical to counteract carbohydrate starvation, oxidative and nitrosative stress . PLoS ONE , 7 ( 12 ): e52850 . https://doi.org/10.1371/journal.pone.0052850 https://doi.org/10.1371/journal.pone.0052850 Cellular responses of Candida albicans to phagocytosis and the extracellular activities of neutrophils are critical to counteract carbohydrate starvation, oxidative and nitrosative stress Mitchell G , Ge L , Huang QY , et al. , 2015 . Avoidance of autophagy mediated by PlcA or ActA is required for Listeria monocytogenes growth in macrophages . Infect Immun , 83 ( 5 ): 2175 - 2184 . https://doi.org/10.1128/IAI.00110-15 https://doi.org/10.1128/IAI.00110-15 Avoidance of autophagy mediated by PlcA or ActA is required for Listeria monocytogenes growth in macrophages Mizushima N , Komatsu M , 2011 . Autophagy: renovation of cells and tissues . Cell , 147 ( 4 ): 728 - 741 . https://doi.org/10.1016/j.cell.2011.10.026 https://doi.org/10.1016/j.cell.2011.10.026 Autophagy: renovation of cells and tissues Mogensen TH , Paludan SR , 2001 . Molecular pathways in virus-induced cytokine production . Microbiol Mol Biol Rev , 65 ( 1 ): 131 - 150 . https://doi.org/10.1128/MMBR.65.1.131-150.2001 https://doi.org/10.1128/MMBR.65.1.131-150.2001 Molecular pathways in virus-induced cytokine production Mostowy S , 2013 . Autophagy and bacterial clearance: a not so clear picture . Cell Microbiol , 15 ( 3 ): 395 - 402 . https://doi.org/10.1111/cmi.12063 https://doi.org/10.1111/cmi.12063 Autophagy and bacterial clearance: a not so clear picture Nakagawa I , Amano A , Mizushima N , et al. , 2004 . Autophagy defends cells against invading group A Streptococcus . Science , 306 ( 5698 ): 1037 - 1040 . https://doi.org/10.1126/science.1103966 https://doi.org/10.1126/science.1103966 Autophagy defends cells against invading group A Streptococcus Narendra D , Tanaka A , Suen DF , et al. , 2008 . Parkin is recruited selectively to impaired mitochondria and promotes their autophagy . J Cell Biol , 183 ( 5 ): 795 - 803 . https://doi.org/10.1083/jcb.200809125 https://doi.org/10.1083/jcb.200809125 Parkin is recruited selectively to impaired mitochondria and promotes their autophagy Neumann Y , Bruns SA , Rohde M , et al. , 2016 . Intracellular Staphylococcus aureus eludes selective autophagy by activating a host cell kinase . Autophagy , 12 ( 11 ): 2069 - 2084 . https://doi.org/10.1080/15548627.2016.1226732 https://doi.org/10.1080/15548627.2016.1226732 Intracellular Staphylococcus aureus eludes selective autophagy by activating a host cell kinase Nicola AM , Albuquerque P , Martinez LR , et al. , 2012 . Macrophage autophagy in immunity to Cryptococcus neoformans and Candida albicans . Infect Immun , 80 ( 9 ): 3065 - 3076 . https://doi.org/10.1128/IAI.00358-12 https://doi.org/10.1128/IAI.00358-12 Macrophage autophagy in immunity to Cryptococcus neoformans and Candida albicans Noad J , von der Malsburg A , Pathe C , et al. , 2017 . LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-κB . Nat Microbiol , 2 ( 7 ): 17063 . https://doi.org/10.1038/nmicrobiol.2017.63 https://doi.org/10.1038/nmicrobiol.2017.63 LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-κB Obara K , Ohsumi Y , 2011 . PtdIns 3-kinase orchestrates autophagosome formation in yeast . J Lipids , 2011 : 498768 . https://doi.org/10.1155/2011/498768 https://doi.org/10.1155/2011/498768 PtdIns 3-kinase orchestrates autophagosome formation in yeast Ogawa M , Mimuro H , Yoshikawa Y , et al. , 2011 . Manipulation of autophagy by bacteria for their own benefit . Microbiol Immunol , 55 ( 7 ): 459 - 471 . https://doi.org/10.1111/j.1348-0421.2011.00343.x https://doi.org/10.1111/j.1348-0421.2011.00343.x Manipulation of autophagy by bacteria for their own benefit Öhman T , Teirilä L , Lahesmaa-Korpinen AM , et al. , 2014 . Dectin-1 pathway activates robust autophagy-dependent unconventional protein secretion in human macrophages . J Immunol , 192 ( 12 ): 5952 - 5962 . https://doi.org/10.4049/jimmunol.1303213 https://doi.org/10.4049/jimmunol.1303213 Dectin-1 pathway activates robust autophagy-dependent unconventional protein secretion in human macrophages Ohshima J , Lee Y , Sasai M , et al. , 2014 . Role of mouse and human autophagy proteins in IFN-‍γ‍-induced cell-autonomous responses against Toxoplasma gondii . J Immunol , 192 ( 7 ): 3328 - 3335 . https://doi.org/10.4049/jimmunol.1302822 https://doi.org/10.4049/jimmunol.1302822 Role of mouse and human autophagy proteins in IFN-‍γ‍-induced cell-autonomous responses against Toxoplasma gondii Okamoto S , Nagase S , 2018 . Pathogenic mechanisms of invasive group a Streptococcus infections by influenza virus-group A Streptococcus superinfection . Microbiol Immunol , 62 ( 3 ): 141 - 149 . https://doi.org/10.1111/1348-0421.12577 https://doi.org/10.1111/1348-0421.12577 Pathogenic mechanisms of invasive group a Streptococcus infections by influenza virus-group A Streptococcus superinfection Orvedahl A , Levine B , 2008 . Viral evasion of autophagy . Autophagy , 4 ( 3 ): 280 - 285 . https://doi.org/10.4161/auto.5289 https://doi.org/10.4161/auto.5289 Viral evasion of autophagy Otto M , 2014 . Staphylococcus aureus toxins . Curr Opin Microbiol , 17 : 32 - 37 . https://doi.org/10.1016/j.mib.2013.11.004 https://doi.org/10.1016/j.mib.2013.11.004 Staphylococcus aureus toxins Pauwels AM , Trost M , Beyaert R , et al. , 2017 . Patterns, receptors, and signals: regulation of phagosome maturation . Trends Immunol , 38 ( 6 ): 407 - 422 . https://doi.org/10.1016/j.it.2017.03.006 https://doi.org/10.1016/j.it.2017.03.006 Patterns, receptors, and signals: regulation of phagosome maturation Ploen D , Hildt E , 2015 . Hepatitis C virus comes for dinner: how the hepatitis C virus interferes with autophagy . World J Gastroenterol , 21 ( 28 ): 8492 - 8507 . https://doi.org/10.3748/wjg.v21.i28.8492 https://doi.org/10.3748/wjg.v21.i28.8492 Hepatitis C virus comes for dinner: how the hepatitis C virus interferes with autophagy Polajnar M , Dietz MS , Heilemann M , et al. , 2017 . Expanding the host cell ubiquitylation machinery targeting cytosolic Salmonella . EMBO Rep , 18 ( 9 ): 1572 - 1585 . https://doi.org/10.15252/embr.201643851 https://doi.org/10.15252/embr.201643851 Expanding the host cell ubiquitylation machinery targeting cytosolic Salmonella Portes J , Barrias E , Travassos R , et al. , 2020 . Toxoplasma gondii mechanisms of entry into host cells . Front Cell Infect Microbiol , 10 : 294 . https://doi.org/10.3389/fcimb.2020.00294 https://doi.org/10.3389/fcimb.2020.00294 Toxoplasma gondii mechanisms of entry into host cells Prentice E , Jerome WG , Yoshimori T , et al. , 2004a . Coronavirus replication complex formation utilizes components of cellular autophagy . J Biol Chem , 279 ( 11 ): 10136 - 10141 . https://doi.org/10.1074/jbc.M306124200 https://doi.org/10.1074/jbc.M306124200 Coronavirus replication complex formation utilizes components of cellular autophagy Prentice E , McAuliffe J , Lu XT , et al. , 2004b . Identification and characterization of severe acute respiratory syndrome coronavirus replicase proteins . J Virol , 78 ( 18 ): 9977 - 9986 . https://doi.org/10.1128/JVI.78.18.9977-9986.2004 https://doi.org/10.1128/JVI.78.18.9977-9986.2004 Identification and characterization of severe acute respiratory syndrome coronavirus replicase proteins Py BF , Lipinski MM , Yuan JY , 2007 . Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection . Autophagy , 3 ( 2 ): 117 - 125 . https://doi.org/10.4161/auto.3618 https://doi.org/10.4161/auto.3618 Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection Queval CJ , Brosch R , Simeone R , 2017 . The macrophage: a disputed fortress in the battle against Mycobacterium tuberculosis . Front Microbiol , 8 : 2284 . https://doi.org/10.3389/fmicb.2017.02284 https://doi.org/10.3389/fmicb.2017.02284 The macrophage: a disputed fortress in the battle against Mycobacterium tuberculosis Raught B , Gingras AC , Sonenberg N , 2001 . The target of rapamycin (TOR) proteins . Proc Natl Acad Sci USA , 98 ( 13 ): 7037 - 7044 . https://doi.org/10.1073/pnas.121145898 https://doi.org/10.1073/pnas.121145898 The target of rapamycin (TOR) proteins Ravenhill BJ , Boyle KB , von Muhlinen N , et al. , 2019 . The cargo receptor NDP52 initiates selective autophagy by recruiting the ULK complex to cytosol-invading bacteria . Mol Cell , 74 ( 2 ): 320 - 329.e6 . https://doi.org/10.1016/j.molcel.2019.01.041 https://doi.org/10.1016/j.molcel.2019.01.041 The cargo receptor NDP52 initiates selective autophagy by recruiting the ULK complex to cytosol-invading bacteria Reggiori F , Tucker KA , Stromhaug PE , et al. , 2004 . The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure . Dev Cell , 6 ( 1 ): 79 - 90 . https://doi.org/10.1016/s1534-5807(03)00402-7 https://doi.org/10.1016/s1534-5807(03)00402-7 The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure Reggiori F , Monastyrska I , Shintani T , et al. , 2005a . The actin cytoskeleton is required for selective types of autophagy, but not nonspecific autophagy, in the yeast Saccharomyces cerevisiae . Mol Biol Cell , 16 ( 12 ): 5843 - 5856 . https://doi.org/10.1091/mbc.e05-07-0629 https://doi.org/10.1091/mbc.e05-07-0629 The actin cytoskeleton is required for selective types of autophagy, but not nonspecific autophagy, in the yeast Saccharomyces cerevisiae Reggiori F , Shintani T , Chong H , et al. , 2005b . Atg9 cycles between mitochondria and the pre-autophagosomal structure in yeasts . Autophagy , 1 ( 2 ): 101 - 109 . https://doi.org/10.4161/auto.1.2.1840 https://doi.org/10.4161/auto.1.2.1840 Atg9 cycles between mitochondria and the pre-autophagosomal structure in yeasts Reggiori F , Monastyrska I , Verheije MH , et al. , 2010 . Coronaviruses hijack the LC3-I-positive edemosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication . Cell Host Microbe , 7 ( 6 ): 500 - 508 . https://doi.org/10.1016/j.chom.2010.05.013 https://doi.org/10.1016/j.chom.2010.05.013 Coronaviruses hijack the LC3-I-positive edemosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication Reggiori F , Komatsu M , Finley K , et al. , 2012 . Autophagy: more than a nonselective pathway . Int J Cell Biol , 2012 : 219625 . https://doi.org/10.1155/2012/219625 https://doi.org/10.1155/2012/219625 Autophagy: more than a nonselective pathway Richards AL , Jackson WT , 2012 . Intracellular vesicle acidification promotes maturation of infectious poliovirus particles . PLoS Pathog , 8 ( 11 ): e1003046 . https://doi.org/10.1371/journal.ppat.1003046 https://doi.org/10.1371/journal.ppat.1003046 Intracellular vesicle acidification promotes maturation of infectious poliovirus particles Romano PS , Arboit MA , Vázquez CL , et al. , 2009 . The autophagic pathway is a key component in the lysosomal dependent entry of Trypanosoma cruzi into the host cell . Autophagy , 5 ( 1 ): 6 - 18 . https://doi.org/10.4161/auto.5.1.7160 https://doi.org/10.4161/auto.5.1.7160 The autophagic pathway is a key component in the lysosomal dependent entry of Trypanosoma cruzi into the host cell Rudkin FM , Bain JM , Walls C , et al. , 2013 . Altered dynamics of Candida albicans phagocytosis by macrophages and PMNs when both phagocyte subsets are present . mBio , 4 ( 6 ): e00810-13 . https://doi.org/10.1128/mBio.00810-13 https://doi.org/10.1128/mBio.00810-13 Altered dynamics of Candida albicans phagocytosis by macrophages and PMNs when both phagocyte subsets are present Rudnicka W , Kaczmarek M , Szeliga J , et al. , 1997 . The host response to Listeria monocytogenes mutants defective in genes encoding phospholipases C ( plcA , plcB ) and actin assembly ( actA ) . Microbiol Immunol , 41 ( 11 ): 847 - 853 . https://doi.org/10.1111/j.1348-0421.1997.tb01939.x https://doi.org/10.1111/j.1348-0421.1997.tb01939.x The host