Abstract

1. Introduction

Over the past 20 years, the incidence and prevalence of Inflammatory bowel disease (IBD) have increased in the newly industrialized countries of Asia, South America, the Middle East, and Africa, and the rate is particularly significant in South America and East Asia. Thus, IBD is gradually expanding to become a global disease of public health concern¹. According to China’s epidemiological data, the incidence of IBD, ulcerative colitis (UC) and Crohn’s disease (CD), in the north of China is lower than in the south. For instance, the age-standardized incidence of IBD in Daqing City (Heilongjiang Province), Wuhan, and Guangzhou are 1.77/100,000, 1.96/100,000, and 3.14/100,000 respectively (1, 2). According to a study (3), the number of IBD patients in China will reach 1.5 million by 2025. Similar observations have been reported, with an estimated 6·8 million cases of IBD globally, where the USA had the highest age-standardized prevalence rate (464·5 [438·6–490·9] per 100 000 population), followed by the UK (449·6 [420·6–481·6] per 100 000) (4).

IBD has evolved from a common and fatal condition to a manageable chronic condition (5), which is divided into two broad categories, mainly UC and CD (6, 7). The main clinical manifestations are persistent abdominal pain, diarrhea, and bloody stool, accompanied by malnutrition, weight loss, mental distress, and other symptoms. If the course of the disease is prolonged, there is a possibility of colorectal cancer, a severe threat to human health. It has been observed that people with a history of digestive disease, a family history of IBD, and a functional imbalance in the body’s immune system are more likely to develop IBD than the general population (8). As a chronic non-specific intestinal inflammatory disease, IBD is associated with environmental, gut microbial, genetic, and immune factors. If IBD is not correctly diagnosed and treated in time, the disease becomes severe and lesions accumulate in organs of the body, with complications for disease such as colon cancer, coronary heart disease, primary sclerosing cholangitis, and phlebitis.

Ubiquitination is an important post-translational modification of proteins, and the enzymes involved mainly include the E1 ubiquitin-activating enzyme (E1), E2 ubiquitin binding enzyme (E2), and E3 ubiquitin-ligase (E3). Ubiquitin modification can regulate the localization and function of proteins in cells, degrade proteins, and regulate life activities such as signal transmission, gene expression regulation, cell proliferation, differentiation, apoptosis, inflammation and immunity (9). Abnormal ubiquitination can cause cancer, metabolic syndrome, neurodegenerative diseases, autoimmune diseases, inflammatory diseases, infections, and muscular dystrophy. Recent studies have reported associations between ubiquitination and/or deubiquitination and the onset and development of IBD (10). A genome-wide association analysis (GWAS) study showed that rare variants of E3 ligase RNF186 were associated with IBD (11). At the same time, the expression of ubiquitin mRNA in the colonic tissue of experimental colitis rats was significantly higher than that in the normal group. Therefore, abnormal ubiquitination may be one of the important mechanisms of colonic inflammation and immune damage in IBD.

In recent years, extracellular vesicles (Evs), as a strategy of “cell-free therapy,” have become a “new favorite” in research. With the development of various related technologies, more and more researchers have turned their attention to the use of Evs for disease diagnosis, prognosis, and therapeutic clinical applications. Mesenchymal stem cells (MSCs) and their derived exosomes (MSC-Exs) have been shown to play a significant role in the repair of various diseases, including IBD (12). MSCs and MSC-Exs play an important role in the information transmission process between damaged intestinal cells and can be involved in the regulation of intestinal inflammation and damage repair, showing great potential in the treatment of IBD (13). The main mechanism by which mesenchymal stem cells-derived extracellular vesicles (MSC-Evs) inhibit the activation of colon macrophages depends on the inhibition of NF-κB and iNOS transduction signals. After injection of MSC-Evs, the expression of NF-κB p65 in colon macrophages can be downregulated, and the production of NO, IL-1β, and IL-18 can be reduced, thus alleviating the symptoms of colitis (14, 15). At the same time, ubiquitination plays an essential role in the regulation of multiple biological functions, including inflammation. Studies in mice with colitis found that ubiquitin protein from inflammatory tissue is upregulated, and ubiquitin (Ub) is involved in the signaling pathway that regulates the expression of inflammatory factors (mTOR signaling pathway) (16). Wu et al. found that human umbilical cord mesenchymal stem cells-derived exosome (hucMSC-Ex) can down-regulate the expression level of ubiquitin protein. This, in turn, reduces NF-KB and mTOR activation (17). In addition, hucMSC-Ex can modulate the expression of polyubiquitination, including K48. It is concluded that MSC-Ex may play an anti-inflammatory role by regulating the level of ubiquitin modification. Currently, the product development and clinical translational application of MSCs and MSC-Exs are a hot topic in drug development, and cell-free therapy plays a unique role as a breakthrough clinical therapy technology. However, no literature currently summarizes the research progress of MSCs regulating ubiquitin modification to repair IBD. This review can provide a theoretical basis for Cell-free therapy to treat IBD through ubiquitin modification, which has important research value.

2. Mesenchymal stem cells

MSCs are a class of pluripotent stem cells with the function of self-renewal, self-proliferation, and multi-differentiation (18, 19). They positively express CD73, CD90, and CD105 and negatively express CD19, and CD45 (20). MSCs are derived from a wide range of sources, including bone marrow, adipose tissue, endometrial polyps, umbilical cord, amniotic fluid, and placenta (21). They generally possess the functions of inducing regeneration, maintaining general tissue homeostasis, and homing at target sites, which are their inherent characteristics (22). However, the differentiation and proliferation potential of MSCs from different sources may be very different (23).

MSCs can interact with cells of both the innate and adaptive immune systems. Evidence has shown that MSCs exert immunomodulatory functions by regulating the activation, proliferation, and differentiation of immune effector cells, including natural killer cells (NK), macrophages (Mø), dendritic cells (DC), B lymphocytes, and T lymphocytes (24). MSCs can down-regulate NKp30 and natural-killer group 2, member D (NKG2D), to inhibit the cytotoxic activity of resting NK cells, and the latter is an activated receptor involved in NK cell activation and target cell killing (25). MSCs can regulate Th1/Th2 balance (T helper cells) by influencing the levels of interleukin-4 (IL4) and interferon (IFN-γ) in effector T cells (26). MSCs can also reduce inflammation, improve tissue damage, and prevent infection by secreting a variety of immunomodulatory factors, including IFN-γ, prostaglandin E2 (PGE2), and growth factors (TGF-β, VEGF) (27). In conclusion, MSCs have strong immunomodulatory properties but are less immunogenic.

At present, MSCs are widely used in the research and treatment of various human diseases such as cardiovascular diseases, osteoarthritis, metabolic disease, etc. (28)). LAI et al. believe that MSCs play a role through their secreted products (29). It has been reported that MSCs can secrete a variety of Evs, including exosomes (30). In recent years, exosomes, as a promising substitute for MSCs, have attracted more attention, and have great research significance for experimental and clinical applications.

