蛋白质修饰在炎症性肠病中作用研究进展

Emerging role of protein modification in inflammatory bowel disease 蛋白质修饰在炎症性肠病中作用研究进展 1 2 equal first-author 3 equal 1 1 4 1 1 1 1 corresp Fei MAO, maofei2003@ujs.edu.cn Fei MAO, maofei2003@ujs.edu.cn maofei2003@ujs.edu.cn https://orcid.org/0000-0001-5840-4436 Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, China Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang 212013, China Clinical Laboratory, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi 214002, China Clinical Laboratory, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi 214002, China Clinical Laboratory, the People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang 212300, China Clinical Laboratory, the People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang 212300, China Directorate of University Health Services, University of Cape Coast, Cape Coast 02630, Ghana Directorate of University Health Services, University of Cape Coast, Cape Coast 02630, Ghana The onset of inflammatory bowel disease (IBD) involves many factors, including environmental parameters, microorganisms, and the immune system. Although research on IBD continues to expand, the specific pathogenesis mechanism is still unclear. Protein modification refers to chemical modification after protein biosynthesis, also known as post-translational modification (PTM), which causes changes in the properties and functions of proteins. Since proteins can be modified in different ways, such as acetylation, methylation, and phosphorylation, the functions of proteins in different modified states will also be different. Transitions between different states of protein or changes in modification sites can regulate protein properties and functions. Such modifications like neddylation, sumoylation, glycosylation, and acetylation can activate or inhibit various signaling pathways (e.g., nuclear factor-‍κB (NF-‍κB), extracellular signal-regulated kinase (ERK), and protein kinase B (AKT)) by changing the intestinal flora, regulating immune cells, modulating the release of cytokines such as interleukin-1β (IL-‍‍1β), tumor necrosis factor-α (TNF‍-‍α), and interferon-‍γ (IFN-‍γ), and ultimately leading to the maintenance of the stability of the intestinal epithelial barrier. In this review, we focus on the current understanding of PTM and describe its regulatory role in the pathogenesis of IBD. 炎症性肠病（inflammatory bowel disease，IBD）的发病涉及许多因素，包括环境、微生物和免疫系统的改变。尽管对IBD的研究不断深入，但具体的发病机制尚不清楚。蛋白质修饰是指蛋白质生物合成后的化学修饰，也称为翻译后修饰（post-translational modification，PTM），使蛋白质的性质和功能发生变化。由于蛋白质可以通过乙酰化、甲基化和磷酸化等不同方式进行修饰，因此不同修饰状态的蛋白质的功能也会有所不同。蛋白质不同状态之间的转换或修饰位点的变化可以调节蛋白质的特性和功能，如NEDD8蛋白修饰、SUMO化修饰、糖基化和乙酰化等修饰可以通过改变肠道菌群、调节免疫细胞、调节细胞因子（如IL-1β、TNF-α、IFN-γ），最终维持肠上皮屏障的稳定性。在这篇综述中，我们关注当前对PTM的理解，并描述其在IBD发病机制中的调节作用。 Inflammatory bowel disease (IBD) Protein modification Neddylation Sumoylation Glycosylation Acetylation 炎症性肠病（IBD） 蛋白质修饰 NEDD8蛋白修饰 SUMO化修饰 糖基化 乙酰化 1 Introduction 1 Inflammatory bowel disease (IBD) is a chronic inflammatory disease with a range of underlying causes. At present, most scholars consider that IBD is mainly caused by the imbalance of a combination of environmental, genetic, and innate immunity factors ( Baumgart and Carding, 2007 Baumgart and Carding, 2007 ; Ananthakrishnan, 2015 Ananthakrishnan, 2015 ). The study has shown that the pathogenesis of IBD mainly involves damage to the mucosal barrier and the luminal microbiota, which ultimately leads to a persistent imbalance of the intestinal immune system ( Schreiner et al., 2019 Schreiner et al., 2019 ). The imbalance of microflora coupled with chronic irritation as an immune response results in the decrease of mucosal permeability. Exposed bacterial Toll-like receptor (TLR) ligands directly activate antigens of innate and T cell immune responses. The dysfunction of regulatory T (Treg) cells and antigen-presenting cells (APCs) also leads to reduced tolerance to microbial antigens or induces a cross-reactive autoimmune response between the host and microbial antigens ( Singh et al., 2012 Singh et al., 2012 ). Signaling pathway transcription factors (such as nuclear factor-‍κB (NF-‍κB)) have been recognized as major regulators of inflammation and immune homeostasis ( Mitchell and Carmody, 2018 Mitchell and Carmody, 2018 ). The proper folding and post-translational modification (PTM) of proteins are essential for appropriate function. Misfolded and aggregated proteins can cause cellular stress and death ( Wang and Kaufman, 2016 Wang and Kaufman, 2016 ). Unfolded protein response (UPR) is a highly conserved stress response that enables cells to deal with the endoplasmic reticulum (ER) stress imposed by secretory demands associated with environmental forces. Under these conditions, the role of UPR in immunity and inflammation is becoming more recognized, including the development, differentiation, function, and survival of immune cells, which are crucial for maintaining intestinal epithelial homeostasis ( Grootjans et al., 2016 Grootjans et al., 2016 ). Protein modification refers to the chemical modification of proteins after biosynthesis, which is also known as PTM, and includes the addition of groups (such as methylation, acetylation, glycosylation, and phosphorylation), the covalent coupling of small peptides or proteins (such as ubiquitination, neddylation, and sumoylation), and chemical changes to amino acids (such as citrullination) ( Wang and Wang, 2019 Wang and Wang, 2019 ). PTM is not always carried out on de novo synthesized proteins, but it can rapidly and reversibly change the functional relevance of the proteome, thereby achieving tight control and quick response to inflammation ( Ehrentraut and Colgan, 2012 Ehrentraut and Colgan, 2012 ). In this review, we focus on the research progress on protein modification, particularly neddylation, sumoylation, glycosylation, and acetylation, as documented in IBD. 2 Neddylation 1 Ubiquitination is an important PTM in eukaryotes ( Haglund and Dikic, 2005 Haglund and Dikic, 2005 ). The complex formed by ubiquitinated protein and substrate is easily recognized by the proteasome, and facilitates the recruitment of proteins to the signal platform ( Tsukamoto, 2016 Tsukamoto, 2016 ; Glorian et al., 2017 Glorian et al., 2017 ). There are multiple lysine residues in the ubiquitin molecule, which interact with specific substrates in an enzyme cascade reaction to promote substrate degradation or promote protein entry into corresponding signaling pathways. As a PTM, neddylation combines the ubiquitinated protein, the neural precursor cell expressed developmentally downregulated protein 8 (NEDD8), with its target substrate protein, which in turn regulates various cellular processes ( Song et al., 2016 Song et al., 2016 ). The difference between ubiquitination and neddylation is that the former participates in most biological processes in the organism, while the latter has only few target substrates ( Rabut and Peter, 2008 Rabut and Peter, 2008 ). One of the most studied ubiquitin-like molecules, NEDD8, is widely expressed in adult tissues as a conserved nuclear protein ( Kamitani et al., 1997 Kamitani et al., 1997 ; Hori et al., 1999 Hori et al., 1999 ; Kim et al., 2013 Kim et al., 2013 ). The most specific substrate proteins for neddylation belong to the cullin family. There are eight members of the cullin family in the human genome, including cullin 1‍–‍3, 4A, 4B, 5, 7, and 9, also known as Parkin-like cytoplasmic proteins (PARCs) ( Pan et al., 2004 Pan et al., 2004 ). In addition to cullin proteins, there are several other neddylation target proteins, such as murine double microsome 2 (Mdm2), von Hippel-Lindau tumor suppressor protein (pVHL), human antigen R (HuR), epidermal growth factor receptor (EGFR), tumor suppressor p53 (TP53), ribosomal protein (RP), liver kinase B1 (LKB1), and protein kinase B (PK/AKT) ( Stickle et al., 2004 Stickle et al., 2004 ; Xirodimas et al., 2004 Xirodimas et al., 2004 , 2008 2008 ; Oved et al., 2006 Oved et al., 2006 ; Embade et al., 2012 Embade et al., 2012 ; Barbier-Torres et al., 2015 Barbier-Torres et al., 2015 ). NEDD8 is continuously catalyzed by the E1 enzyme (a heterodimer of NEDD8-activating enzyme E1 subunit 1 (NAE1) and ubiquitin-like modifier activating enzyme 3 (UBA3)), ubiquitin-conjugating enzyme 12 (UBC12), and NEDD8 E3 ligase, and finally combines with the corresponding substrate protein to form a unique complex structure. NEDD8 bound to the substrate cannot degrade the protein but can regulate the conformation, stability, positioning, and function of the substrate protein ( Zhao et al., 2014 Zhao et al., 2014 ). This process of protein modification is called neddylation. The function of neddylation has the following main aspects ( Enchev et al., 2015 Enchev et al., 2015 ): (1) regulating the interaction between proteins; (2) regulating the activity of transcription factors to control cell cycle and proliferation; (3) antagonizing ubiquitination. Ubiquitin is upregulated in inflamed tissues, such as in the case of colitis mice, and is related to the mammalian target of rapamycin (mTOR) signaling pathway ( Fujimoto et al., 2017 Fujimoto et al., 2017 ). Studies have found that human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes reduce ubiquitin protein expression and inhibit the activation of NF-‍κB and mTOR ( Wu et al., 2018 Wu et al., 2018 ). Epithelial barrier dysfunction is the hallmark of mucosal inflammatory diseases, including IBD, which leads to the transfer of its infiltrate to the serous membrane ( Koch and Nusrat, 2012 Koch and Nusrat, 2012 ). The destruction of the epithelial barrier may be related to the increased apoptosis of cells by activating caspase 3 ( Nava et al., 2010 Nava et al., 2010 ). Once caspase 3 is activated, it can initiate an irreversible apoptotic cascade, leading to DNA fragmentation and eventually increased cell death ( Porter and Jänicke, 1999 Porter and Jänicke, 1999 ). The study has proved that the stimulation of intestinal inflammation significantly enhances the caspase 3-dependent apoptosis response by relying on neddylation, which has a negative impact on the integrity of the mucosal barrier ( Ehrentraut et al., 2016 Ehrentraut et al., 2016 ). Sentrin-specific protease 8 (SENP8) is essential for regulating NF-‍κB-mediated inflammation ( Ehrentraut et al., 2013 Ehrentraut et al., 2013 ). In human tissue samples from patients with