response to Listeria monocytogenes mutants defective in genes encoding phospholipases C (plcA, plcB) and actin assembly (actA) Ruland J , Hartjes L , 2019 . CARD‒BCL-10‒MALT1 signalling in protective and pathological immunity . Nat Rev Immunol , 19 ( 2 ): 118 - 134 . https://doi.org/10.1038/s41577-018-0087-2 https://doi.org/10.1038/s41577-018-0087-2 CARD‒BCL-10‒MALT1 signalling in protective and pathological immunity Sakurai A , Maruyama F , Funao J , et al. , 2010 . Specific behavior of intracellular Streptococcus pyogenes that has undergone autophagic degradation is associated with bacterial streptolysin O and host small G proteins Rab5 and Rab7 . J Biol Chem , 285 ( 29 ): 22666 - 22675 . https://doi.org/10.1074/jbc.M109.100131 https://doi.org/10.1074/jbc.M109.100131 Specific behavior of intracellular Streptococcus pyogenes that has undergone autophagic degradation is associated with bacterial streptolysin O and host small G proteins Rab5 and Rab7 Salassa BN , Romano PS , 2019 . Autophagy: a necessary process during the Trypanosoma cruzi life-cycle . Virulence , 10 ( 1 ): 460 - 469 . https://doi.org/10.1080/21505594.2018.1543517 https://doi.org/10.1080/21505594.2018.1543517 Autophagy: a necessary process during the Trypanosoma cruzi life-cycle Salazar F , Brown GD , 2018 . Antifungal innate immunity: a perspective from the last 10 years . J Innate Immun , 10 ( 5-6 ): 373 - 397 . https://doi.org/10.1159/000488539 https://doi.org/10.1159/000488539 Antifungal innate immunity: a perspective from the last 10 years Sanjuan MA , Dillon CP , Tait SWG , et al. , 2007 . Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis . Nature , 450 ( 7173 ): 1253 - 1257 . https://doi.org/10.1038/nature06421 https://doi.org/10.1038/nature06421 Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis Sasai M , Yamamoto M , 2019 . Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection . Exp Mol Med , 51 ( 12 ): 1 - 10 . https://doi.org/10.1038/s12276-019-0353-9 https://doi.org/10.1038/s12276-019-0353-9 Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection Schille S , Crauwels P , Bohn R , et al. , 2018 . LC3-associated phagocytosis in microbial pathogenesis . Int J Med Microbiol , 308 ( 1 ): 228 - 236 . https://doi.org/10.1016/j.ijmm.2017.10.014 https://doi.org/10.1016/j.ijmm.2017.10.014 LC3-associated phagocytosis in microbial pathogenesis Schnaith A , Kashkar H , Leggio SA , et al. , 2007 . Staphylococcus aureus subvert autophagy for induction of caspase-independent host cell death . J Biol Chem , 282 ( 4 ): 2695 - 2706 . https://doi.org/10.1074/jbc.M609784200 https://doi.org/10.1074/jbc.M609784200 Staphylococcus aureus subvert autophagy for induction of caspase-independent host cell death Schneider M , Ackermann K , Stuart M , et al. , 2012 . Severe acute respiratory syndrome coronavirus replication is severely impaired by MG132 due to proteasome-independent inhibition of m-calpain . J Virol , 86 ( 18 ): 10112 - 10122 . https://doi.org/10.1128/JVI.01001-12 https://doi.org/10.1128/JVI.01001-12 Severe acute respiratory syndrome coronavirus replication is severely impaired by MG132 due to proteasome-independent inhibition of m-calpain Schuck S , 2020 . Microautophagy-distinct molecular mechanisms handle cargoes of many sizes . J Cell Sci , 133 ( 17 ): jcs246322 . https://doi.org/10.1242/jcs.246322 https://doi.org/10.1242/jcs.246322 Microautophagy-distinct molecular mechanisms handle cargoes of many sizes Scott SV , Guan J , Hutchins MU , et al. , 2001 . Cvt19 is a receptor for the cytoplasm-to-vacuole targeting pathway . Mol Cell , 7 ( 6 ): 1131 - 1141 . https://doi.org/10.1016/s1097-2765(01)00263-5 https://doi.org/10.1016/s1097-2765(01)00263-5 Cvt19 is a receptor for the cytoplasm-to-vacuole targeting pathway Sekito T , Kawamata T , Ichikawa R , et al. , 2009 . Atg17 recruits Atg9 to organize the pre-autophagosomal structure . Genes Cells , 14 ( 5 ): 525 - 538 . https://doi.org/10.1111/j.1365-2443.2009.01299.x https://doi.org/10.1111/j.1365-2443.2009.01299.x Atg17 recruits Atg9 to organize the pre-autophagosomal structure Shi CS , Kehrl JH , 2008 . MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages . J Biol Chem , 283 ( 48 ): 33175 - 33182 . https://doi.org/10.1074/jbc.M804478200 https://doi.org/10.1074/jbc.M804478200 MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages Shintani T , Klionsky DJ , 2004a . Autophagy in health and disease: a double-edged sword . Science , 306 ( 5698 ): 990 - 995 . https://doi.org/10.1126/science.1099993 https://doi.org/10.1126/science.1099993 Autophagy in health and disease: a double-edged sword Shintani T , Klionsky DJ , 2004b . Cargo proteins facilitate the formation of transport vesicles in the cytoplasm to vacuole targeting pathway . J Biol Chem , 279 ( 29 ): 29889 - 29894 . https://doi.org/10.1074/jbc.M404399200 https://doi.org/10.1074/jbc.M404399200 Cargo proteins facilitate the formation of transport vesicles in the cytoplasm to vacuole targeting pathway Shroff A , Sequeira R , Patel V , et al. , 2018 . Knockout of autophagy gene, ATG5 in mice vaginal cells abrogates cytokine response and pathogen clearance during vaginal infection of Candida albicans . Cell Immunol , 324 : 59 - 73 . https://doi.org/10.1016/j.cellimm.2017.12.012 https://doi.org/10.1016/j.cellimm.2017.12.012 Knockout of autophagy gene, ATG5 in mice vaginal cells abrogates cytokine response and pathogen clearance during vaginal infection of Candida albicans Smeekens SP , Malireddi RK , Plantinga TS , et al. , 2014 . Autophagy is redundant for the host defense against systemic Candida albicans infections . Eur J Clin Microbiol Infect Dis , 33 ( 5 ): 711 - 722 . https://doi.org/10.1007/s10096-013-2002-x https://doi.org/10.1007/s10096-013-2002-x Autophagy is redundant for the host defense against systemic Candida albicans infections Snijder EJ , van der Meer Y , Zevenhoven-Dobbe J , et al. , 2006 . Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex . J Virol , 80 ( 12 ): 5927 - 5940 . https://doi.org/10.1128/JVI.02501-05 https://doi.org/10.1128/JVI.02501-05 Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex Stévenin V , Chang YY , le Toquin Y , et al. , 2019 . Dynamic growth and shrinkage of the Salmonella -containing vacuole determines the intracellular pathogen niche . Cell Rep , 29 ( 12 ): 3958 - 3973.e7 . https://doi.org/10.1016/j.celrep.2019.11.049 https://doi.org/10.1016/j.celrep.2019.11.049 Dynamic growth and shrinkage of the Salmonella-containing vacuole determines the intracellular pathogen niche Subauste CS , 2019 . Interplay between Toxoplasma gondii , autophagy, and autophagy proteins . Front Cell Infect Microbiol , 9 : 139 . https://doi.org/10.3389/fcimb.2019.00139 https://doi.org/10.3389/fcimb.2019.00139 Interplay between Toxoplasma gondii, autophagy, and autophagy proteins Sudhakar P , Jacomin AC , Hautefort I , et al. , 2019 . Targeted interplay between bacterial pathogens and host autophagy . Autophagy , 15 ( 9 ): 1620 - 1633 . https://doi.org/10.1080/15548627.2019.1590519 https://doi.org/10.1080/15548627.2019.1590519 Targeted interplay between bacterial pathogens and host autophagy Tam JM , Mansour MK , Khan NS , et al. , 2014 . Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages . J Infect Dis , 210 ( 11 ): 1844 - 1854 . https://doi.org/10.1093/infdis/jiu290 https://doi.org/10.1093/infdis/jiu290 Dectin-1-dependent LC3 recruitment to phagosomes enhances fungicidal activity in macrophages Tang J , Lin GX , Langdon WY , et al. , 2018 . Regulation of C-type lectin receptor-mediated antifungal immunity . Front Immunol , 9 : 123 . https://doi.org/10.3389/fimmu.2018.00123 https://doi.org/10.3389/fimmu.2018.00123 Regulation of C-type lectin receptor-mediated antifungal immunity Tanida I , Ueno T , Kominami E , 2008 . LC3 and autophagy . Methods Mol Biol , 445 : 77 - 88 . https://doi.org/10.1007/978-1-59745-157-4_4 https://doi.org/10.1007/978-1-59745-157-4_4 LC3 and autophagy Tekirdag K , Cuervo AM , 2018 . Chaperone-mediated autophagy and endosomal microautophagy: jointed by a chaperone . J Biol Chem , 293 ( 15 ): 5414 - 5424 . https://doi.org/10.1074/jbc.R117.818237 https://doi.org/10.1074/jbc.R117.818237 Chaperone-mediated autophagy and endosomal microautophagy: jointed by a chaperone Thurston TLM , Wandel MP , von Muhlinen N , et al. , 2012 . Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion . Nature , 482 ( 7385 ): 414 - 418 . https://doi.org/10.1038/nature10744 https://doi.org/10.1038/nature10744 Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion Tian XJ , Gala U , Zhang YP , et al. , 2015 . A voltage-gated calcium channel regulates lysosomal fusion with endosomes and autophagosomes and is required for neuronal homeostasis . PLoS Biol , 13 ( 3 ): e1002103 . https://doi.org/10.1371/journal.pbio.1002103 https://doi.org/10.1371/journal.pbio.1002103 A voltage-gated calcium channel regulates lysosomal fusion with endosomes and autophagosomes and is required for neuronal homeostasis Towers CG , Thorburn A , 2016 . Therapeutic targeting of autophagy . EBioMedicine , 14 : 15 - 23 . https://doi.org/10.1016/j.ebiom.2016.10.034 https://doi.org/10.1016/j.ebiom.2016.10.034 Therapeutic targeting of autophagy Upadhyay S , Philips JA , 2019 . LC3-associated phagocytosis: host defense and microbial response . Curr Opin Immunol , 60 : 81 - 90 . https://doi.org/10.1016/j.coi.2019.04.012 https://doi.org/10.1016/j.coi.2019.04.012 LC3-associated phagocytosis: host defense and microbial response Vita GM , de Simone G , Leboffe L , et al. , 2020 . Human serum albumin binds streptolysin O (SLO) toxin produced by group a Streptococcus and inhibits its cytotoxic and hemolytic effects . Front Immunol , 11 : 507092 . https://doi.org/10.3389/fimmu.2020.507092 https://doi.org/10.3389/fimmu.2020.507092 Human serum albumin binds streptolysin O (SLO) toxin produced by group a Streptococcus and inhibits its cytotoxic and hemolytic effects Wang Y , Qin ZH , 2013 . Coordination of autophagy with other cellular activities . Acta Pharmacol Sin , 34 ( 5 ): 585 - 594 . https://doi.org/10.1038/aps.2012.194 https://doi.org/10.1038/aps.2012.194 Coordination of autophagy with other cellular activities Wang YB , Weiss LM , Orlofsky A , 2009 . Host cell autophagy is induced by Toxoplasma gondii and contributes to parasite growth . J Biol Chem , 284 ( 3 ): 1694 - 1701 . https://doi.org/10.1074/jbc.M807890200 https://doi.org/10.1074/jbc.M807890200 Host cell autophagy is induced by Toxoplasma gondii and contributes to parasite growth Wen N , Lv Q , Du ZG , 2020 . MicroRNAs involved in drug resistance of breast cancer by regulating autophagy . J Zhejiang Univ-Sci B (Biomed & Biotechnol) , 21 ( 9 ): 690 - 702 . https://doi.org/10.1631/jzus.B2000076 https://doi.org/10.1631/jzus.B2000076 MicroRNAs involved in drug resistance of breast cancer by regulating autophagy Wieczorek M , Abualrous ET , Sticht J , et al. , 2017 . Major histocompatibility complex (MHC) class I and MHC class II proteins: conformational plasticity in antigen presentation . Front Immunol , 8 : 292 . https://doi.org/10.3389/fimmu.2017.00292 https://doi.org/10.3389/fimmu.2017.00292 Major histocompatibility complex (MHC) class I and MHC class II proteins: conformational plasticity in antigen presentation Wu MY , Lu JH , 2019 . Autophagy and macrophage functions: inflammatory response and phagocytosis . Cells , 9 ( 1 ): 70 . https://doi.org/10.3390/cells9010070 https://doi.org/10.3390/cells9010070 Autophagy and macrophage functions: inflammatory response and phagocytosis Xie ZP , Nair U , Klionsky DJ , 2008 . Atg8 controls phagophore expansion during autophagosome formation . Mol Biol Cell , 19 ( 8 ): 3290 - 3298 . https://doi.org/10.1091/mbc.E07-12-1292 https://doi.org/10.1091/mbc.E07-12-1292 Atg8 