3. Biogenesis, composition, and characteristics of MSC-derived exosomes

Extracellular vesicles (Evs) secreted by cells are divided into apoptotic bodies, microvesicles, and exosomes based on their size, content, and formation mechanism (31). Table 1 presents the classification and function of Evs. Evs are released by almost all living cells and are found in blood, urine, and bronchoalveolar lavage fluid (32). At present, exosomal research is the most attractive and constantly expanding. In 1983, the research team of Rose M. Johnstone (33), a professor in the Department of Biochemistry of McGill University in Canada, first found exosomes in sheep reticulocytes, which were considered to be cell follicles that could transport nonessential proteins between cells and were considered the “garbage” of cell metabolism. With further study, Johnstone named these small vesicles as exosomes in 1987.

Exosomes, uniform in size and 50 to 200nm in diameter, have no cellular structure and are highly stable (34–36). Exosomes facilitate intercellular communication by carrying bioactive substances including mRNA, miRNA, IncRNA, DNA fragments, proteins, and lipids from parent cells, thereby regulating the activities of target cells. They positively express markers such as the tetraspanins protein family (CD63, CD81, and CD9), MVB biogenic proteins (Alix, TSG101, and ESCRT Complex), membrane transporters and heat shock proteins (HSP70, HSP90), lipid-associated proteins, etc. (37).

Exosome biogenesis includes three main stages of endosomes, multivesicular body (MVBs) formation and exosome release ( Figure 1 ), which involve double invagination of the plasma membrane (38, 39). Exosomes originate in the endosomal system of cells. Extracellular substances first enter the cell through membrane invagination and endocytosis, fuse with early endosomes (ESEs), and gradually develop and mature into late endosomes (LSEs). Late endosomal invagination leads to the emergence of intracavitary vesicles (ILVs), and multiple ILVs aggregate to form MVBs. MVBs are fused with the cell membrane and released outwards as exosomes in lipid bilayers.

Open in a separate window

Figure 1

Biogenesis and composition of exosomes. (A) Exosomes originate from endosomal pathways, and extracellular substances enter cells through membrane invagination and endocytosis and then develop into early endosomes (ESEs), late endosomes (LSEs), and intracavitary vesicles (ILVs). Multiple intracavitary vesicles (ILVs) aggregate to form MVBs. MVBs can fuse with lysosomes to degrade and release content into the cytoplasm or be released outside the cell by budding through the cell membrane, and the latter is called exosomes. (B) Exosome composition.

Because exosomes can be detected in body fluids, they are considered noninvasive or minimally invasive biomarkers for disease diagnosis. Studies have implicated exosomes in the pathophysiology of several diseases (40). For example, Gui et al. found that compared with healthy controls, the expressions of miR-1 and miR19b-3p in CSF exosomes of Parkinson’s disease (PD) patients were down-regulated, while miR-153, miR-409–3p, and miR-10a5p were up-regulated (41). The exosomal miRNAs significantly correlated with the severity of PD and may be an effective biomarker for evaluating disease development in clinical PD patients. Exosomes can also be used as diagnostic markers of cancer. Roccaro et al. showed that the expression of miRNA-15a in bone marrow MSC-exosomes (BMMSC-Ex) of multiple myeloma patients is significantly down-regulated, which is closely related to the characteristics of multiple myeloma (42). In addition, the presence of high levels of Evs expressing TGF-β2 in the breast milk of normally lactating women can induce breast cancer. What is interesting is that exosomes can play a therapeutic role by delivering drugs themselves or as functional cargo for drug delivery (43, 44). For example, MSC-Exs are used in the treatment of graft-versus-host disease (GVHD), with significant therapeutic effects observed after repeated injection without serious side effects (45, 46).

MSC-Exs have similar biological functions to MSCs, playing an important role in improving tissue repair, immune regulation, inhibiting inflammatory response, and reducing apoptosis (47). They exhibit no tumorigenicity, and are easier to extract, modify, and store (48). MSC-Ex is a natural, non-toxic vesicle that can deliver mRNA, miRNA, and protein. Therefore, it has received extensive attention as a cell-free therapeutic carrier in treating autoimmune diseases, including IBD (49). MSC-Ex research has made substantial progress in the treatment of multiple sclerosis, type-1 diabetes, and other diseases (50–52) ( Table 2 shows the application of MSCs and MSC-Ex in various clinical diseases). In the DSS-induced IBD model, hucMSC-Exs treatment reduces the infiltration of macrophages in colon tissue and inhibits the expression of IL-7 (74). Moreover, hucMSC-Exs alleviate insulin secretion function in T2DM by reversing peripheral insulin resistance and alleviating β cell destruction, providing a new approach for T2DM treatment (60). In clinical treatment, MSC-Exs have obvious advantages over MSCs and may completely replace MSC therapy in the future.

4. Ubiquitination

Ubiquitination is an important process that regulates the normal expression of genes, along with phosphorylation, glycosylation, acetylation, amidation, etc. (76, 77) Ubiquitination modifies post-translated proteins (PTMs), including protein degradation, signal transduction, and DNA damage repair (78, 79). Ubiquitination modulates various cellular activities involved in inflammatory responses, innate or adaptive immune responses, and ribosomal functions, which are essential for many cell life processes (80).

Cellular processes depend on ubiquitin (Ub) and ubiquitin-like proteins (UBLs) in ubiquitination systems. Ub, a highly conserved small protein in eukaryotes, contains 76 amino acid residues and is a significant part of regulating the everyday life activities of biological proteins (81). The UBLs found so far include NEDD8 (neural-precursor-cell expressed developmentally down-regulated 8) and SUMO (1–5, small ubiquitin-like modifier). Although they have similar functions to Ub, the receptors and signaling molecules they contact are not the same and play different roles. Related studies have shown that NEDD8 which has the same homologous sequence (> 50%) as Ub, binds to Cullin, the subunit cullin of Cullin-ring ligase (the largest multi-unit E3s ubiquitase family, CRLs). After overactivation, it promotes the degradation of tumor suppressor factors (p21, p27) and the occurrence and evolution of cancer (82). Yang W et al. experimentally demonstrated that increased SUMOylating has a neuroprotective effect and seems necessary for survival, at least under certain conditions (ischemia) (83). This theory was further validated in animal models, which found that cerebral ischemia in mice leads to a significant increase in SUMO2/3 conjugates in the hippocampus and cerebral cortex, and a neuroblastoma cell model undergoing hypoxia/glucose deprivation followed by a short period of reoxygenation under the same conditions also exhibits significant increases in SUMO2/3 conjugation (84, 85).