active IBD, it was observed that regardless of the type of colitis (ulcerative colitis (UC) or Crohn's disease (CD)), the messenger RNA (mRNA) level of SENP8 was significantly lower than that of healthy people ( Ehrentraut et al., 2016 Ehrentraut et al., 2016 ). The NAE plays an important role in neddylation because it makes activated NEDD8 easy to combine with the E2 enzyme ( Soucy et al., 2009 Soucy et al., 2009 ). MLN4924 is a representative NAE inhibitor, which can exert a good inhibitory effect on NAE, thereby regulating the function and expression of the target protein (Godbersen et al., 2014). Through affecting the substrate protein of neddylation, MLN4924 has potential effects of causing DNA damage, regulating the conduction of transcription factors, and inducing cancer cell apoptosis ( Milhollen et al., 2010 Milhollen et al., 2010 ; Han et al., 2016 Han et al., 2016 ). In mice treated with lipopolysaccharide (LPS) pretreated with MLN4924, pro-inflammatory cytokines such as interleukin-‍1β (IL-‍‍‍1β), interferon-‍γ (IFN-‍γ), and tumor necrosis factor-α (TNF-‍α) were downregulated, indicating that MLN4924 also has anti-inflammatory effects via inhibiting cullin 1 neddylation ( Ehrentraut et al., 2013 Ehrentraut et al., 2013 ). Cullin neddylation results in the activation of cullin-RING ligase (CRL), the largest family of E3 ubiquitin ligases, which is responsible for the ubiquitination and degradation of many key signal transduction/regulatory proteins ( Zhao and Sun, 2013 Zhao and Sun, 2013 ). Our previous study has revealed that exosomes derived from hucMSCs can inhibit cullin 1 neddylation through microRNA-326 (miR-326)‍-targeted NEDD8, thereby alleviating IBD in mice ( Wang et al., 2020 Wang et al., 2020 ). Other studies have proved that the deterioration of inhibitor of NF-‍κB (IκB) mainly depends on neddylation, and blocking cullin activation results in the accumulation of many CRL substrates (including IκB), thus inhibiting NF-‍κB activity ( Muniandy et al., 2018 Muniandy et al., 2018 ; Schwechheimer, 2018 Schwechheimer, 2018 ). In addition, since the microenvironment of inflammatory lesions is hypoxic, large amounts of adenine nucleotide metabolites are produced ( Colgan and Taylor, 2010 Colgan and Taylor, 2010 ; Kominsky et al., 2010 Kominsky et al., 2010 ). The extracellular accumulation of adenosine leads to the accumulation of cullin 1 and the inhibition of NF-‍κB activity ( Khoury et al., 2007 Khoury et al., 2007 ). The hypoxia inducible factor-1 (HIF-1) protein is one of the main regulators of oxygen homeostasis. It coordinates the metabolism of adenine nucleotides and regulates adenosine signaling. Low concentrations of MLN4924 promote HIF signal transduction and inhibit NF-‍κB signal transduction ( Curtis et al., 2015a Curtis et al., 2015a ). The inhibition of cullin 2 neddylation was demonstrated to regulate HIF to alleviate mucosal inflammation ( Curtis et al., 2015b Curtis et al., 2015b ). Other research findings indicate that the inhibition of NF-‍κB activation related to intestinal symbiotic bacteria depends on cullin de-neddylation ( Neish et al., 2000 Neish et al., 2000 ). For instance, it was proved that symbiotic bacteria can affect the esterification state of cullin 1 by producing reactive oxygen species (ROS), and that when co-cultured with commensal bacteria, epithelial cells would react with the increase of ROS, leading to transient and reversible dendriticization of cullin 1 and the inhibition of NF-‍‍κB signaling pathway ( Kumar et al., 2007 Kumar et al., 2007 ). Neddylation in IBD is described in Fig. 1 Fig. 1 . 3 Sumoylation 1 Sumoylation is a reversible and dynamic PTM, which involves the formation of an isopeptide bond between the carboxy-terminal glycine (Gly)‍-residue of small ubiquitin-like modifier protein (SUMO) and the lysine (Lys)‍-side chain of the receptor protein. As a crucial molecule, SUMO participates in the regulation of DNA damage repair, immune response, and cell apoptosis ( Han et al., 2018 Han et al., 2018 ). Three SUMO paralogs (SUMO1, SUMO2, and SUMO3) exist in mammals ( Hay, 2005 Hay, 2005 ). In the sumoylation-binding process, SUMO is activated via the E1 enzyme (a heterodimer of SUMO-activating enzyme subunit 1 (SAE1) and SAE2), and then transferred to the E2-conjugating enzyme, UBC9, and finally activated by E3 ligase (protein inhibitor of activated signal transducer and activator of transcription (STAT) (PIAS)) ‍during its transfer to the substrate. Once SUMO is coupled to the substrate, it can be uncoupled by different SUMO isopeptidases called whistle protein-specific proteases (SENP1–3 and SENP5–7), thereby regulating the level of protein sumoylation ( Flotho and Melchior, 2013 Flotho and Melchior, 2013 ). The uncoupling of SUMO from the protein substrate of SUMO acylation is also a key step towards maintaining the balance of SUMO signal during the SUMO acylation process, which is called de-sumoylation ( Verma et al., 2018 Verma et al., 2018 ). The imbalance between sumoylation and de-sumoylation is related to the occurrence and development of various diseases ( Yang et al., 2017 Yang et al., 2017 ). Studies have shown that modulators related to the inflammatory cascade are affected by changes in the sumoylation function ( Ribet et al., 2010 Ribet et al., 2010 ; Flotho and Melchior, 2013 Flotho and Melchior, 2013 ; Verma et al., 2015 Verma et al., 2015 ). The molecules involved include RelA, which is a component of the main regulatory NF-‍κB and its repressor (IκB-‍α) ( Mabb and Miyamoto, 2007 Mabb and Miyamoto, 2007 ). Mitogen-activated protein kinase (MAPK) signaling is another important signaling pathway for amino acids and intestinal inflammation ( Coskun et al., 2011 Coskun et al., 2011 ). MAPK signals in mammals are mainly composed of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK as pathway mediators, which play an important role in cell growth, proliferation, differentiation, and inflammation ( Docena et al., 2010 Docena et al., 2010 ; Raza et al., 2017 Raza et al., 2017 ; You et al., 2017 You et al., 2017 ). The metabolism of cellular ROS is stably regulated by various proteins involved in the redox mechanism of phosphoinositide 3-kinase (PI3K)/AKT signaling. AKT activates the IκB kinase (IKK), thereby stimulating p38 MAPK in IL-1β receptor signal transduction ( Tokuhira et al., 2015 Tokuhira et al., 2015 ). Yavvari et al. (2019) Yavvari et al. (2019) demonstrated that SUMO3 ligase and the encoding plasmid DNA to target sumoylation through nanogel oral delivery of PIAS inhibited NF-‍κB-mediated inflammatory signals to achieve the effect of treating IBD. Mustfa et al. (2017) Mustfa et al. (2017) reported that the sumoylation of intestinal epithelial cells (IECs) can inhibit the activity of major regulatory factors including serine-threonine kinase AKT1, thereby reducing the severity of IBD. Evidence showed that SUMO participates in the regulation of host proteins of innate immunity, thus promoting the regulation process of interferon production during viral infection ( Saul et al., 2015 Saul et al., 2015 ; Xia et al., 2015 Xia et al., 2015 ; Hannoun et al., 2016 Hannoun et al., 2016 ; Liu et al., 2016 Liu et al., 2016 ). Other study has also indicated that increased levels of nitric oxide (NO) after pathogen recognition can promote the S-nitrosylation of SUMO-conjugating enzyme 1 (SCE1) in cysteine 139 (Cys139), thereby inhibiting the activity of SCE1 and UBC9. The S-nitrosylation of SCE1 on Cys139 enables NO to drive immune activation by alleviating the inhibitory effect mediated by SUMO1/2 and reducing pathogen susceptibility ( Skelly et al., 2019 Skelly et al., 2019 ). The retinoic acid receptor (RAR)-related orphan receptor-‍γt (ROR-‍γt) mediating IL-17 transcription dysregulation is the core of the pathogenesis of several inflammatory diseases, while the molecular mechanism that controls the activity of ROR-‍γt transcription factors in IL-17 regulation has not been fully clarified ( Honda and Littman, 2016 Honda and Littman, 2016 ; Veldhoen, 2017 Veldhoen, 2017 ). It has been documented that the SUMO conjugation enzyme UBC9 interacts with the conserved GKAE motif in ROR-γt to induce the sumoylation of ROR-γt and inhibit IL-17 expression. The sumoylation of ROR-γt helps histone deacetylase 2 (HDAC2) bind to the IL-17 promoter and consequently inhibits its transcription to relieve colitis ( Singh et al., 2018 Singh et al., 2018 ). Sumoylation is essential for maintaining the dynamic balance of intestinal flora, barrier integrity, and inflammation control during bacterial invasion ( Demarque et al., 2011 Demarque et al., 2011 ; Fritah et al., 2014 Fritah et al., 2014 ). The intestinal mucosa of patients with CD allows the abnormal attachment of invasive Escherichia coli (AIEC), which adheres to and invades IECs, survives in macrophages, and induces inflammation. According to Dalmasso et al. (2019) Dalmasso et al. (2019) , infection with the AIEC LF82 reference strain significantly reduced the level of SUMO-coupled protein in human intestinal epithelial T84 cells and manipulated host sumoylation to prevent the autophagy reaction from replicating in cells. Furthermore, Singh et al. (2018) Singh et al. (2018) showed that T helper 17 (Th17) cells expressing sumoylation-deficient ROR-‍γt are highly vulnerable to E. coli after being transferred to Rag1 -/- mice. Shigella flexneri , a pathogen causing bacillary dysentery, invades the human colon epithelium and causes massive inflammation and destruction ( Perdomo et al., 1994 Perdomo et al., 1994 ). Research by Fritah et al. (2014) Fritah et al. (2014) indicated that the SUMO pathway is an important part of the host's innate protection, as it reduces the invasion of the intestinal epithelium by shigellosis and the pro-inflammatory transcriptional response of the intestine through sumoylation. Sumoylation in IBD is described in Fig. 2 Fig. 2 . 