controls phagophore expansion during autophagosome formation Xiong QH , Yang M , Li P , et al. , 2019 . Bacteria exploit autophagy for their own benefit . Infect Drug Resist , 12 : 3205 - 3215 . https://doi.org/10.2147/IDR.S220376 https://doi.org/10.2147/IDR.S220376 Bacteria exploit autophagy for their own benefit Yamamoto H , Kakuta S , Watanabe TM , et al. , 2012 . Atg9 vesicles are an important membrane source during early steps of autophagosome formation . J Cell Biol , 198 ( 2 ): 219 - 233 . https://doi.org/10.1083/jcb.201202061 https://doi.org/10.1083/jcb.201202061 Atg9 vesicles are an important membrane source during early steps of autophagosome formation Yamasaki A , Watanabe Y , Adachi W , et al. , 2016 . Structural basis for receptor-mediated selective autophagy of aminopeptidase I aggregates . Cell Rep , 16 ( 1 ): 19 - 27 . https://doi.org/10.1016/j.celrep.2016.05.066 https://doi.org/10.1016/j.celrep.2016.05.066 Structural basis for receptor-mediated selective autophagy of aminopeptidase I aggregates Yang YS , Kato M , Wu X , et al. , 2019 . Yeast ataxin-2 forms an intracellular condensate required for the inhibition of TORC1 signaling during respiratory growth . Cell , 177 ( 3 ): 697 - 710.e17 . https://doi.org/10.1016/j.cell.2019.02.043 https://doi.org/10.1016/j.cell.2019.02.043 Yeast ataxin-2 forms an intracellular condensate required for the inhibition of TORC1 signaling during respiratory growth Yi XH , Zhang B , Fu YR , et al. , 2020 . STAT1 and its related molecules as potential biomarkers in Mycobacterium tuberculosis infection . J Cell Mol Med , 24 ( 5 ): 2866 - 2878 . https://doi.org/10.1111/jcmm.14856 https://doi.org/10.1111/jcmm.14856 STAT1 and its related molecules as potential biomarkers in Mycobacterium tuberculosis infection Yin ZY , Pascual C , Klionsky DJ , 2016 . Autophagy: machinery and regulation . Microb Cell , 3 ( 12 ): 588 - 596 . https://doi.org/10.15698/mic2016.12.546 https://doi.org/10.15698/mic2016.12.546 Autophagy: machinery and regulation Yin ZY , Liu X , Ariosa A , et al. , 2019 . Psp2, a novel regulator of autophagy that promotes autophagy-related protein translation . Cell Res , 29 ( 12 ): 994 - 1008 . https://doi.org/10.1038/s41422-019-0246-4 https://doi.org/10.1038/s41422-019-0246-4 Psp2, a novel regulator of autophagy that promotes autophagy-related protein translation Yorimitsu T , Klionsky DJ , 2005 . Autophagy: molecular machinery for self-eating . Cell Death Differ , 12 ( S2 ):‍ 1542 - 1552 . https://doi.org/10.1038/sj.cdd.4401765 https://doi.org/10.1038/sj.cdd.4401765 Autophagy: molecular machinery for self-eating Yoshikawa Y , Ogawa M , Hain T , et al. , 2009 . Listeria monocytogenes ActA-mediated escape from autophagic recognition . Nat Cell Biol , 11 ( 10 ): 1233 - 1240 . https://doi.org/10.1038/ncb1967 https://doi.org/10.1038/ncb1967 Listeria monocytogenes ActA-mediated escape from autophagic recognition Yu ZQ , Sun LL , Jiang ZD , et al. , 2020 . Atg38-Atg8 interaction in fission yeast establishes a positive feedback loop to promote autophagy . Autophagy , 16 ( 11 ): 2036 - 2051 . https://doi.org/10.1080/15548627.2020.1713644 https://doi.org/10.1080/15548627.2020.1713644 Atg38-Atg8 interaction in fission yeast establishes a positive feedback loop to promote autophagy Yuan WP , Strømhaug PE , Dunn WA , 1999 . Glucose-induced autophagy of peroxisomes in Pichia pastoris requires a unique E1-like protein . Mol Biol Cell , 10 ( 5 ): 1353 - 1366 . https://doi.org/10.1091/mbc.10.5.1353 https://doi.org/10.1091/mbc.10.5.1353 Glucose-induced autophagy of peroxisomes in Pichia pastoris requires a unique E1-like protein Zachari M , Ganley IG , 2017 . The mammalian ULK1 complex and autophagy initiation . Essays Biochem , 61 ( 6 ): 585 - 596 . https://doi.org/10.1042/EBC20170021 https://doi.org/10.1042/EBC20170021 The mammalian ULK1 complex and autophagy initiation Zare-Bidaki M , Hakimi H , Abdollahi SH , et al. , 