From a more microscopic point of view, the Ub molecule itself contains seven lysine (Lys) residues, and the amino terminus of the Lys residues (K6, K11, K27, K29, K33, K48, and K63) on the substrate protein monopeptide can be labeled for monoubiquitination. Table 3 summary of the different types of ubiquitination and their functions. When the Ub molecule forms a specific isopeptide bond with the carboxyl terminus of another Ub molecule through Lys residues, it is further coupled to form a multiubiquitin chain. Ubiquitin can also bind to non-lysine residues, such as cysteine (Cys). Ubiquitin chains with different links have different cellular functions, constituting the “ubiquitin code” of diversity and complexity (86). Monoubiquitination is generally associated with receptor internalization, while polyubiquitination is usually associated with proteasome degradation signaling (87). Related studies have found that K48 and K11 connected ubiquitin chains mediate substrate proteins to be digested into amino acids by soluble peptidase (26S proteasome complex) in cytoplasm or nucleus through a series of enzymatic reactions (88, 89). Many experimental studies have shown that the polyubiquitin chain of K63 is associated with non-proteasome functions, such as DNA repair, protein sorting, immune modulation, and regulation of the activation of the NF-κB signaling pathway, and also protects target proteins from multiple signaling pathway functions, including T cell receptors, Toll-like receptors (TLRs) and RIG-I-like receptor-mediated signal transduction (90–93). The mechanisms determining whether a protein is monoubiquitinated or polyubiquitinated are not fully understood and require further studies.

Table 3

Summary of the different types of ubiquitination and their functions.

	Ubiquitin type	Function
	K11	Protein degradation, regulation of cell cycle, DNA damage, and signal transduction.
	K48	Protein degradation.
	K63	DNA repair, translation, signal transduction, and trafficking.
	Others	Protein degradation and DNA repair.

Open in a separate window

Ubiquitination of proteins is accomplished through a series of continuous enzymatic reactions (94–96) ( Table 4 ). For the enzymes required for ubiquitination, it is currently estimated that eukaryotic organisms have two E1 enzymes (UBA1 and UBA6), with approximately 30–50 E2 enzymes and more than 600 E3 enzymes. In a tertiary E1-E2-E3 enzyme-linked reaction in mammals, any two members of the E1 family can label all E2 with Ub, and 40 known E2 enzymes can further transmit Ub to the E3s family. Auxiliary E4 enzymes have been explored (97); When the substrate protein signals, the E1 enzyme activates ubiquitin and starts the ubiquitination process, which requires ATP to provide energy. Then, the E3 ubiquitin ligase specifically recognizes the substrate protein and guides the E2 conjugation-carried Ub to covalently bind to the substrate protein ( Figure 2 ) (98). In the ubiquitination system, these three different types of enzymes cooperate to complete the task of modifying proteins. The ubiquitin activator E1 binds to the tail of the ubiquitin molecule, and regulates the downstream of the ubiquitination reaction. Ubiquitin coupling E2 enzyme controls the length and connection type during the assembly of ubiquitin chains, and K48 and K63-mediated polyubiquitination regulates the inflammatory development of the NF-κB signaling pathway. The specificity of the ubiquitin chain is widely believed to be determined by E2-E3 (RING-E3s) matching or substrate-E3 (HECT and with E6-APC) complexes (99).

Open in a separate window

Figure 2

Binding of ubiquitin to protein substrates is a multi-step process. Ubiquitin molecules can be attached to ubiquitin or proteases containing lysine residues such as K6, K11, K27, K29, K33, K48, and K63. First, ATP provides energy, and the E1 enzyme activates ubiquitin and initiates the ubiquitination process. E2 enzyme can provide ubiquitin directly to the protein substrate through lysine (K) residues in the target protein. The third step is to bind the E2 ubiquitase-linked ubiquitin to the E3 ligase-linked target protein, and there are two binding forms, respectively,① E2-Ub-substrate protein-E3 or ② Ub substrate protein-E3. Ubiquitin protein ligase (E3) can promote the interaction with substrate proteins. Ubiquitination is a reversible post-translational protein modification; thus, the substrate carrying the ubiquitin chain can be deactivated by the UPS (Ubiquitin-proteasome system) or DUBs (Deubiquitinating enzymes), and free ubiquitin monomers can be re-recruited for the next round of ubiquitination. The ubiquitin chain usually determines the fate of ubiquitinated proteins.

The stability, functional activity, and interaction of the modified proteins may change, but the modification is a reversible PTM process that can be removed by the UPS (Ubiquitin-proteasome system) or DUBs (Deubiquitinating enzymes) (100). The UPS can remove proteins that have been damaged or are no longer needed in cells (tumor suppressor proteins, cell cycle regulatory proteins, etc.), which is an energy-consuming but highly efficient way to degrade proteins. When the substrate has four or more UB or UBLs, the 26s protease hydrolyzes it into peptide chains, releasing ubiquitin monomers that can be recycled (101). DUBs catalytic deubiquitination modification makes the ubiquitination process maintain the dynamic balance of the cellular process. After DUBs are bound to the ubiquitin substrate protein complex, the ubiquitin chain is broken by severing the isopeptide bond between Lys and the C-terminal of ubiquitin, and the ubiquitin monomer is free and can be collected, thus starting the next round of ubiquitination.

There are approximately over 100 types of DUBs, including ubiquitin-specific proteases (USP), ubiquitin-c-terminal hydrolases (UCH), and so on (102, 103).Different DUBs play different roles in inflammation and cancer development by affecting their substrates’ protein stability, enzyme activity, or subcellular localization (104). The USPs family is the most commonly studied DUB family. USPs regulate protein activation by dissociating single or multiple ubiquitin chains from ubiquitinated substrates (105). In malignant tumors, USP18 is elevated and activates AKT/mTOR signaling, promotes phosphorylated AKT (p-AKT) and p-mTOR protein expression, leading to cancer cell proliferation and migration (106). USP11 controls its stability by promoting deubiquitination of a residual protein (VGLL, a tumor suppressor) and exerts its tumor suppressor effect through the VGLL4/YAP-TEAD regulatory ring (107). Overexpression of USP14 inhibits I-κB and increases NF-κB phosphorylation while increasing cancer cell migration, invasion, and EMT (108). Under selective conditions, USP7, USP10, USP29, USP42, and other DUBs regulate p53 ubiquitination levels (109).

5. The relationship between ubiquitination, MSC/MSC-Ex, and IBD

The occurrence of IBD is mainly due to the abnormal amplification of the immune response of the intestinal mucosal immune system to microbial antigens from the gut in some specific populations carrying susceptible genes under certain circumstances, resulting in inflammatory damage of the intestinal mucosa. In 2001, NOD2 was identified as a susceptibility gene for CD due to its polymorphism (110). In addition, approximately 240 gene loci have been found to be associated with IBD susceptibility and occurrence, of which about 30 are CD and UC (111, 112). The loss of balance between proinflammatory and anti-inflammatory factors leads to the activation of NF-κB, TNFα, NLR, and TLR pathways to expand the range of inflammation and promote the development of IBD ( Figure 3 ). According to mechanistic studies, a variety of signaling pathways have regulatory effects on IBD, but the specific activation, effects, and regulatory mechanisms largely remain unclear. Therefore, further exploratory studies on the pathogenesis of IBD, new targets for its treatment, and diagnostic biomarkers are needed.