4 Glycosylation 1 Glycosylation comprises the transfer of sugar to protein under the action of glycosyltransferase and the formation of glycosidic bonds with amino acid residues on the protein. Proteins undergo glycosylation to form glycoproteins. Glycosylation, that can modulate the physiological properties of small molecules and peptides, has specific effects such as improved metabolic stability, membrane permeability, biodistribution, and ligand–target interactions ( Wadzinski et al., 2018 Wadzinski et al., 2018 ). According to the type of glycoside chain, the common types of protein glycosylation are O-glycosidic bond and N-glycosidic bond. In O-glycosylation, the hydroxyl groups of serine, threonine, hydroxylysine, and hydroxyproline are used as the connection points to form an O-glycosidic bond, which is one of the most abundant and diverse types of protein PTM. O-glycans regulate the structure, stability, and function of proteins, and play a universal and highly specific role in most biological processes ( Joshi et al., 2018 Joshi et al., 2018 ). In the case of N-glycosylation, the amide group of asparagine, the α‍-amino group of the N-terminal amino acid, and the ω‍-amino group of lysine or arginine are used as the connection points to form an N-glycosidic bond. It was reported that more than 50% of all eukaryotic proteins are N-glycosylated. Such bonds also play an important role in a series of biological events, such as protein folding and quality control ( Tamir and Eichler, 2017 Tamir and Eichler, 2017 ). Glycans regulate cellular and humoral immune responses, including the assembly of major histocompatibility complex (MHC) antigens and human leukocyte antigen (HLA), the regulation of immune receptor clusters, endocytosis, receptor signaling, and immunoglobulin function ( Demetriou et al., 2001 Demetriou et al., 2001 ; Grigorian et al., 2009 Grigorian et al., 2009 , 2012 2012 ; Ryan and Cobb, 2012 Ryan and Cobb, 2012 ; Johnson et al., 2013 Johnson et al., 2013 ; Wolfert and Boons, 2013 Wolfert and Boons, 2013 ; Pereira et al., 2018 Pereira et al., 2018 ). They also control the development, activation, signal transduction, differentiation, and proliferation of T cells and the selection of thymocytes. The participation of N-glycosylation in the pathogenesis of inflammatory diseases has been reported to be an early event ( Mkhikian et al., 2011 Mkhikian et al., 2011 ). The intestinal T cells of IBD patients and healthy people express different glycoprotein profiles, essentially showing that IBD patients have low expression of N-glycans and high expression of core fucosylation. These changes increase T cell-mediated intestinal immune response ( Dias et al., 2014 Dias et al., 2014 ; Fujii et al., 2016 Fujii et al., 2016 ; Dias et al., 2018 Dias et al., 2018 ). Grigorian et al. (2012) Grigorian et al. (2012) reported that IL-2 and IL-7 alter the expression of Golgi branching enzyme, which controls N-glycosylation in T cells and regulates the inflammatory environment. T cells in mice expressing human fucosyltransferase 2 (FUT2) have genetic defects and abnormal N-glycosylation levels, which can promote the development of colitis by regulating T cells ( Brown et al., 2004 Brown et al., 2004 ). As a key glycosyl hydrolase, α‍-mannosidase II (α‍-MII) plays a pivotal role in the maturation of N-glycans. IECs establish a first-line intestinal barrier to regulate immunity, and selectively express α‍-MII. In the absence of the mannosidase α class 2A member 1 ( MAN2A1 ) gene encoding α-MII, the maturation of N-glycans in IECs is inhibited, the sensitivity to dextran sulfate (DSS)‍-induced colitis is reduced, and neutrophil infiltration in the colonic mucosa is attenuated by the downregulated expression level of neutrophil chemotactic factor ( Suzuki et al., 2018 Suzuki et al., 2018 ). Similar to phosphorylation, glycosylation has been shown to play a key role in regulating the balance between the soluble and filamentous insoluble state of keratin. Keratin 18 (K18) glycosylation can protect IECs from damage ( Srikanth et al., 2010 Srikanth et al., 2010 ). As formerly stated, the pathogenesis of IBD involves many factors, including host genetics, immune disorders, and changes in the intestinal flora ( Sugihara et al., 2019 Sugihara et al., 2019 ). Abnormal glycosylation significantly changes the function of key proteins in the intestinal niche, and glycosylation is very important for fine-tuning intestinal processes to ensure homeostasis. A disruption of this homeostasis process potentially leads to IBD ( Hanić et al., 2019 Hanić et al., 2019 ). Emerging evidence suggests that IBD is associated with the increased expression of truncated O-glycans and changes in the structure of terminal glycans. Other factors like IBD gene, incorrect positioning of glycosyltransferase, altered expression of glycosyltransferase and glycosidase, as well as malnutrition lead to changes in glyc‍ogen ( Sommer et al., 2014 Sommer et al., 2014 ). These glycan changes destroy the mucus layer, glycan–lectin interaction, host–microbe interaction, and mucosal immunity, and ultimately lead to the occurrence of IBD. Epithelin is particularly important in regulating the intestinal flora through providing bacterial ligands and nutrients, and ultimately determining the spatial organization of gut microbiome ( Kudelka et al., 2020 Kudelka et al., 2020 ). The glycan sugar chains that cover the cell surface are also called glycocalyxes. These mediate the interaction between intestinal cells and the microbiota, including influencing intestinal homeostasis and mucosal immune response ( Verhelst et al., 2020 Verhelst et al., 2020 ). Fluctuations in the glycocalyx or insufficient dietary glycan content may lead to malnutrition, and in turn lead to IBD and possible colon cancer ( Hibberd et al., 2017 Hibberd et al., 2017 ). The study has also established that individuals lacking FUT2 have altered gut microbial composition and increased sensitivity to infection and inflammation ( Rausch et al., 2011 Rausch et al., 2011 ). Changes in mucin glycosylation increase the sensitivity of core 1- or core 3-derived O-glycans to colitis and raise the permeability of the intestinal epithelium, leading to bacterial infiltration and pathogen growth ( Sommer et al., 2014 Sommer et al., 2014 ). Moreover, it has been reported that symbiotic bacteria (such as Bacteroides) can induce epithelial fucosylation ( Goto et al., 2014 Goto et al., 2014 ). The fragment crystallizable (Fc)‍-glycosylation of immunoglobulin G (IgG) affects its effector function, and the galactosylation level of IgG in UC or CD patients is lower than that of healthy individuals ( Šimurina et al., 2018 Šimurina et al., 2018 ). The decreased glycosylation observed in the intestinal mucus of patients with IBD indicates that the lack of galactosylation of IgG on the inner mucus layer may lead to increased contact between bacteria and the epithelium, triggering inflammation ( Theodoratou et al., 2014 Theodoratou et al., 2014 ). Galactosylation in IBD is described in Fig. 3 Fig. 3 . 5 Acetylation 1 Reversible protein acetylation is the main regulatory mechanism that controls protein function. The first biologically functional protein acetylation to be studied was the acetylation of histones ( Baeza et al., 2016 Baeza et al., 2016 ). In the past 15 years, an increasing number of studies have shown that protein acetylation-related enzymes, including histone acetyltransferases (HATs), HDACs, and acetyllysine-binding proteins, participate in many cell functions other than transcription regulation ( Verdin and Ott, 2015 Verdin and Ott, 2015 ). Evidence showed that histone acetylation is related to the immune pathway ( Shakespear et al., 2011 Shakespear et al., 2011 ), and epigenetic regulators of histone modification can regulate the gene-specific expression of T cell differentiation during inflammation ( Foster and Medzhitov, 2009 Foster and Medzhitov, 2009 ; Wei et al., 2009 Wei et al., 2009 ; Rodriguez et al., 2015 Rodriguez et al., 2015 ). IL-17A produced by Th17 cells plays a role as a pro-inflammatory cytokine in the development of IBD. In colon tissues lacking Mof (males absent on the first; responsible for the acetylation of histone H4 at lysine 16 (H4K16)), a series of key genes related to Th17 genes (including IL-17A , IL-22 , ROR-γt , ROR-α , STAT3 , transforming growth factor-‍β1 ( TGF-‍β1 ), and IL-6 ) were significantly downregulated and the NF-κB signaling pathway was inhibited, thereby alleviating DSS-induced colitis in mice ( Yang et al., 2018 Yang et al., 2018 ). IL1-β is a pro-inflammatory cytokine that can act as a mediator of inflammatory cell infiltration and mucosal barrier destruction in intestinal inflammation ( Weber et al., 2010 Weber et al., 2010 ). Zhong et al. (2018) Zhong et al. (2018) found that neonates with colitis expressed high levels of norepinephrine and epinephrine, which promoted histone acetylation at the IL-1β gene promoter, leading to abnormally increased IL-1β expression levels. TGF-‍β1, as an immunosuppressive cytokine, can transmit negative signals in many immune cells ( Letterio and Roberts, 1998 Letterio and Roberts, 1998 ). Studies have shown reduced activity of TGF-‍‍β1 in IBD patients, which was related to the increase in the level of recombinant mothers against decapentaplegic homolog 7 (SMAD7). SMAD7 is an intracellular protein that binds to the TGF-‍β1 receptor and inhibits the signal transduction induced by TGF-‍β1 ( Monteleone et al., 2001 Monteleone et al., 2001 ). In the mucosa of IBD patients, SMAD7 is highly acetylated on lysine residues, and ubiquitin-mediated protein degradation is inhibited ( Monteleone et al., 2004 Monteleone et al., 2004 ). SMAD7 is also regulated by P300 (a protein with inherent acetyltransferase activity) ( Monteleone et al., 2005 Monteleone et al., 2005 ). Research by Sedda et al. (2018) Sedda et al. (2018) showed that SMAD7 and sirtuin 1 (SIRT1) have a negative regulatory effect on each other and amplify inflammatory signals in the intestine. SIRT1 is a type III nicotinamide adenine dinucleotide positive (NAD + )‍-dependent deacetylase, which mainly participates in a variety of cell biological functions through the deacetylation of certain non-histone and histone proteins. The study has indicated that SIRT1 can inhibit inflammation and regulate immune cells ( He et al., 2017 He et al., 2017 ). It also promotes the proteosomal degradation of various intracellular proteins mediated by ubiquitin and triggers anti-inflammatory signals. The low expression of SIRT1 in IBD patients leads to persistent inflammation ( Caruso et al., 2014 Caruso et al., 2014 ). Research by Melhem et al. (2016) Melhem et al. (2016) proved that after DSS-induced colitis in rats, the expression of SIRT1 decreased and the degree of acetylation of heat shock factor protein 1 (HSF1) increased. According to reports, histone acetylation is related to the transcriptional activity of inflammatory cytokines ( Ventham et al., 2013 Ventham et al., 2013 ; Meng et al., 2016 Meng et al., 2016 ). HDAC2 inhibits the transcription of IL-6 and other inflammatory factors through histone deacetylation ( Zhang et al., 2015 Zhang et al., 2015 ). According to Yin et al. (2018) Yin et al. (2018) , matrix metalloproteinase (MMP) increases the expression of HDACs, which leads to the inhibition of histone H3/H4 acetylation and TLR-4 pathway-related signaling pathways, the decreased secretion of pro-inflammatory cytokines, and the increase of anti-inflammatory cytokines. Certain types of keratin in epithelial cells provide strength and integrity. The main keratins expressed by IECs are K8, K18, and K19. The solubility of keratin is regulated and its degradation is inhibited through acetylation. A large number of acetylation sites were reported in K8. Majumdar et al. (2012) Majumdar et al. (2012) found that mice lacking K8 were more likely to develop colitis. Dierckx et al. (2019) Dierckx et al. (2019) revealed that glycoprotein acetylation (GlycA) levels in patients with active IBD are significantly higher than those in healthy controls ( Dierckx et al., 2019 Dierckx et al., 2019 ). As a multifactorial chronic disease, IBD usually relates to changes in the composition and function of the intestinal flora. The elimination of pathogenic microbiota has been widely applied in the treatment of IBD ( Grimm and Riedel, 2016 Grimm and Riedel, 2016 ). Studies have shown that Lactobacillus plantarum (LP) can act as a probiotic to enhance the intestinal epithelial barrier ( Qin et al., 2009 Qin et al., 2009 ; Liu et al., 2010 Liu et al., 2010 , 2011b 2011b ). LP can significantly reduce the damage of IECs caused by enteropathogenic E. coli (EPEC) ( Liu et al., 2011a Liu et al., 2011a ). Thermogenic bacteria usually produce butyrate through carbohydrate fermentation or amino acid degradation. Butyrate plays an important protective role in the intestinal homeostasis of adaptive and innate immunity. It was reported that butyrate can increase the acetylation of histones, thereby regulating the activation of Treg and reducing the activation of NF-‍κB ( Silva et al., 2018 Silva et al., 2018 ). Freundella prausnitzii produces butyrate and reduces Th17 differentiation by inhib‍iting the metabolism of HDAC3 and cellular-myelocytomatosis viral oncogene (c-Myc) in T cells to reduce colitis ( Zhang et al., 2019 Zhang et al., 2019 ). Acetylation in IBD is described in Fig. 4 Fig. 4 . In summary, the ultimate effects of PTMs are to change the structure and function of the substrate proteins. Proteins are widely expressed in mammalian tissues and receive various stimulation signals both in vivo and in vitro. Under normal circumstances, protein modification (glycosylation or acetylation) plays a central role in maintaining the correct transcription, translation, and function of proteins. Under special pathological stimuli, however, over- or undermodification can cause cells (immune cells, tissue cells, etc.) to have abnormal function, which in turn activates a series of signaling pathways. Although the several PTMs introduced in this review differ in the substrate-ubiquitin-like molecule binding process, and the directly activated target molecules are also different, their final outcomes during the occurrence of IBD are the destruction of the intestinal epithelial barrier, the changed permeability of IEC, the promotion of the infiltration of inflammatory factors and immune cells, and the induction of classic inflammatory signaling pathways, such as NF-‍κB. At the same time, the IEC barrier is weakened and the invasion of intestinal bacteria is intensified, leading to the imbalance of the microbial environment and the dominance of pathogenic bacteria, further aggravating the development of IBD. The relationships and differences between the roles of PTMs in the occurrence of IBD are listed in Table 1 Table 1 and Fig. 5 Fig. 5 . IBD: ‍inflammatory bowel disease; PTM: post-translational modification; NEDD8: neural precursor cell expressed developmentally downregulated protein 8; SUMO: small ubiquitin-like modifier protein; Mdm2: murine double microsome 2; PVHL: von Hippel-Lindau tumor suppressor protein; HuR: human antigen R; EGFR: epidermal growth factor receptor; ROR-‍γt: retinoic acid receptor (RAR)‍-related orphan receptor-‍γt; K18: keratin 18; IgG: immunoglobulin G; SMAD7: recombinant mothers against decapentaplegic homolog 7; HSF1: heat shock factor protein 1; ROS: reactive oxygen species; HIF-1: hypoxia inducible factor-1; NO: nitric oxide; NAE1: NEDD8-activating enzyme E1 subunit 1; UBA3: ubiquitin-like modifier activating enzyme 3; UBC: ubiquitin-conjugating enzyme; CRL: cullin-RING ligase; SAE: SUMO-activating enzyme; PIAS: protein inhibitor of activated signal transducer and activator of transcription; SENP: sentrin-specific protease; FUT2: fucosyltransferase 2; HAT: histone acetyltransferase; HDAC: histone deacetylase; mTOR: mammalian target of rapamycin; NF-‍κB: nuclear factor-κB; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; TLR-4: Toll-like receptor-4. PTM Modification molecule Substrates Stimulus signals Related enzymes Main effects Pathogenesis involved in IBD Neddylation NEDD8 Cullin 1–3, 4A, 4B, 5, 7, 9; Mdm2, PVHL, HuR, EGFR, p53 ROS, HIF-1 NAE1, UBA3, UBC12, CRL Prevents protein degradation; regulates protein conformational stability and positioning; regulates the activity of transcription factors; antagonizes ubiquitination mTOR and NF-‍κB signaling pathways; cascade reaction mediated by caspase 3 Sumoylation SUMO ROR-γt ROS, NO SAE1/SAE2, UBC9, PIAS, SENP DNA damage repair; immune response; apoptosis NF-κB, MAPKs, PI3K/AKT signaling pathway; maintaining the dynamic balance of intestinal flora and bacterial invasion Glycosylation O-Glycosidic bond, N-Glycosidic bond K18, IgG FUT2, α-MⅡ Mediates cellular and humoral immune response T cell-mediated intestinal immune response; regulating the homeostasis of intestinal flora Acetylation Acetyl SMAD7, HSF1, K8, K18, K19 Butyric acid HAT, HDAC Transcriptional regulation; regulates T cell differentiation gene expression NF-κB, TLR-4 signal pathway; inflammatory factor secretion 6 Conclusions 1 We can find that regardless of the kind of modification, once the protein structure and function change, the permeability of the intestinal epithelium will also be different. The homeostasis of the intestinal microenvironment is subsequently destroyed paving the way for invading bacteria, which, to an extent, also aggravates the infiltration of immune cells, and recruits various inflammatory factors. To a certain degree, we can infer that these protein modifications play a combined role in IBD. IBD is an intestinal disease that has been studied more frequently, and its mechanism has been explored from many aspects. There are different types of protein structures and functions that are widely implicated in the treatment of diseases. In the quest to find effective treatments for IBD, researchers have modified existing proteins and studied their therapeutic utilities. In addition to genetic engineering, one of the most researched areas in this regard is the change of the properties and biological characteristics of proteins through chemical modification. The pursuit of a more in-depth understanding of protein modifications in the immune system, microbial environment, and other components of the inflamed intestinal environment has become a new and promising direction for potential effective IBD therapies. References Ananthakrishnan AN , 2015 . Epidemiology and risk factors for IBD . Nat Rev Gastroenterol Hepatol , 12 ( 4 ): 205 - 217 . https://doi.org/10.1038/nrgastro.2015.34 https://doi.org/10.1038/nrgastro.2015.34 Epidemiology and risk factors for IBD Baeza J , Smallegan MJ , Denu JM , 2016 . Mechanisms and dynamics of protein acetylation in mitochondria . Trends Biochem Sci , 41 ( 3 ): 231 - 244 . https://doi.org/10.1016/j.tibs.2015.12.006 https://doi.org/10.1016/j.tibs.2015.12.006 Mechanisms and dynamics of protein acetylation in mitochondria Barbier-Torres L , Delgado TC , García-Rodríguez JL , et al. , 2015 . Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer . Oncotarget , 6 ( 4 ): 2509 - 2523 . https://doi.org/10.18632/oncotarget.3191 https://doi.org/10.18632/oncotarget.3191 Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer Baumgart DC , Carding SR , 2007 . Inflammatory bowel disease: cause and immunobiology . Lancet , 369 ( 9573 ): 1627 - 1640 . https://doi.org/10.1016/s0140-6736(07)60750-8 https://doi.org/10.1016/s0140-6736(07)60750-8 Inflammatory bowel disease: cause and immunobiology Brown SJ , Miller AM , Cowan PJ , et al. , 2004 . Altered immune system glycosylation causes colitis in α1,2-fucosyltransferase transgenic mice . Inflamm Bowel Dis , 10 ( 5 ): 546 - 556 . https://doi.org/10.1097/00054725-200409000-00008 https://doi.org/10.1097/00054725-200409000-00008 Altered immune system glycosylation causes colitis in α1,2-fucosyltransferase transgenic mice Caruso R , Marafini I , Franzè E , et al. , 2014 . Defective expression of SIRT1 contributes to sustain inflammatory pathways in the gut . Mucosal Immunol , 7 ( 6 ): 1467 - 1479 . https://doi.org/10.1038/mi.2014.35 https://doi.org/10.1038/mi.2014.35 Defective expression of SIRT1 contributes to sustain inflammatory pathways in the gut Colgan SP , Taylor CT , 2010 . Hypoxia: an alarm signal during intestinal inflammation . Nat Rev Gastroenterol Hepatol , 7 ( 5 ): 281 - 287 . https://doi.org/10.1038/nrgastro.2010.39 https://doi.org/10.1038/nrgastro.2010.39 Hypoxia: an alarm signal during intestinal inflammation Coskun M , Olsen J , Seidelin JB , et al. , 2011 . MAP kinases in inflammatory bowel disease . Clin Chim Acta , 412 ( 7-8 ): 513 - 520 . https://doi.org/10.1016/j.cca.2010.12.020 https://doi.org/10.1016/j.cca.2010.12.020 MAP kinases in inflammatory bowel disease Curtis VF , Ehrentraut SF , Colgan SP , 2015a . Actions of adenosine on cullin neddylation: implications for inflammatory responses . Comput Struct Biotechnol J , 13 : 273 - 276 . https://doi.org/10.1016/j.csbj.2014.10.002 https://doi.org/10.1016/j.csbj.2014.10.002 Actions of adenosine on cullin neddylation: implications for inflammatory responses Curtis VF , Ehrentraut SF , Campbell