2014 . TLR4 in toxoplasmosis; friends or foe? Microb Pathog , 69 - 70 : 28 - 32 . https://doi.org/10.1016/j.micpath.2014.03.006 https://doi.org/10.1016/j.micpath.2014.03.006 TLR4 in toxoplasmosis; friends or foe? Zhai WJ , Wu FJ , Zhang YY , et al. , 2019 . The immune escape mechanisms of Mycobacterium tuberculosis . Int J Mol Sci , 20 ( 2 ): 340 . https://doi.org/10.3390/ijms20020340 https://doi.org/10.3390/ijms20020340 The immune escape mechanisms of Mycobacterium tuberculosis Zhang XW , Bai XC , Chen ZJ , 2020 . Structures and mechanisms in the cGAS-STING innate immunity pathway . Immunity , 53 ( 1 ): 43 - 53 . https://doi.org/10.1016/j.immuni.2020.05.013 https://doi.org/10.1016/j.immuni.2020.05.013 Structures and mechanisms in the cGAS-STING innate immunity pathway Zhao MM , Wang RS , Zhou YL , et al. , 2020 . Emerging relationship between RNA helicases and autophagy . J Zhejiang Univ-Sci B (Biomed & Biotechnol) , 21 ( 10 ): 767 - 778 . https://doi.org/10.1631/jzus.B2000245 https://doi.org/10.1631/jzus.B2000245 Emerging relationship between RNA helicases and autophagy Zhao ZJ , Thackray LB , Miller BC , et al. , 2007 . Coronavirus replication does not require the autophagy gene ATG5 . Autophagy , 3 ( 6 ): 581 - 585 . https://doi.org/10.4161/auto.4782 https://doi.org/10.4161/auto.4782 Coronavirus replication does not require the autophagy gene ATG5 Zhao ZJ , Fux B , Goodwin M , et al. , 2008 . Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens . Cell Host Microbe , 4 ( 5 ): 458 - 469 . https://doi.org/10.1016/j.chom.2008.10.003 https://doi.org/10.1016/j.chom.2008.10.003 Autophagosome-independent essential function for the autophagy protein Atg5 in cellular immunity to intracellular pathogens Zhu LQ , Mou CX , Yang X , et al. , 2016 . Mitophagy in TGEV infection counteracts oxidative stress and apoptosis . Oncotarget , 7 ( 19 ): 27122 - 27141 . https://doi.org/10.18632/oncotarget.8345 https://doi.org/10.18632/oncotarget.8345 Mitophagy in TGEV infection counteracts oxidative stress and apoptosis Zhu XM , Li L , Wu M , et al. , 2019 . Current opinions on autophagy in pathogenicity of fungi . Virulence , 10 ( 1 ): 481 - 489 . https://doi.org/10.1080/21505594.2018.1551011 https://doi.org/10.1080/21505594.2018.1551011 Current opinions on autophagy in pathogenicity of fungi Zientara-Rytter K , Subramani S , 2020 . Mechanistic insights into the role of Atg11 in selective autophagy . J Mol Biol , 432 ( 1 ): 104 - 122 . https://doi.org/10.1016/j.jmb.2019.06.017 https://doi.org/10.1016/j.jmb.2019.06.017 Mechanistic insights into the role of Atg11 in selective autophagy Liangwei DUAN and Hui WANG conceived and designed the review. Qianqian ZHENG and Liangwei DUAN drafted the manuscript. Yang ZHANG, Jiaoyang LI, and Shiyu ZHANG prepared the figures. Liangwei DUAN and Hui WANG revised the manuscript. All authors have read and approved the final manuscript. This work was supported by the National Natural Science Foundation of China (Nos. 81871312 and 81701546) and the Natural Science Foundation of Henan Province (No. 182300410327). We would like to apologize to those researchers whose related work was not cited in this review. We would like to thank Yichuan XIAO (Chinese Academy of Sciences, Shanghai, China) and Tonglei SHI (Nankai University, Tianjin, China) for helpful comments and discussions on the manuscript. 10.1631/jzus.B2100285 1673-1581（2022）01-0019-23 This work was supported by the National Natural Science Foundation of China (Nos. 81871312 and 81701546) and the Natural Science Foundation of Henan Province (No. 182300410327). 2021-03-21 2021-07-05 2022-01-15 2022-04-19 2021-12-09 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2021 2022 浙江大学出版社 Qianqian ZHENG, Liangwei DUAN, Yang ZHANG, Jiaoyang LI, Shiyu ZHANG, and Hui WANG declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. Compliance with ethics guidelines 浙江大学学报（英文版）（B辑：生物医学和生物技术） 1 23