Open in a separate window

Figure 3

Key signaling pathways associated with IBD ① TLR stimulation triggers MyD88 to interact with IRAK4 (interleukin-1 receptor-associated kinase 4) and ② NLRs interact with RIP2, causing TRAF3, TRAF6, and Lys63 polyubiquitinizes RIP1, to recruit TAK1/TAB2/3 complex or IkK complex. This triggers the activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways, promoting the transcription of proinflammatory and anti-inflammatory genes. Endosomal TLRs transmit signals through a TRIF-dependent pathway, and TRIF, along with RIP1 and TRAF3, activates TAK1 or IKKϵ, leading to phosphorylation of IRF3 and expression of interferon β.

The immune system is mainly composed of the innate and adaptive systems (113, 114). Ubiquitination plays a vital role in the regulation of innate immune signal transduction, but so far, only Lys residues have been identified as ubiquitination sites in innate immune signal molecules. Whether ubiquitination of non-lysine residues plays a role in innate immune signal transduction needs further study. Adaptive immunity relies on specific immune cells (T and B lymphocytes), mediating humoral and cellular immunity, and is characterized by the presence of highly specific antigen recognition receptors, namely T cell receptors (TCR) and B cell receptors (BCR). The regulatory effects of ubiquitination on immune cells are varied and not fully understood. MSCs and MSC-Exs have been shown to target the treatment of inflammatory diseases, including IBD, asthma, and rheumatoid arthritis (115, 116). Ubiquitination is involved in the inflammatory response in IBD, serving as a potential therapeutic target through the modulation of MSC and MSC-Ex.

6. Conclusion

Scientists have been exploring more effective and easier ways to treat IBD, mainly focusing on the interaction between genetic, environmental, immunological, and gut microbial factors, to discover further fundamental mechanisms of IBD occurrence and preventive strategies. The aim is to reduce patients’ medical and disease burden and improve the quality of life of affected individuals (224). Despite the best efforts, the application of MSCs and MSC-Exs remains a black box filled with unknown secrets. Studies have reported that treatment with MSCs or similar cells may promote the likelihood of cancer in patients; although this risk is unlikely to exist, there is still a chance of occurrence (225). As research continues to deepen and clinical trials advance, we hope to better understand the risks and potential benefits of exosome treatment for patients. Thus, the search for new, safe, efficient, and low-cost treatments for IBD, including MSC-Exs, is still underway.

Several experimental conclusions have proved that ubiquitin modification is involved in regulating important signaling pathways, such as NF-κB, NOD, TGF-β, and TNF-α. In addition, the dysregulation of components of the ubiquitination system often leads to various diseases such as cancer, IBD, and other autoimmune diseases. Some ubiquitin enzymes are known to directly regulate various inflammation-related transcription factors from the Smad, p53, Jun, and other families, and the ubiquitination-mediated degradation of signaling intermediates is an essential means to terminate inflammatory responses (226). However, how ubiquitination mediates the transmission and function of inflammatory signals to trigger the occurrence of IBD is largely unexplored and requires further studies. Moreover, the link between ubiquitination, IBD, and MSCs/MSC-Exs could provide an experimental basis for a novel therapeutic target and subsequent clinical application. More exploratory studies are needed in this area.

Acknowledgments

Funding Statement

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was sponsored by the National Natural Science Fund of China (Grant no. 82250410378), 2022 Jiangsu Excellent postdoctoral program (Grant no. 2022ZB634), Zhenjiang key research and development plan (social development) (Grant no. SH2022062, SH2022091 and SH2023050) and Project of Suzhou Science and Technology (Grant no. SKY2022027).

References

1. Yang H, Li Y, Wu W, Sun Q, Zhang Y, Zhao W, et al. . The incidence of inflammatory bowel disease in Northern China: a prospective population-based study. PloS One. (2014) 9:e101296. 10.1371/journal.pone.0101296 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

2. Zeng Z, Zhu Z, Yang Y, Ruan W, Peng X, Su Y, et al. . Incidence and clinical characteristics of inflammatory bowel disease in a developed region of Guangdong Province, China: a prospective population-based study. J Gastroenterol Hepatol. (2013) 28:1148–53. 10.1111/jgh.12164 [Abstract] [CrossRef] [Google Scholar]

3. Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. (2015) 12:720–7. 10.1038/nrgastro.2015.150 [Abstract] [CrossRef] [Google Scholar]

4. GBD 2017 Inflammatory Bowel Disease Collaborators . The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. (2020) 5:17–30. 10.1016/S2468-1253(19)30333-4 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

5. Zhao M, Gönczi L, Lakatos PL, Burisch J. The burden of inflammatory bowel disease in europe in 2020. J Crohns Colitis. (2021) 15:1573–87. 10.1093/ecco-jcc/jjab029 [Abstract] [CrossRef] [Google Scholar]

6. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. (2014) 146:1489–99. 10.1053/j.gastro.2014.02.009 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

7. Mulder DJ, Noble AJ, Justinich CJ, Duffin JM. A tale of two diseases: the history of inflammatory bowel disease. J Crohns Colitis. (2014) 8:341–8. 10.1016/j.crohns.2013.09.009 [Abstract] [CrossRef] [Google Scholar]

8. Xu F, Dahlhamer JM, Zammitti EP, Wheaton AG, Croft JB. Health-risk behaviors and chronic conditions among adults with inflammatory bowel disease - United States, 2015 and 2016. MMWR Morb Mortal Wkly Rep. (2018) 67:190–5. 10.15585/mmwr.mm6706a4 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

9. Hu H, Sun SC. Ubiquitin signaling in immune responses. Cell Res. (2016) 26:457–83. 10.1038/cr.2016.40 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

10. Zou M, Zeng QS, Nie J, Yang JH, Luo ZY, Gan HT. The role of E3 ubiquitin ligases and deubiquitinases in inflammatory bowel disease: friend or foe? Front Immunol. (2021) 12:769167. 10.3389/fimmu.2021.769167 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

11. Beaudoin M, Goyette P, Boucher G, Lo KS, Rivas MA, Stevens C, et al. . Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. PloS Genet. (2013) 9:e1003723. 10.1371/journal.pgen.1003723 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

12. Yu H, Yang X, Xiao X, Xu M, Yang Y, Xue C, et al. . Human adipose mesenchymal stem cell-derived exosomes protect mice from DSS-induced inflammatory bowel disease by promoting intestinal-stem-cell and epithelial regeneration. Aging Dis. (2021) 12:1423–37. 10.14336/AD.2021.0601 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

13. da Costa Gonçalves F, Paz AH. Cell membrane and bioactive factors derived from mesenchymal stromal cells: Cell-free based therapy for inflammatory bowel diseases. World J Stem Cells. (2019) 11:618–33. 10.4252/wjsc.v11.i9.618 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