EL , et al. , 2015b . Stabilization of HIF through inhibition of Cullin-2 neddylation is protective in mucosal inflammatory responses . FASEB J , 29 ( 1 ): 208 - 215 . https://doi.org/10.1096/fj.14-259663 https://doi.org/10.1096/fj.14-259663 Stabilization of HIF through inhibition of Cullin-2 neddylation is protective in mucosal inflammatory responses Dalmasso G , Nguyen HTT , Faïs T , et al. , 2019 . Crohn’s disease-associated adherent-invasive Escherichia coli manipulate host autophagy by impairing SUMOylation . Cells , 8 ( 1 ): 35 . https://doi.org/10.3390/cells8010035 https://doi.org/10.3390/cells8010035 Crohn’s disease-associated adherent-invasive Escherichia coli manipulate host autophagy by impairing SUMOylation Demarque MD , Nacerddine K , Neyret-Kahn H , et al. , 2011 . Sumoylation by Ubc9 regulates the stem cell compartment and structure and function of the intestinal epithelium in mice . Gastroenterology , 140 ( 1 ): 286 - 296 . https://doi.org/10.1053/j.gastro.2010.10.002 https://doi.org/10.1053/j.gastro.2010.10.002 Sumoylation by Ubc9 regulates the stem cell compartment and structure and function of the intestinal epithelium in mice Demetriou M , Granovsky M , Quaggin S , et al. , 2001 . Negative regulation of T-cell activation and autoimmunity by Mgat5 N -glycosylation . Nature , 409 ( 6821 ): 733 - 739 . https://doi.org/10.1038/35055582 https://doi.org/10.1038/35055582 Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation Dias AM , Dourado J , Lago P , et al. , 2014 . Dysregulation of T cell receptor N -glycosylation: a molecular mechanism involved in ulcerative colitis . Hum Mol Genet , 23 ( 9 ): 2416 - 2427 . https://doi.org/10.1093/hmg/ddt632 https://doi.org/10.1093/hmg/ddt632 Dysregulation of T cell receptor N-glycosylation: a molecular mechanism involved in ulcerative colitis Dias AM , Correia A , Pereira MS , et al. , 2018 . Metabolic control of T cell immune response through glycans in inflammatory bowel disease . Proc Natl Acad Sci USA , 115 ( 20 ): E4651 - E4660 . https://doi.org/10.1073/pnas.1720409115 https://doi.org/10.1073/pnas.1720409115 Metabolic control of T cell immune response through glycans in inflammatory bowel disease Dierckx T , Verstockt B , Vermeire S , et al. , 2019 . GlycA, a nuclear magnetic resonance spectroscopy measure for protein glycosylation, is a viable biomarker for disease activity in IBD . J Crohns Colitis , 13 ( 3 ): 389 - 394 . https://doi.org/10.1093/ecco-jcc/jjy162 https://doi.org/10.1093/ecco-jcc/jjy162 GlycA, a nuclear magnetic resonance spectroscopy measure for protein glycosylation, is a viable biomarker for disease activity in IBD Docena G , Rovedatti L , Kruidenier L , et al. , 2010 . Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease . Clin Exp Immunol , 162 ( 1 ): 108 - 115 . https://doi.org/10.1111/j.1365-2249.2010.04203.x https://doi.org/10.1111/j.1365-2249.2010.04203.x Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease Ehrentraut SF , Colgan SP , 2012 . Implications of protein post-translational modifications in IBD . Inflamm Bowel Dis , 18 ( 7 ): 1378 - 1388 . https://doi.org/10.1002/ibd.22859 https://doi.org/10.1002/ibd.22859 Implications of protein post-translational modifications in IBD Ehrentraut SF , Kominsky DJ , Glover LE , et al. , 2013 . Central role for endothelial human deneddylase-1/SENP8 in fine-tuning the vascular inflammatory response . J Immunol , 190 ( 1 ): 392 - 400 . https://doi.org/10.4049/jimmunol.1202041 https://doi.org/10.4049/jimmunol.1202041 Central role for endothelial human deneddylase-1/SENP8 in fine-tuning the vascular inflammatory response Ehrentraut SF , Curtis VF , Wang RX , et al. , 2016 . Perturbation of neddylation-dependent NF-‍‍κB responses in the intestinal epithelium drives apoptosis and inhibits resolution of mucosal inflammation. Mol Biol Cell , 27 ( 23 ) :3687 -3694 .https://doi.org/10.1091/mbc.E16-05-027 .https://doi.org/10.1091/mbc.E16-05-027 3 Perturbation of neddylation-dependent NF-‍‍κB responses in the intestinal epithelium drives apoptosis and inhibits resolution of mucosal inflammation. Mol Biol Cell Embade N , Fernández-Ramos D , Varela-Rey M , et al. , 2012 . Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation . Hepatology , 55 ( 4 ): 1237 - 1248 . https://doi.org/10.1002/hep.24795 https://doi.org/10.1002/hep.24795 Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation Enchev RI , Schulman BA , Peter M , 2015 . Protein neddylation: beyond cullin-RING ligases . Nat Rev Mol Cell Biol , 16 ( 1 ): 30 - 44 . https://doi.org/10.1038/nrm3919 https://doi.org/10.1038/nrm3919 Protein neddylation: beyond cullin-RING ligases Flotho A , Melchior F , 2013 . Sumoylation: a regulatory protein modification in health and disease . Annu Rev Biochem , 82 : 357 - 385 . https://doi.org/10.1146/annurev-biochem-061909-093311 https://doi.org/10.1146/annurev-biochem-061909-093311 Sumoylation: a regulatory protein modification in health and disease Foster SL , Medzhitov R , 2009 . Gene-specific control of the TLR-induced inflammatory response . Clin Immunol , 130 ( 1 ): 7 - 15 . https://doi.org/10.1016/j.clim.2008.08.015 https://doi.org/10.1016/j.clim.2008.08.015 Gene-specific control of the TLR-induced inflammatory response Fritah S , Lhocine N , Golebiowski F , et al. , 2014 . Sumoylation controls host anti-bacterial response to the gut invasive pathogen Shigella flexneri . EMBO Rep , 15 ( 9 ): 965 - 972 . https://doi.org/10.15252/embr.201338386 https://doi.org/10.15252/embr.201338386 Sumoylation controls host anti-bacterial response to the gut invasive pathogen Shigella flexneri Fujii H , Shinzaki S , Iijima H , et al. , 2016 . Core fucosylation on T cells, required for activation of T-cell receptor signaling and induction of colitis in mice, is increased in patients with inflammatory bowel disease . Gastroenterology , 150 ( 7 ): 1620 - 1632 . https://doi.org/10.1053/j.gastro.2016.03.002 https://doi.org/10.1053/j.gastro.2016.03.002 Core fucosylation on T cells, required for activation of T-cell receptor signaling and induction of colitis in mice, is increased in patients with inflammatory bowel disease Fujimoto K , Kinoshita M , Tanaka H , et al. , 2017 . Regulation of intestinal homeostasis by the ulcerative colitis-associated gene RNF186 . Mucosal Immunol , 10 ( 2 ): 446 - 459 . https://doi.org/10.1038/mi.2016.58 https://doi.org/10.1038/mi.2016.58 Regulation of intestinal homeostasis by the ulcerative colitis-associated gene RNF186 Glorian V , Allègre J , Berthelet J , et al. , 2017 . DNA damage and S phase-dependent E2F1 stabilization requires the cIAP1 E3-ubiquitin ligase and is associated with K63-poly-ubiquitination on lysine 161/164 residues . Cell Death Dis , 8 ( 5 ): e2816 . https://doi.org/10.1038/cddis.2017.222 https://doi.org/10.1038/cddis.2017.222 DNA damage and S phase-dependent E2F1 stabilization requires the cIAP1 E3-ubiquitin ligase and is associated with K63-poly-ubiquitination on lysine 161/164 residues Godbersen JC , Humphries LA , Danilova OV , et al. , 2014 . The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-‍κB activation and induces apoptosis in chronic lymphocytic leukemia B cells. Clin Cancer Res , 20 ( 6 ): 1576 - 1589 . https://doi.org/10.1158/1078-0432.Ccr-13-0987 https://doi.org/10.1158/1078-0432.Ccr-13-0987 The Nedd8-activating enzyme inhibitor MLN4924 thwarts Goto Y , Obata T , Kunisawa J , et al. , 2014 . Innate lymphoid cells regulate intestinal epithelial cell glycosylation . Science , 345 ( 6202 ): 1254009 . https://doi.org/10.1126/science.1254009 https://doi.org/10.1126/science.1254009 Innate lymphoid cells regulate intestinal epithelial cell glycosylation Grigorian A , Torossian S , Demetriou M , 2009 . T-cell growth, cell surface organization, and the galectin-glycoprotein lattice . Immunol Rev , 230 ( 1 ): 232 - 246 . https://doi.org/10.1111/j.1600-065X.2009.00796.x https://doi.org/10.1111/j.1600-065X.2009.00796.x T-cell growth, cell surface organization, and the galectin-glycoprotein lattice Grigorian A , Mkhikian H , Demetriou M , 2012 . Interleukin-2, interleukin-7, T cell-mediated autoimmunity, and N-glycosylation . Ann N Y Acad Sci , 1253 ( 1 ): 49 - 57 . https://doi.org/10.1111/j.1749-6632.2011.06391.x https://doi.org/10.1111/j.1749-6632.2011.06391.x Interleukin-2, interleukin-7, T cell-mediated autoimmunity, and N-glycosylation Grimm V , Riedel CU , 2016 . Manipulation of the microbiota using probiotics . In: Schwiertz A (Ed.), Microbiota of the Human Body: Implications in Health and Disease . Springer , Cham , p. 109 - 117 . https://doi.org/10.1007/978-3-319-31248-4_8 https://doi.org/10.1007/978-3-319-31248-4_8 Manipulation of the microbiota using probiotics Grootjans J , Kaser A , Kaufman RJ , et al. , 2016 . The unfolded protein response in immunity and inflammation . Nat Rev Immunol , 16 ( 8 ): 469 - 484 . https://doi.org/10.1038/nri.2016.62 https://doi.org/10.1038/nri.2016.62 The unfolded protein response in immunity and inflammation Haglund K , Dikic I , 2005 . Ubiquitylation and cell signaling . EMBO J , 24 ( 19 ): 3353 - 3359 . https://doi.org/10.1038/sj.emboj.7600808 https://doi.org/10.1038/sj.emboj.7600808 Ubiquitylation and cell signaling Han K , Wang QY , Cao HL , et al. , 2016 . The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia . Oncotarget , 7 ( 17 ): 23812 - 23824 . https://doi.org/10.18632/oncotarget.8068 https://doi.org/10.18632/oncotarget.8068 The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia Han ZJ , Feng YH , Gu BH , et al. , 2018 . The post-translational modification, SUMOylation, and cancer (Review) . Int J Oncol , 52 ( 4 ): 1081 - 1094 . https://doi.org/10.3892/ijo.2018.4280 https://doi.org/10.3892/ijo.2018.4280 The post-translational modification, SUMOylation, and cancer (Review) Hanić M , Trbojević-Akmačić I , Lauc G , 2019 . Inflammatory bowel disease—glycomics perspective . Biochim Biophys Acta Gen Subj , 1863 ( 10 ): 1595 - 1601 . https://doi.org/10.1016/j.bbagen.2019.07.001 https://doi.org/10.1016/j.bbagen.2019.07.001 Inflammatory bowel disease—glycomics perspective Hannoun Z , Maarifi G , Chelbi-Alix MK , 2016 . The implication of SUMO in intrinsic and innate immunity . Cytokine Growth Factor Rev , 29 : 3 - 16 . https://doi.org/10.1016/j.cytogfr.2016.04.003 https://doi.org/10.1016/j.cytogfr.2016.04.003 The implication of SUMO in intrinsic and innate immunity Hay RT , 2005 . SUMO: a history of modification . Mol Cell , 18 ( 1 ): 1 - 12 . https://doi.org/10.1016/j.molcel.2005.03.012 https://doi.org/10.1016/j.molcel.2005.03.012 SUMO: a history of modification He ML , Tan B , Vasan K , et al. , 2017 . SIRT1 and AMPK pathways are essential for the proliferation and survival of primary effusion lymphoma cells . J Pathol , 242 ( 3 ): 309 - 321 . https://doi.org/10.1002/path.4905 https://doi.org/10.1002/path.4905 SIRT1 and AMPK pathways are essential for the proliferation and survival of primary effusion lymphoma cells Hibberd AA , Lyra A , Ouwehand AC , et al. , 2017 . Intestinal microbiota is altered in patients with colon cancer and modified by probiotic intervention . BMJ Open Gastroenterol , 4 ( 1 ): e000145 . https://doi.org/10.1136/bmjgast-2017-000145 https://doi.org/10.1136/bmjgast-2017-000145 Intestinal microbiota is altered in patients with colon cancer and modified by probiotic intervention Honda K , Littman DR , 2016 . The microbiota in adaptive immune homeostasis and disease . Nature , 535 ( 7610 ): 75 - 84 . https://doi.org/10.1038/nature18848 https://doi.org/10.1038/nature18848 The microbiota in adaptive immune homeostasis and disease Hori T , Osaka F , Chiba T , et al. , 1999 . Covalent modification of all members of human cullin family proteins by NEDD8 . Oncogene , 18 ( 48 ): 6829 - 6834 . https://doi.org/10.1038/sj.onc.1203093 https://doi.org/10.1038/sj.onc.1203093 Covalent modification of all members of human cullin family proteins by NEDD8 Johnson JL , Jones MB , Ryan SO , et al. , 2013 . The regulatory power of glycans and their binding partners in immunity . Trends Immunol , 34 ( 6 ): 290 - 298 . https://doi.org/10.1016/j.it.2013.01.006 https://doi.org/10.1016/j.it.2013.01.006 The regulatory power of glycans and their binding partners in immunity Joshi HJ , Narimatsu Y , Schjoldager KT , et al. , 2018 . SnapShot: O-glycosylation pathways across kingdoms . Cell , 172 ( 3 ): 632 - 632.e2 . https://doi.org/10.1016/j.cell.2018.01.016 https://doi.org/10.1016/j.cell.2018.01.016 SnapShot: O-glycosylation pathways across kingdoms Kamitani T , Kito K , Nguyen HP , et al. , 1997 . Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein . J Biol Chem , 272 ( 45 ): 28557 - 28562 . https://doi.org/10.1074/jbc.272.45.28557 https://doi.org/10.1074/jbc.272.45.28557 Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein Khoury J , Ibla JC , Neish AS , et al. , 2007 . Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation . J Clin Invest , 117 ( 3 ): 703 - 711 . https://doi.org/10.1172/jci30049 https://doi.org/10.1172/jci30049 Antiinflammatory adaptation to hypoxia through adenosine-mediated cullin-1 deneddylation Kim DY , Kwon E , Hartley PD , et al. , 2013 . CBFβ stabilizes HIV Vif to counteract APOBEC3 at the expense of RUNX1 target gene expression . Mol Cell , 49 ( 4 ): 632 - 644 . https://doi.org/10.1016/j.molcel.2012.12.012 https://doi.org/10.1016/j.molcel.2012.12.012 CBFβ stabilizes HIV Vif to counteract APOBEC3 at the expense of RUNX1 target gene expression Koch S , Nusrat A , 2012 . The life and death of epithelia during inflammation: lessons learned from the gut . Annu Rev Pathol Mech Dis , 7 : 35 - 60 . https://doi.org/10.1146/annurev-pathol-011811-120905 https://doi.org/10.1146/annurev-pathol-011811-120905 The life and death of epithelia during inflammation: lessons learned from the gut Kominsky DJ , Campbell EL , Colgan SP , 2010 . Metabolic shifts in immunity and inflammation . J Immunol , 184 ( 8 ): 4062 - 4068 . https://doi.org/10.4049/jimmunol.0903002 https://doi.org/10.4049/jimmunol.0903002 Metabolic shifts in immunity and inflammation Kudelka MR , Stowell SR , Cummings RD , et al. , 2020 . Intestinal epithelial glycosylation in homeostasis and gut microbiota interactions in IBD . Nat Rev Gastroenterol Hepatol , 17 ( 10 ): 597 - 617 . https://doi.org/10.1038/s41575-020-0331-7 https://doi.org/10.1038/s41575-020-0331-7 Intestinal epithelial glycosylation in homeostasis and gut microbiota interactions in IBD Kumar A , Wu HX , Collier-Hyams LS , et al. , 2007 . Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species . EMBO J , 26 ( 21 ): 4457 - 4466 . https://doi.org/10.1038/sj.emboj.7601867 https://doi.org/10.1038/sj.emboj.7601867 Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species Letterio JJ , Roberts AB , 1998 . Regulation of immune responses by TGF-‍β . Annu Rev Immunol , 16 : 137 - 161 . https://doi.org/10.1146/annurev.immunol.16.1.137 https://doi.org/10.1146/annurev.immunol.16.1.137 Regulation of immune responses by TGF-‍β Liu J , Qian C , Cao XT , 2016 . Post-translational modification control of innate immunity . Immunity , 45 ( 1 ): 15 - 30 . https://doi.org/10.1016/j.immuni.2016.06.020 https://doi.org/10.1016/j.immuni.2016.06.020 Post-translational modification control of innate immunity Liu ZH , Shen TY , Zhang P , et al. , 2010 . Protective effects of Lactobacillus plantarum against epithelial barrier dysfunction of human colon cell line NCM460 . World J Gastroenterol , 16 ( 45 ): 5759 - 5765 . https://doi.org/10.3748/wjg.v16.i45.5759 https://doi.org/10.3748/wjg.v16.i45.5759 Protective effects of Lactobacillus plantarum against epithelial barrier dysfunction of human colon cell line NCM460 Liu ZH , Shen TY , Zhang P , et al. , 2011a . Lactobacillus plantarum surface layer adhesive protein protects intestinal epithelial cells against tight junction injury induced by enteropathogenic Escherichia coli . Mol Biol Rep , 38 ( 5 ): 3471 - 3480 . https://doi.org/10.1007/s11033-010-0457-8 https://doi.org/10.1007/s11033-010-0457-8 Lactobacillus plantarum surface layer adhesive protein protects intestinal epithelial cells against tight junction injury induced by enteropathogenic Escherichia coli Liu ZH , Zhang P , Ma YL , et al. , 2011b . Lactobacillus plantarum prevents the development of colitis in IL-10-deficient mouse by reducing the intestinal permeability . Mol Biol Rep , 38 ( 2 ): 1353 - 1361 . https://doi.org/10.1007/s11033-010-0237-5 https://doi.org/10.1007/s11033-010-0237-5 Lactobacillus plantarum prevents the development of colitis in IL-10-deficient mouse by reducing the intestinal permeability Mabb AM , Miyamoto S , 2007 . SUMO and NF-κB ties . Cell Mol Life Sci , 64 ( 15 ): 1979 - 1996 . https://doi.org/10.1007/s00018-007-7005-2 https://doi.org/10.1007/s00018-007-7005-2 SUMO and NF-κB ties Majumdar D , Tiernan JP , Lobo AJ , et al. , 2012 . Keratins in colorectal epithelial function and disease . Int J Exp Pathol , 93 ( 5 ): 305 - 318 . https://doi.org/10.1111/j.1365-2613.2012.00830.x https://doi.org/10.1111/j.1365-2613.2012.00830.x Keratins in colorectal epithelial function and disease Melhem H , Hansmannel F , Bressenot A , et al. , 2016 . Methyl-deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress . Gut , 65 ( 4 ): 595 - 606 . https://doi.org/10.1136/gutjnl-2014-307030 https://doi.org/10.1136/gutjnl-2014-307030 Methyl-deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress Meng J , Liu XG , Zhang P , et al. , 2016 . Rb selectively inhibits innate IFN-‍β production by enhancing deacetylation of IFN-β promoter through HDAC1 and HDAC8 . J Autoimmun , 73 : 42 - 53 . https://doi.org/10.1016/j.jaut.2016.05.012 https://doi.org/10.1016/j.jaut.2016.05.012 Rb selectively inhibits innate IFN-‍β production by enhancing deacetylation of IFN-β promoter through HDAC1 and HDAC8 Milhollen MA , Traore T , Adams-Duffy J , et al. , 2010 . MLN4924, a NEDD8-activating enzyme inhibitor , is active in diffuse large B-cell lymphoma models : rationale for treatment of NF-‍‍‍‍κB-dependent lymphoma. Blo o d, 116 ( 9 ):1515 -1523 .https://doi.org/10.1182/blood-2010-03-272 .https://doi.org/10.1182/blood-2010-03-272 567 MLN4924, a NEDD8-activating enzyme inhibitor Mitchell JP , Carmody RJ , 2018 . NF-‍κB and the transcriptional control of inflammation . Int Rev Cell Mol Biol , 335 : 41 - 84 . https://doi.org/10.1016/bs.ircmb.2017.07.007 https://doi.org/10.1016/bs.ircmb.2017.07.007 NF-‍κB and the transcriptional control of inflammation Mkhikian H , Grigorian A , Li CF , et al. , 2011 . Genetics and the environment converge to dysregulate N -glycosylation in multiple sclerosis . Nat Commun , 2 : 334 . https://doi.org/10.1038/ncomms1333 https://doi.org/10.1038/ncomms1333 Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis Monteleone G , Kumberova A , Croft NM , et al. , 2001 . Blocking Smad7 restores TGF-‍β1 signaling in chronic inflammatory bowel disease . J Clin Invest , 108 ( 4 ): 601 - 609 . https://doi.org/10.1172/jci12821 https://doi.org/10.1172/jci12821 Blocking Smad7 restores TGF-‍β1 signaling in chronic inflammatory bowel disease Monteleone G , Pallone F , MacDonald TT , 2004 . Smad7 in TGF-‍β‍-mediated negative regulation of gut inflammation . Trends Immunol , 25 ( 10 ): 513 - 517 . https://doi.org/10.1016/j.it.2004.07.008 https://doi.org/10.1016/j.it.2004.07.008 Smad7 in TGF-‍β‍-mediated negative regulation of gut inflammation Monteleone G , del Vecchio Blanco G , Monteleone I , et al. , 2005 . Post-transcriptional regulation of Smad7 in the gut of patients with inflammatory bowel disease . Gastroenterology , 129 ( 5 ): 1420 - 1429 . https://doi.org/10.1053/j.gastro.2005.09.005 https://doi.org/10.1053/j.gastro.2005.09.005 Post-transcriptional regulation of Smad7 in the gut of patients with inflammatory bowel disease Muniandy K , Gothai S , Badran KMH , et al. , 2018 . Suppression of proinflammatory cytokines and mediators in LPS-induced RAW 264.7 macrophages by stem extract of Alternanthera sessilis via the inhibition of the NF-‍‍‍κB pathway. J Immunol Res, 2018 :343068 4.https://doi.org/10.1155/2018/34306 4.https://doi.org/10.1155/2018/34306 84 Suppression of proinflammatory cytokines and mediators in LPS-induced RAW Mustfa SA , Singh M , Suhail A , et al. , 2017 . SUMOylation pathway alteration coupled with downregulation of SUMO E2 enzyme at mucosal epithelium modulates inflammation in inflammatory bowel disease . Open Biol , 7 ( 6 ): 170024 . https://doi.org/10.1098/rsob.170024 https://doi.org/10.1098/rsob.170024 SUMOylation pathway alteration coupled with downregulation of SUMO E2 enzyme at mucosal epithelium modulates inflammation in inflammatory bowel disease Nava P , Koch S , Laukoetter MG , et al. , 2010 . Interferon-‍γ regulates intestinal epithelial homeostasis through converging β‍-catenin signaling pathways . Immunity , 32 ( 3 ): 392 - 402 . https://doi.org/10.1016/j.immuni.2010.03.001 https://doi.org/10.1016/j.immuni.2010.03.001 Interferon-‍γ regulates intestinal epithelial homeostasis through converging β‍-catenin signaling pathways Neish AS , Gewirtz AT , Zeng H , et al. , 2000 . Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination . Science , 289 ( 5484 ): 1560 - 1563 . https://doi.org/10.1126/science.289.5484.1560 https://doi.org/10.1126/science.289.5484.1560 Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination Oved S , Mosesson Y , Zwang Y , et al. , 2006 . Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases . J Biol Chem , 281 ( 31 ): 21640 - 21651 . https://doi.org/10.1074/jbc.M513034200 https://doi.org/10.1074/jbc.M513034200 Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases Pan ZQ , Kentsis A , Dias DC , et al. , 2004 . Nedd8 on cullin: building an expressway to protein destruction . Oncogene , 23 ( 11 ): 1985 - 1997 . https://doi.org/10.1038/sj.onc.1207414 https://doi.org/10.1038/sj.onc.1207414 Nedd8 on cullin: building an expressway to protein destruction Perdomo OJ , Cavaillon JM , Huerre M , et al. , 1994 . Acute inflammation causes epithelial invasion and mucosal destruction in experimental shigellosis . J Exp Med , 180 ( 4 ): 1307 - 1319 . https://doi.org/10.1084/jem.180.4.1307 https://doi.org/10.1084/jem.180.4.1307 Acute inflammation causes epithelial invasion and mucosal destruction in experimental shigellosis Pereira MS , Alves I , Vicente M , et al. , 2018 . Glycans as key checkpoints of T cell activity and function . Front Immunol , 9 : 2754 . https://doi.org/10.3389/fimmu.2018.02754 https://doi.org/10.3389/fimmu.2018.02754 Glycans as key checkpoints of T cell activity and function Porter AG , Jänicke RU , 1999 . Emerging roles of caspase-3 in apoptosis . Cell Death Differ , 6 ( 2 ): 99 - 104 . https://doi.org/10.1038/sj.cdd.4400476 https://doi.org/10.1038/sj.cdd.4400476 Emerging roles of caspase-3 in apoptosis Qin HL , Zhang ZW , Hang XM , et al. , 2009 . L . plantarum prevents Enteroinvasive Escherichia coli -induced tight junction proteins changes in intestinal epithelial cells . BMC Microbiol , 9 : 63 . https://doi.org/10.1186/1471-2180-9-63 https://doi.org/10.1186/1471-2180-9-63 plantarum prevents Enteroinvasive Escherichia coli-induced tight junction proteins changes in intestinal epithelial cells Rabut G , Peter M , 2008 . Function and regulation of protein neddylation . EMBO Rep , 9 ( 10 ): 969 - 976 . https://doi.org/10.1038/embor.2008.183 https://doi.org/10.1038/embor.2008.183 Function and regulation of protein neddylation Rausch P , Rehman A , Künzel S , et al. , 2011 . Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 ( Secretor ) genotype . Proc Natl Acad Sci USA , 108 ( 47 ): 19030 - 19035 . https://doi.org/10.1073/pnas.1106408108 https://doi.org/10.1073/pnas.1106408108 Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype Raza A , Crothers JW , McGill MM , et al. , 2017 . Anti-inflammatory roles of p38α MAPK in macrophages are context dependent and require IL-10 . J Leukoc Biol , 102 ( 5 ): 1219 - 1227 . https://doi.org/10.1189/jlb.2AB0116-009RR https://doi.org/10.1189/jlb.2AB0116-009RR Anti-inflammatory roles of p38α MAPK in macrophages are context dependent and require IL-10 Ribet D , Hamon M , Gouin E , et al. , 2010 . Listeria monocytogenes impairs SUMOylation for efficient infection . Nature , 464 ( 7292 ): 1192 - 1195 . https://doi.org/10.1038/nature08963 https://doi.org/10.1038/nature08963 Listeria monocytogenes impairs SUMOylation for efficient infection Rodriguez RM , Lopez-Larrea C , Suarez-Alvarez B , 2015 . Epigenetic dynamics during CD4 + T cells lineage commitment . Int J Biochem Cell Biol , 67 : 75 - 85 . https://doi.org/10.1016/j.biocel.2015.04.020 https://doi.org/10.1016/j.biocel.2015.04.020 Epigenetic dynamics during CD4+ T cells lineage commitment Ryan SO , Cobb BA , 2012 . Roles for major histocompatibility complex glycosylation in immune function . Semin Immunopathol , 34 ( 3 ): 425 - 441 . https://doi.org/10.1007/s00281-012-0309-9 https://doi.org/10.1007/s00281-012-0309-9 Roles for major histocompatibility complex glycosylation in immune function Saul VV , Niedenthal R , Pich A , et al. , 2015 . SUMO modification of TBK1 at the adaptor-binding C-terminal coiled-coil domain contributes to its antiviral activity . Biochim Biophys Acta , 1853 ( 1 ): 136 - 143 . https://doi.org/10.1016/j.bbamcr.2014.10.008 https://doi.org/10.1016/j.bbamcr.2014.10.008 SUMO modification of TBK1 at the adaptor-binding C-terminal coiled-coil domain contributes to its antiviral activity Schreiner P , Neurath MF , Ng SC , et al. , 2019 . Mechanism-based treatment strategies for IBD: cytokines, cell adhesion molecules, JAK inhibitors, gut flora, and more . Inflamm Intest Dis , 4 ( 3 ): 79 - 96 . https://doi.org/10.1159/000500721 https://doi.org/10.1159/000500721 Mechanism-based treatment strategies for IBD: cytokines, cell adhesion molecules, JAK inhibitors, gut flora, and more Schwechheimer C , 2018 . NEDD8—its role in the regulation of Cullin-RING ligases . Curr Opin Plant Biol , 45 : 112 - 119 . https://doi.org/10.1016/j.pbi.2018.05.017 https://doi.org/10.1016/j.pbi.2018.05.017 NEDD8—its role in the regulation of Cullin-RING ligases Sedda S , Franzè E , Bevivino G , et al. , 2018 . Reciprocal regulation between Smad7 and Sirt1 in the gut . Front Immunol , 9 : 1854 . https://doi.org/10.3389/fimmu.2018.01854 https://doi.org/10.3389/fimmu.2018.01854 Reciprocal regulation between Smad7 and Sirt1 in the gut Shakespear MR , Halili MA , Irvine KM , et al. , 2011 . Histone deacetylases as regulators of inflammation and immunity . Trends Immunol , 32 ( 7 ): 335 - 343 . https://doi.org/10.1016/j.it.2011.04.001 https://doi.org/10.1016/j.it.2011.04.001 Histone deacetylases as regulators of inflammation and immunity Silva JPB , Navegantes-Lima KC , Oliveira ALB , et al. , 2018 . Protective mechanisms of butyrate on inflammatory bowel disease . Curr Pharm Des , 24 ( 35 ): 4154 - 4166 . https://doi.org/10.2174/1381612824666181001153605 https://doi.org/10.2174/1381612824666181001153605 Protective mechanisms of butyrate on inflammatory bowel disease Šimurina M , de Haan N , Vučković F , et al. , 2018 . Glycosylation of immunoglobulin G associates with clinical features of inflammatory bowel diseases . Gastroenterology , 154 ( 5 ): 1320 - 1333.e10 . https://doi.org/10.1053/j.gastro.2018.01.002 https://doi.org/10.1053/j.gastro.2018.01.002 Glycosylation of immunoglobulin G associates with clinical features of inflammatory bowel diseases Singh AK , Khare P , Obaid A , et al. , 2018 . SUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2 . Nat Commun , 9 : 4515 . https://doi.org/10.1038/s41467-018-06924-5 https://doi.org/10.1038/s41467-018-06924-5 SUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2 Singh UP , Singh NP , Busbee B , et al. , 2012 . Alternative medicines as emerging therapies for inflammatory bowel diseases . Int Rev Immunol , 31 ( 1 ): 66 - 84 . https://doi.org/10.3109/08830185.2011.642909 https://doi.org/10.3109/08830185.2011.642909 Alternative medicines as emerging therapies for inflammatory bowel diseases Skelly MJ , Malik SI , le Bihan T , et al. , 2019 . A role for S-nitrosylation of the SUMO-conjugating enzyme SCE1 in plant immunity . Proc Natl Acad Sci USA , 116 ( 34 ): 17090 - 17095 . https://doi.org/10.1073/pnas.1900052116 https://doi.org/10.1073/pnas.1900052116 A role for S-nitrosylation of the SUMO-conjugating enzyme SCE1 in plant immunity Sommer F , Adam N , Johansson MEV , et al. , 2014 . Altered mucus glycosylation in core 1 O-glycan-deficient mice affects microbiota composition and intestinal architecture . PLoS ONE , 9 ( 1 ): e85254 . https://doi.org/10.1371/journal.pone.0085254 https://doi.org/10.1371/journal.pone.0085254 Altered mucus glycosylation in core 1 O-glycan-deficient mice affects microbiota composition and intestinal architecture Song H , Huai WW , Yu ZX , et al. , 2016 . MLN4924, a first-in-class NEDD8-activating enzyme inhibitor, attenuates IFN-β production . J Immunol , 196 ( 7 ): 3117 - 3123 . https://doi.org/10.4049/jimmunol.1501752 https://doi.org/10.4049/jimmunol.1501752 MLN4924, a first-in-class NEDD8-activating enzyme inhibitor, attenuates IFN-β production Soucy TA , Smith PG , Milhollen MA , et al. , 2009 . An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer . Nature , 458 ( 7239 ): 732 - 736 . https://doi.org/10.1038/nature07884 https://doi.org/10.1038/nature07884 An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer Srikanth B , Vaidya MM , Kalraiya RD , 2010 . O -GlcNAcylation determines the solubility, filament organization, and stability of keratins 8 and 18 . J Biol Chem , 285 ( 44 ): 34062 - 34071 . https://doi.org/10.1074/jbc.M109.098996 https://doi.org/10.1074/jbc.M109.098996 O-GlcNAcylation determines the solubility, filament organization, and stability of keratins 8 and 18 Stickle NH , Chung J , Klco JM , et al. , 2004 . pVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development . Mol Cell Biol , 24 ( 8 ): 3251 - 3261 . https://doi.org/10.1128/mcb.24.8.3251-3261.2004 https://doi.org/10.1128/mcb.24.8.3251-3261.2004 pVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development Sugihara K , Morhardt TL , Kamada N , 2019 . The role of dietary nutrients in inflammatory bowel disease . Front Immunol , 9 : 3183 . https://doi.org/10.3389/fimmu.2018.03183 https://doi.org/10.3389/fimmu.2018.03183 The role of dietary nutrients in inflammatory bowel disease Suzuki K , Yamada T , Yamazaki K , et al. , 2018 . Intestinal epithelial cell-specific deletion of α-mannosidase II ameliorates experimental colitis . Cell Struct Funct , 43 ( 1 ): 25 - 39 . https://doi.org/10.1247/csf.17022 https://doi.org/10.1247/csf.17022 Intestinal epithelial cell-specific deletion of α-mannosidase II ameliorates experimental colitis Tamir A , Eichler J , 2017 . N-glycosylation is important for proper Haloferax volcanii S-layer stability and function . Appl Environ Microbiol , 83 ( 6 ): e03152-16 . https://doi.org/10.1128/aem.03152-16 https://doi.org/10.1128/aem.03152-16 N-glycosylation is important for proper Haloferax volcanii S-layer stability and function Theodoratou E , Campbell H , Ventham NT , et al. , 2014 . The role of glycosylation in IBD . Nat Rev Gastroenterol Hepatol , 11 ( 10 ): 588 - 600 . https://doi.org/10.1038/nrgastro.2014.78 https://doi.org/10.1038/nrgastro.2014.78 The role of glycosylation in IBD Tokuhira N , Kitagishi Y , Suzuki M , et al. , 2015 . PI3K/AKT/PTEN pathway as a target for Crohn’s disease therapy (Review) . Int J Mol Med , 35 ( 1 ): 10 - 16 . https://doi.org/10.3892/ijmm.2014.1981 https://doi.org/10.3892/ijmm.2014.1981 PI3K/AKT/PTEN pathway as a target for Crohn’s disease therapy (Review) Tsukamoto S , 2016 . Search for inhibitors of the ubiquitin-proteasome system from natural sources for cancer therapy . Chem Pharm Bull , 64 ( 2 ): 112 - 118 . https://doi.org/10.1248/cpb.c15-00768 https://doi.org/10.1248/cpb.c15-00768 Search for inhibitors of the ubiquitin-proteasome system from natural sources for cancer therapy Veldhoen M , 2017 . Interleukin 17 is a chief orchestrator of immunity . Nat Immunol , 18 ( 6 ): 612 - 621 . https://doi.org/10.1038/ni.3742 https://doi.org/10.1038/ni.3742 Interleukin 17 is a chief orchestrator of immunity Ventham NT , Kennedy NA , Nimmo ER , et al. , 2013 . Beyond gene discovery in inflammatory bowel disease: the emer ging role of epigenetics. Gastroenterology , 145 ( 2 ): 293 - 308 . https://doi.org/10.1053/j.gastro.2013.05.050 https://doi.org/10.1053/j.gastro.2013.05.050 Beyond gene discovery in inflammatory bowel disease: the emer Verdin E , Ott M , 2015 . 