14. Wu H, Fan H, Shou Z, Xu M, Chen Q, Ai C, et al. . Extracellular vesicles containing miR-146a attenuate experimental colitis by targeting TRAF6 and IRAK1. Int Immunopharmacol. (2019) 68:204–12. 10.1016/j.intimp.2018.12.043 [Abstract] [CrossRef] [Google Scholar]

15. Yang J, Liu XX, Fan H, Tang Q, Shou ZX, Zuo DM, et al. . Extracellular Vesicles Derived from Bone Marrow Mesenchymal Stem Cells Protect against Experimental Colitis via Attenuating Colon Inflammation, Oxidative Stress and Apoptosis. PloS One. (2015) 10:e0140551. 10.1371/journal.pone.0140551 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

16. Fujimoto K, Kinoshita M, Tanaka H, Okuzaki D, Shimada Y, Kayama H, et al. . Regulation of intestinal homeostasis by the ulcerative colitis-associated gene RNF186. Mucosal Immunol. (2017) 10:446–59. 10.1038/mi.2016.58 [Abstract] [CrossRef] [Google Scholar]

17. Wu Y, Qiu W, Xu X, Kang J, Wang J, Wen Y, et al. . Exosomes derived from human umbilical cord mesenchymal stem cells alleviate inflammatory bowel disease in mice through ubiquitination. Am J Transl Res. (2018) 10:2026–36. [Europe PMC free article] [Abstract] [Google Scholar]

18. He H, Zhao ZH, Han FS, Liu XH, Wang R, Zeng YJ. Overexpression of protein kinase C ε improves retention and survival of transplanted mesenchymal stem cells in rat acute myocardial infarction. Cell Death Dis. (2016) 7:e2056. 10.1038/cddis.2015.417 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

19. Kim KW, Moon SJ, Park MJ, Kim BM, Kim EK, Lee SH, et al. . Optimization of adipose tissue-derived mesenchymal stem cells by rapamycin in a murine model of acute graft-versus-host disease [published correction appears in Stem Cell Res Ther. Stem Cell Res Ther. (2015) 6:202. 10.1186/s13287-015-0197-8 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

20. Park JY, Jeon HJ, Kim TY, Lee KY, Park K, Lee ES, et al. . Comparative analysis of mesenchymal stem cell surface marker expression for human dental mesenchymal stem cells. Regener Med. (2013) 8:453–66. 10.2217/rme.13.23 [Abstract] [CrossRef] [Google Scholar]

21. Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant. (2011) 20:5–14. 10.3727/096368910X [Abstract] [CrossRef] [Google Scholar]

22. Li Z, Hu X, Zhong JF. Mesenchymal stem cells: characteristics, function, and application. Stem Cells Int. (2019) 2019:8106818. 10.1155/2019/8106818 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

23. Maleki M, Ghanbarvand F, Reza Behvarz M, Ejtemaei M, Ghadirkhomi E. Comparison of mesenchymal stem cell markers in multiple human adult stem cells. Int J Stem Cells. (2014) 7:118–26. 10.15283/ijsc.2014.7.2.118 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

24. Djouad F, Charbonnier LM, Bouffi C, Louis-Plence P, Bony C, Apparailly F, et al. . Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells. (2007) 25:2025–32. 10.1634/stemcells.2006-0548 [Abstract] [CrossRef] [Google Scholar]

25. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. (2008) 8:726–36. 10.1038/nri2395 [Abstract] [CrossRef] [Google Scholar]

26. Musiał-Wysocka A, Kot M, Majka M. The pros and cons of mesenchymal stem cell-based therapies. Cell Transplant. (2019) 28:801–12. 10.1177/0963689719837897 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

27. Zhang X, He J, Wang W. Progress in the use of mesenchymal stromal cells for osteoarthritis treatment. Cytotherapy. (2021) 23:459–70. 10.1016/j.jcyt.2021.01.008 [Abstract] [CrossRef] [Google Scholar]

28. Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. (2013) 45:e54. 10.1038/emm.2013.94 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

29. Lai RC, Yeo RW, Lim SK. Mesenchymal stem cell exosomes. Semin Cell Dev Biol. (2015) 40:82–8. 10.1016/j.semcdb.2015.03.001 [Abstract] [CrossRef] [Google Scholar]

30. Pathan M, Fonseka P, Chitti SV, Kang T, Sanwlani R, Van Deun J, et al. . Vesiclepedia 2019: a compendium of RNA, proteins, lipids and metabolites in extracellular vesicles. Nucleic Acids Res. (2019) 47:D516–9. 10.1093/nar/gky1029 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

31. Srivastava A, Rathore S, Munshi A, Ramesh R. Extracellular vesicles in oncology: from immune suppression to immunotherapy. AAPS J. (2021) 23:30. 10.1208/s12248-021-00554-4 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

32. Jeyaram A, Jay SM. Preservation and storage stability of extracellular vesicles for therapeutic applications. AAPS J. (2017) 20:1. 10.1208/s12248-017-0160-y [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

33. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. (1987) 262:9412–20. 10.1016/S0021-9258(18)48095-7 [Abstract] [CrossRef] [Google Scholar]

34. Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl). (2013) 91:431–7. 10.1007/s00109-013-1020-6 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

35. Lin J, Li J, Huang B, Liu J, Chen X, Chen XM, et al. . Exosomes: novel biomarkers for clinical diagnosis. ScientificWorldJournal. (2015) 2015:657086. 10.1155/2015/657086 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

36. Simons M, Raposo G. Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol. (2009) 21:575–81. 10.1016/j.ceb.2009.03.007 [Abstract] [CrossRef] [Google Scholar]

37. Joo HS, Suh JH, Lee HJ, Bang ES, Lee JM. Current knowledge and future perspectives on mesenchymal stem cell-derived exosomes as a new therapeutic agent. Int J Mol Sci. (2020) 21:727. 10.3390/ijms21030727 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

38. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. (2020) 367:eaau6977. 10.1126/science.aau6977 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

39. Maas SLN, Breakefield XO, Weaver AM. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. (2017) 27:172–88. 10.1016/j.tcb.2016.11.003 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

40. Yao YF, Qu MW, Li GC, Zhang FB, Rui HC. Circulating exosomal miRNAs as diagnostic biomarkers in Parkinson's disease. Eur Rev Med Pharmacol Sci. (2018) 22:5278–83. 10.26355/eurrev_201808_15727 [Abstract] [CrossRef] [Google Scholar]

41. Gui Y, Liu H, Zhang L, Lv W, Hu X. Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget. (2015) 6:37043–53. 10.18632/oncotarget.v6i35 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

42. Roccaro AM, Sacco A, Maiso P, Azab AK, Tai YT, Reagan M, et al. . BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression [published correction appears in J Clin Invest. J Clin Invest. (2013) 123:1542–55. 10.1172/JCI66517 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

43. Andaloussi S EL, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discovery. (2013) 12:347–57. 10.1038/nrd3978 [Abstract] [CrossRef] [Google Scholar]

44. Namee NM, O'Driscoll L. Extracellular vesicles and anti-cancer drug resistance. Biochim Biophys Acta Rev Cancer. (2018) 1870:123–36. 10.1016/j.bbcan.2018.07.003 [Abstract] [CrossRef] [Google Scholar]

45. Galipeau J, Sensébé L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell. (2018) 22:824–33. 10.1016/j.stem.2018.05.004 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

46. Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M, et al. . Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. (2004) 363:1439–41. 10.1016/S0140-6736(04)16104-7 [Abstract] [CrossRef] [Google Scholar]

47. Shen Z, Huang W, Liu J, Tian J, Wang S, Rui K. Effects of mesenchymal stem cell-derived exosomes on autoimmune diseases. Front Immunol. (2021) 12:749192. 10.3389/fimmu.2021.749192 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

48. Phinney DG, Pittenger MF. Concise Review: MSC-Derived Exosomes for Cell-Free Therapy [published correction appears in Stem Cells. Stem Cells. (2017) 35:851–8. 10.1002/stem.2575 [Abstract] [CrossRef] [Google Scholar]

49. Fang Y, Ni J, Wang YS, Zhao Y, Jiang LQ, Chen C, et al. . Exosomes as biomarkers and therapeutic delivery for autoimmune diseases: Opportunities and challenges. Autoimmun Rev. (2023) 22:103260. 10.1016/j.autrev.2022.103260 [Abstract] [CrossRef] [Google Scholar]

50. Pusic AD, Pusic KM, Kraig RP. What are exosomes and how can they be used in multiple sclerosis therapy? Expert Rev Neurother. (2014) 14:353–5. 10.1586/14737175.2014.890893 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

51. Riazifar M, Mohammadi MR, Pone EJ, Yeri A, Lässer C, Segaliny AI, et al. . Stem cell-derived exosomes as nanotherapeutics for autoimmune and neurodegenerative disorders. ACS Nano. (2019) 13:6670–88. 10.1021/acsnano.9b01004 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

52. Mahdipour E, Salmasi Z, Sabeti N. Potential of stem cell-derived exosomes to regenerate β islets through Pdx-1 dependent mechanism in a rat model of type 1 diabetes. J Cell Physiol. (2019) 234:20310–21. 10.1002/jcp.28631 [Abstract] [CrossRef] [Google Scholar]

53. Zeinaloo A, Zanjani KS, Bagheri MM, Mohyeddin-Bonab M, Monajemzadeh M, Arjmandnia MH. Intracoronary administration of autologous mesenchymal stem cells in a critically ill patient with dilated cardiomyopathy. Pediatr Transplant. (2011) 15:E183–6. 10.1111/j.1399-3046.2010.01366.x [Abstract] [CrossRef] [Google Scholar]

54. Yang Z, Zhang F, Ma W, Chen B, Zhou F, Xu Z, et al. . A novel approach to transplanting bone marrow stem cells to repair human myocardial infarction: delivery via a noninfarct-relative artery. Cardiovasc Ther. (2010) 28:380–5. 10.1111/j.1755-5922.2009.00116.x [Abstract] [CrossRef] [Google Scholar]

55. Arslan F, Lai RC, Smeets MB, Akeroyd L, Choo A, Aguor EN, et al. . Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. (2013) 10:301–12. 10.1016/j.scr.2013.01.002 [Abstract] [CrossRef] [Google Scholar]

56. Li X, Hu X, Chen Q, Jiang T. Bone marrow mesenchymal stem cell-derived exosomes carrying E3 ubiquitin ligase ITCH attenuated cardiomyocyte apoptosis by mediating apoptosis signal-regulated kinase-1. Pharmacogenet Genomics. (2023) 33:117–25. 10.1097/FPC.0000000000000499 [Abstract] [CrossRef] [Google Scholar]

57. Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, et al. . Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial [published correction appears in JAMA. JAMA. (2012) 308:2369–79. 10.1001/jama.2012.25321 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

58. Lachaud CC, Cobo-Vuilleumier N, Fuente-Martin E, Diaz I, Andreu E, Cahuana GM, et al. . Umbilical cord mesenchymal stromal cells transplantation delays the onset of hyperglycemia in the RIP-B7.1 mouse model of experimental autoimmune diabetes through multiple immunosuppressive and anti-inflammatory responses. Front Cell Dev Biol. (2023) 11:1089817. 10.3389/fcell.2023.1089817 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

59. Brandhorst H, Brandhorst D, Abraham A, Acreman S, Schive SW, Scholz H, et al. . Proteomic profiling reveals the ambivalent character of the mesenchymal stem cell secretome: assessing the effect of preconditioned media on isolated human islets. Cell Transplant. (2020) 29:963689720952332. 10.1177/0963689720952332 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

60. Sun Y, Shi H, Yin S, Ji C, Zhang X, Zhang B, et al. . Human mesenchymal stem cell derived exosomes alleviate type 2 diabetes mellitus by reversing peripheral insulin resistance and relieving β-cell destruction. ACS Nano. (2018) 12:7613–28. 10.1021/acsnano.7b07643 [Abstract] [CrossRef] [Google Scholar]

61. Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S, et al. . Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells. (2009) 27:1421–32. 10.1002/stem.68 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

62. Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, et al. . Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study [published correction appears in Ann Rheum Dis. Ann Rheum Dis. (2010) 69:1423–9. 10.1136/ard.2009.123463 [Abstract] [CrossRef] [Google Scholar]

63. Guo J, Yang J, Cao G, Fan H, Guo C, Ma YE, et al. . Xenogeneic immunosuppression of human umbilical cord mesenchymal stem cells in a major histocompatibility complex-mismatched allogeneic acute graft-versus-host disease murine model. Eur J Haematol. (2011) 87:235–43. 10.1111/ejh.2011.87.issue-3 [Abstract] [CrossRef] [Google Scholar]

64. Connick P, Kolappan M, Patani R, Scott MA, Crawley C, He XL, et al. . The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments. Trials. (2011) 12:62. 10.1186/1745-6215-12-62 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

65. Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, et al. . Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. (2015) 3:24–32. 10.1016/S2213-2600(14)70291-7 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

66. Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest. (2013) 143:1590–8. 10.1378/chest.12-2094 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

67. Lightner AL, Sengupta V, Qian S, Ransom JT, Suzuki S, Park DJ, et al. . Bone marrow mesenchymal stem cell-derived extracellular vesicle infusion for the treatment of respiratory failure from COVID-19: A randomized, placebo-controlled dosing clinical trial. Chest. (2023) 164:1444–53. 10.1016/j.chest.2023.06.024 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

68. Harrell CR, Miloradovic D, Sadikot R, Fellabaum C, Markovic BS, Miloradovic D, et al. . Molecular and cellular mechanisms responsible for beneficial effects of mesenchymal stem cell-derived product "Exo-d-MAPPS" in attenuation of chronic airway inflammation. Anal Cell Pathol (Amst). (2020) 2020:3153891. 10.1155/2020/3153891 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