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond . Nat Rev Mol Cell Biol , 16 ( 4 ): 258 - 264 . https://doi.org/10.1038/nrm3931 https://doi.org/10.1038/nrm3931 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond Verhelst X , Dias AM , Colombel JF , et al. , 2020 . Protein glycosylation as a diagnostic and prognostic marker of chronic inflammatory gastrointestinal and liver diseases . Gastroenterology , 158 ( 1 ): 95 - 110 . https://doi.org/10.1053/j.gastro.2019.08.060 https://doi.org/10.1053/j.gastro.2019.08.060 Protein glycosylation as a diagnostic and prognostic marker of chronic inflammatory gastrointestinal and liver diseases Verma S , Mohapatra G , Ahmad SM , et al. , 2015 . Salmonella engages host microRNAs to modulate SUMOylation: a new arsenal for intracellular survival . Mol Cell Biol , 35 ( 17 ): 2932 - 2946 . https://doi.org/10.1128/mcb.00397-15 https://doi.org/10.1128/mcb.00397-15 Salmonella engages host microRNAs to modulate SUMOylation: a new arsenal for intracellular survival Verma V , Croley F , Sadanandom A , 2018 . Fifty shades of SUMO: its role in immunity and at the fulcrum of the growth-defence balance . Mol Plant Pathol , 19 ( 6 ): 1537 - 1544 . https://doi.org/10.1111/mpp.12625 https://doi.org/10.1111/mpp.12625 Fifty shades of SUMO: its role in immunity and at the fulcrum of the growth-defence balance Wadzinski TJ , Steinauer A , Hie L , et al. , 2018 . Rapid phenolic O -glycosylation of small molecules and complex unprotected peptides in aqueous solvent . Nat Chem , 10 ( 6 ): 644 - 652 . https://doi.org/10.1038/s41557-018-0041-8 https://doi.org/10.1038/s41557-018-0041-8 Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent Wang GY , Yuan JT , Cai X , et al. , 2020 . HucMSC-exosomes carrying miR-326 inhibit neddylation to relieve inflammatory bowel disease in mice . Clin Transl Med , 10 ( 2 ): e113 . https://doi.org/10.1002/ctm2.113 https://doi.org/10.1002/ctm2.113 HucMSC-exosomes carrying miR-326 inhibit neddylation to relieve inflammatory bowel disease in mice Wang M , Kaufman RJ , 2016 . Protein misfolding in the endoplasmic reticulum as a conduit to human disease . Nature , 529 ( 7586 ): 326 - 335 . https://doi.org/10.1038/nature17041 https://doi.org/10.1038/nature17041 Protein misfolding in the endoplasmic reticulum as a conduit to human disease Wang R , Wang GH , 2019 . Protein modification and autophagy activation . In: Qin ZH (Ed.), Autophagy : Biology and Diseases: Basic Science. Springer, Singapore, p . 237 - 259 . https://doi.org/10.1007/978-981-15-0602-4_12 https://doi.org/10.1007/978-981-15-0602-4_12 Protein modification and autophagy activation Weber A , Wasiliew P , Kracht M , 2010 . Interleukin-1 (IL-1) pathway . Sci Signal , 3 ( 105 ): cm1 . https://doi.org/10.1126/scisignal.3105cm1 https://doi.org/10.1126/scisignal.3105cm1 Interleukin-1 (IL-1) pathway Wei G , Wei L , Zhu JF , et al. , 2009 . Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4 + T cells . Immunity , 30 ( 1 ): 155 - 167 . https://doi.org/10.1016/j.immuni.2008.12.009 https://doi.org/10.1016/j.immuni.2008.12.009 Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells Wolfert MA , Boons GJ , 2013 . Adaptive immune activation: glycosylation does matter . Nat Chem Biol , 9 ( 12 ): 776 - 784 . https://doi.org/10.1038/nchembio.1403 https://doi.org/10.1038/nchembio.1403 Adaptive immune activation: glycosylation does matter Wu YB , Qiu W , Xu XW , et al. , 2018 . Exosomes derived from human umbilical cord mesenchymal stem cells alleviate inflammatory bowel disease in mice through ubiquitination . Am J Transl Res , 10 ( 7 ): 2026 - 2036 . Exosomes derived from human umbilical cord mesenchymal stem cells alleviate inflammatory bowel disease in mice through ubiquitination Xia PY , Wang S , Xiong Z , et al. , 2015 . IRTKS negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS degradation . Nat Commun , 6 : 8132 . https://doi.org/10.1038/ncomms9132 https://doi.org/10.1038/ncomms9132 IRTKS negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS degradation Xirodimas DP , Saville MK , Bourdon JC , et al. , 2004 . Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity . Cell , 118 ( 1 ): 83 - 97 . https://doi.org/10.1016/j.cell.2004.06.016 https://doi.org/10.1016/j.cell.2004.06.016 Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity Xirodimas DP , Sundqvist A , Nakamura A , et al. , 2008 . Ribosomal proteins are targets for the NEDD8 pathway . EMBO Rep , 9 ( 3 ): 280 - 286 . https://doi.org/10.1038/embor.2008.10 https://doi.org/10.1038/embor.2008.10 Ribosomal proteins are targets for the NEDD8 pathway Yang Y , Guan J , Shaikh AS , et al. , 2018 . Histone acetyltransferase Mof affects the progression of DSS-induced colitis . Cell Physiol Biochem , 47 ( 5 ): 2159 - 2169 . https://doi.org/10.1159/000491527 https://doi.org/10.1159/000491527 Histone acetyltransferase Mof affects the progression of DSS-induced colitis Yang YF , He Y , Wang XX , et al. , 2017 . Protein SUMOylation modification and its associations with disease . Open Biol , 7 ( 10 ): 170167 . https://doi.org/10.1098/rsob.170167 https://doi.org/10.1098/rsob.170167 Protein SUMOylation modification and its associations with disease Yavvari PS , Verma P , Mustfa SA , et al. , 2019 . A nanogel based oral gene delivery system targeting SUMOylation machinery to combat gut inflammation . Nanoscale , 11 ( 11 ): 4970 - 4986 . https://doi.org/10.1039/c8nr09599j https://doi.org/10.1039/c8nr09599j A nanogel based oral gene delivery system targeting SUMOylation machinery to combat gut inflammation Yin MM , Yan XB , Weng WH , et al. , 2018 . Micro integral membrane protein (MIMP), a newly discovered anti-inflammatory protein of Lactobacillus plantarum , enhances the gut barrier and modulates microbiota and inflammatory cytokines . Cell Physiol Biochem , 45 ( 2 ): 474 - 490 . https://doi.org/10.1159/000487027 https://doi.org/10.1159/000487027 Micro integral membrane protein (MIMP), a newly discovered anti-inflammatory protein of Lactobacillus plantarum, enhances the gut barrier and modulates microbiota and inflammatory cytokines You BH , Chae HS , Song J , et al. , 2017 . α-Mangostin amelior ates dextran sulfate sodium-induced colitis through inhibition of NF-‍κB and MAPK pathways. Int Immunopharmacol , 49 : 212 - 221 . https://doi.org/10.1016/j.intimp.2017.05.040 https://doi.org/10.1016/j.intimp.2017.05.040 α-Mangostin amelior Zhang MM , Zhou LX , Wang YM , et al. , 2019 . Faecalibacterium prausnitzii produces butyrate to decrease c-Myc-related metabolism and Th17 differentiation by inhibiting histone deacetylase 3 . Int Immunol , 31 ( 8 ): 499 - 514 . https://doi.org/10.1093/intimm/dxz022 https://doi.org/10.1093/intimm/dxz022 Faecalibacterium prausnitzii produces butyrate to decrease c-Myc-related metabolism and Th17 differentiation by inhibiting histone deacetylase 3 Zhang Q , Zhao K , Shen QC , et al. , 2015 . Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6 . Nature , 525 ( 7569 ): 389 - 393 . https://doi.org/10.1038/nature15252 https://doi.org/10.1038/nature15252 Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6 Zhao YC , Sun Y , 2013 . Cullin-RING ligases as attractive anti-cancer targets . Curr Pharm Des , 19 ( 18 ): 3215 - 3225 . https://doi.org/10.2174/13816128113199990300 https://doi.org/10.2174/13816128113199990300 Cullin-RING ligases as attractive anti-cancer targets Zhao YC , Morgan MA , Sun Y , 2014 . Targeting neddylation pathways to inactivate cullin-RING ligases for anticancer therapy . Antioxid Redox Signal , 21 ( 17 ): 2383 - 2400 . https://doi.org/10.1089/ars.2013.5795 https://doi.org/10.1089/ars.2013.5795 Targeting neddylation pathways to inactivate cullin-RING ligases for anticancer therapy Zhong XS , Winston JH , Luo XJ , et al. , 2018 . Neonatal colonic inflammation epigenetically aggravates epithelial inflammatory responses to injury in adult life . Cell Mol Gastroenterol Hepatol , 6 ( 1 ): 65 - 78 . https://doi.org/10.1016/j.jcmgh.2018.02.014 https://doi.org/10.1016/j.jcmgh.2018.02.014 Neonatal colonic inflammation epigenetically aggravates epithelial inflammatory responses to injury in adult life Gaoying WANG determined the topic of the article, proposed this program, and wrote the article. Jintao YUAN summarized and drew diagram of the mechanism. Dickson Kofi Wiredu OCANSEY modified the language of the article. Ji LUO, Xu ZHANG, Hui QIAN, Wenrong XU, and Fei MAO collected the literature. Fei MAO guided the article and gave opinions. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data. This work was supported by the Zhenjiang Key Research and Development Plan (Social Development) (No. SH2019025), the Scientific Research Project of Health Commission of Jiangsu Province (No. Z2019036), the Science and Technology Innovation Fund Project of Zhenjiang City (No. SH2021066), and the Taicang Science and Technology Planning Project (No. TC2020JCYL17), China. 10.1631/jzus.B2100114 1673-1581（2022）03-0173-16 2021-02-01 2021-08-17 2022-03-15 2022-04-19 2022-02-25 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2022 浙江大学出版社 Gaoying WANG, Jintao YUAN, Ji LUO, Dickson Kofi Wiredu OCANSEY, Xu ZHANG, Hui QIAN, Wenrong XU, and Fei MAO 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） 3 23