69. Yang L, Zhai Y, Hao Y, Zhu Z, Cheng G. The regulatory functionality of exosomes derived from hUMSCs in 3D culture for alzheimer's disease therapy. Small. (2020) 16:e1906273. 10.1002/smll.201906273 [Abstract] [CrossRef] [Google Scholar]

70. Lee M, Ban JJ, Yang S, Im W, Kim M. The exosome of adipose-derived stem cells reduces β-amyloid pathology and apoptosis of neuronal cells derived from the transgenic mouse model of Alzheimer's disease. Brain Res. (2018) 1691:87–93. 10.1016/j.brainres.2018.03.034 [Abstract] [CrossRef] [Google Scholar]

71. Swaminathan M, Kopyt N, Atta MG, Radhakrishnan J, Umanath K, Nguyen S, et al. . Pharmacological effects of exvivo mesenchymal stem cell immunotherapy in patients with acute kidney injury and underlying systemic inflammation. Stem Cells Transl Med. (2021) 10:1588–601. 10.1002/sctm.21-0043 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

72. Zhang G, Zou X, Huang Y, Wang F, Miao S, Liu G, et al. . Mesenchymal stromal cell-derived extracellular vesicles protect against acute kidney injury through anti-oxidation by enhancing nrf2/ARE activation in rats. Kidney Blood Press Res. (2016) 41:119–28. 10.1159/000443413 [Abstract] [CrossRef] [Google Scholar]

73. Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S, Onodera R, et al. . Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. (2011) 134:1790–807. 10.1093/brain/awr063 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

74. Mao F, Wu Y, Tang X, Kang J, Zhang B, Yan Y, et al. . Exosomes derived from human umbilical cord mesenchymal stem cells relieve inflammatory bowel disease in mice. BioMed Res Int. (2017) 2017:5356760. 10.1155/2017/5356760 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

75. Chang X, Song YH, Xia T, He ZX, Zhao SB, Wang ZJ, et al. . Macrophage-derived exosomes promote intestinal mucosal barrier dysfunction in inflammatory bowel disease by regulating TMIGD1 via mircroRNA-223. Int Immunopharmacol. (2023) 121:110447. 10.1016/j.intimp.2023.110447 [Abstract] [CrossRef] [Google Scholar]

76. Singh V, Ram M, Kumar R, Prasad R, Roy BK, Singh KK. Phosphorylation: implications in cancer. Protein J. (2017) 36:1–6. 10.1007/s10930-017-9696-z [Abstract] [CrossRef] [Google Scholar]

77. Diallo I, Seve M, Cunin V, Minassian F, Poisson JF, Michelland S, et al. . Current trends in protein acetylation analysis. Expert Rev Proteomics. (2019) 16:139–59. 10.1080/14789450.2019.1559061 [Abstract] [CrossRef] [Google Scholar]

78. Duan G, Walther D. The roles of post-translational modifications in the context of protein interaction networks. PloS Comput Biol. (2015) 11:e1004049. 10.1371/journal.pcbi.1004049 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

79. Pickart CM. Ubiquitin enters the new millennium. Mol Cell. (2001) 8:499–504. 10.1016/S1097-2765(01)00347-1 [Abstract] [CrossRef] [Google Scholar]

80. Higgins R, Gendron JM, Rising L, Mak R, Webb K, Kaiser SE, et al. . The unfolded protein response triggers site-specific regulatory ubiquitylation of 40S ribosomal proteins. Mol Cell. (2015) 59:35–49. 10.1016/j.molcel.2015.04.026 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

81. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. (1998) 67:425–79. 10.1146/annurev.biochem.67.1.425 [Abstract] [CrossRef] [Google Scholar]

82. Zhou L, Jiang Y, Luo Q, Li L, Jia L. Neddylation: a novel modulator of the tumor microenvironment. Mol Cancer. (2019) 18:77. 10.1186/s12943-019-0979-1 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

83. Flotho A, Melchior F. Sumoylation: a regulatory protein modification in health and disease. Annu Rev Biochem. (2013) 82:357–85. 10.1146/annurev-biochem-061909-093311 [Abstract] [CrossRef] [Google Scholar]

84. Yang W, Sheng H, Warner DS, Paschen W. Transient global cerebral ischemia induces a massive increase in protein sumoylation. J Cereb Blood Flow Metab. (2008) 28:269–79. 10.1038/sj.jcbfm.9600523 [Abstract] [CrossRef] [Google Scholar]

85. Yang W, Thompson JW, Wang Z, Wang L, Sheng H, Foster MW, et al. . Analysis of oxygen/glucose-deprivation-induced changes in SUMO3 conjugation using SILAC-based quantitative proteomics. J Proteome Res. (2012) 11:1108–17. 10.1021/pr200834f [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

86. Akutsu M, Dikic I, Bremm A. Ubiquitin chain diversity at a glance. J Cell Sci. (2016) 129:875–80. 10.1242/jcs.183954 [Abstract] [CrossRef] [Google Scholar]

87. Chen Y, Zhou D, Yao Y, Sun Y, Yao F, Ma L. Monoubiquitination in homeostasis and cancer. Int J Mol Sci. (2022) 23:5925. 10.3390/ijms23115925 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

88. Wang Y, Le WD. Autophagy and ubiquitin-proteasome system. Adv Exp Med Biol. (2019) 1206:527–50. 10.1007/978-981-15-0602-4_25 [Abstract] [CrossRef] [Google Scholar]

89. Lu Y, Lee BH, King RW, Finley D, Kirschner MW. Substrate degradation by the proteasome: a single-molecule kinetic analysis. Science. (2015) 348:1250834. 10.1126/science.1250834 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

90. Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature. (2002) 419:135–41. 10.1038/nature00991 [Abstract] [CrossRef] [Google Scholar]

91. Liu P, Gan W, Su S, Hauenstein AV, Fu TM, Brasher B, et al. . K63-linked polyubiquitin chains bind to DNA to facilitate DNA damage repair. Sci Signal. (2018) 11:eaar8133. 10.1126/scisignal.aar8133 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

92. Ohtake F, Saeki Y, Ishido S, Kanno J, Tanaka K. The K48-K63 branched ubiquitin chain regulates NF-κB signaling. Mol Cell. (2016) 64:251–66. 10.1016/j.molcel.2016.09.014 [Abstract] [CrossRef] [Google Scholar]

93. Skaug B, Jiang X, Chen ZJ. The role of ubiquitin in NF-kappaB regulatory pathways. Annu Rev Biochem. (2009) 78:769–96. 10.1146/annurev.biochem.78.070907.102750 [Abstract] [CrossRef] [Google Scholar]

94. Komander D, Rape M. The ubiquitin code. Annu Rev Biochem. (2012) 81:203–29. 10.1146/annurev-biochem-060310-170328 [Abstract] [CrossRef] [Google Scholar]

95. Deshaies RJ, Joazeiro CA. RING domain E3 ubiquitin ligases. Annu Rev Biochem. (2009) 78:399–434. 10.1146/annurev.biochem.78.101807.093809 [Abstract] [CrossRef] [Google Scholar]

96. Ye Y, Rape M. Building ubiquitin chains: E2 enzymes at work. Nat Rev Mol Cell Biol. (2009) 10:755–64. 10.1038/nrm2780 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

97. Hoppe T. Multiubiquitylation by E4 enzymes: 'one size' doesn't fit all. Trends Biochem Sci. (2005) 30:183–7. 10.1016/j.tibs.2005.02.004 [Abstract] [CrossRef] [Google Scholar]

98. Luo QF, Chen W, Zhang ST. Identification of Nedd4 as a novel regulator in Hedgehog signaling. Chin Med J (Engl). (2012) 125:3851–5. [Abstract] [Google Scholar]

99. Bedford L, Lowe J, Dick LR, Mayer RJ, Brownell JE. Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets. Nat Rev Drug Discovery. (2011) 10:29–46. 10.1038/nrd3321 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

100. Mevissen TE, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M, Arnaudo N, et al. . OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis. Cell. (2013) 154:169–84. 10.1016/j.cell.2013.05.046 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

101. Scheffner M, Nuber U, Huibregtse JM. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature. (1995) 373:81–3. 10.1038/373081a0 [Abstract] [CrossRef] [Google Scholar]

102. Clague MJ, Urbé S, Komander D. Breaking the chains: deubiquitylating enzyme specificity begets function [published correction appears in Nat Rev Mol Cell Biol. Nat Rev Mol Cell Biol. (2019) 20:338–52. 10.1038/s41580-019-0099-1 [Abstract] [CrossRef] [Google Scholar]

103. Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, et al. . A genomic and functional inventory of deubiquitinating enzymes. Cell. (2005) 123:773–86. 10.1016/j.cell.2005.11.007 [Abstract] [CrossRef] [Google Scholar]

104. Cheng J, Guo J, North BJ, Wang B, Cui CP, Li H, et al. . Functional analysis of deubiquitylating enzymes in tumorigenesis and development. Biochim Biophys Acta Rev Cancer. (2019) 1872:188312. 10.1016/j.bbcan.2019.188312 [Abstract] [CrossRef] [Google Scholar]

105. Chen R, Pang X, Li L, Zeng Z, Chen M, Zhang S. Ubiquitin-specific proteases in inflammatory bowel disease-related signalling pathway regulation. Cell Death Dis. (2022) 13:139. 10.1038/s41419-022-04566-6 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

106. Liu M, Gao S, Xu X, Zhang L, Xu B, Lu D. USP18 contributes to the proliferation and migration of ovarian cancer cells by regulating the AKT/mTOR signaling pathway. Acta Biochim Pol. (2022) 69:417–22. 10.18388/abp.2020_5871 [Abstract] [CrossRef] [Google Scholar]

107. Zhang E, Shen B, Mu X, Qin Y, Zhang F, Liu Y, et al. . Ubiquitin-specific protease 11 (USP11) functions as a tumor suppressor through deubiquitinating and stabilizing VGLL4 protein. Am J Cancer Res. (2016) 6:2901–9. 10.1158/0008-5472.CAN-15-2120 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

108. Gong X, Jia L, Zhou L, Hu T. USP14 predicts poorer survival outcomes and promotes tumor progression in endometrial carcinoma by activating NF-κB signaling. Aging (Albany NY). (2023) 15:12120–35. 10.18632/aging.v15i21 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

109. Ke JY, Dai CJ, Wu WL, Gao JH, Xia AJ, Liu GP, et al. . USP11 regulates p53 stability by deubiquitinating p53. J Zhejiang Univ Sci B. (2014) 15:1032–8. 10.1631/jzus.B1400180 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

110. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, et al. . Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. (2001) 411:599–603. 10.1038/35079107 [Abstract] [CrossRef] [Google Scholar]

111. Guan Q. A comprehensive review and update on the pathogenesis of inflammatory bowel disease. J Immunol Res. (2019) 2019:7247238. 10.1155/2019/7247238 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

112. Jarmakiewicz-Czaja S, Zielińska M, Sokal A, Filip R. Genetic and epigenetic etiology of inflammatory bowel disease: an update. Genes. (2022) 13:2388. 10.3390/genes13122388 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

113. Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol. (2012) 4:a006957. 10.1101/cshperspect.a006957 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

114. Kucuksezer UC, Ozdemir C, Akdis M, Akdis CA. Influence of innate immunity on immune tolerance. Acta Med Acad. (2020) 49:164–80. 10.5644/ama2006-124.295 [Abstract] [CrossRef] [Google Scholar]

115. Wang S, Lei B, Zhang E, Gong P, Gu J, He L, et al. . Targeted therapy for inflammatory diseases with mesenchymal stem cells and their derived exosomes: from basic to clinics. Int J Nanomedicine. (2022) 17:1757–81. 10.2147/IJN.S355366 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

116. Grégoire C, Lechanteur C, Briquet A, Baudoux É, Baron F, Louis E, et al. . Review article: mesenchymal stromal cell therapy for inflammatory bowel diseases. Aliment Pharmacol Ther. (2017) 45:205–21. 10.1111/apt.13864 [Abstract] [CrossRef] [Google Scholar]

117. Yu T, Gan S, Zhu Q, Dai D, Li N, Wang H, et al. . Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24. Nat Commun. (2019) 10:4353. 10.1038/s41467-019-12384-2 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

118. Liu J, Huang X, Hao S, Wang Y, Liu M, Xu J, et al. . Peli1 negatively regulates noncanonical NF-κB signaling to restrain systemic lupus erythematosus. Nat Commun. (2018) 9:1136. 10.1038/s41467-018-03530-3 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

119. Ishida T, Mizushima Si, Azuma S, Kobayashi N, Tojo T, Suzuki K, et al. . Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. J Biol Chem. (1996) 271:28745–8. 10.1074/jbc.271.46.28745 [Abstract] [CrossRef] [Google Scholar]

120. Chen ZJ. Ubiquitination in signaling to and activation of IKK. Immunol Rev. (2012) 246:95–106. 10.1111/j.1600-065X.2012.01108.x [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

121. Pflug KM, Sitcheran R. Targeting NF-κB-inducing kinase (NIK) in immunity, inflammation, and cancer. Int J Mol Sci. (2020) 21:8470. 10.3390/ijms21228470 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

122. Zhou B, Huang Y, Feng Q, Zhu H, Xu Z, Chen L, et al. . TRIM16 promotes aerobic glycolysis and pancreatic cancer metastasis by modulating the NIK-SIX1 axis in a ligase-independent manner. Am J Cancer Res. (2022) 12:5205–25. [Europe PMC free article] [Abstract] [Google Scholar]

123. Fujita M, Yamamoto Y, Jiang JJ, Atsumi T, Tanaka Y, Ohki T, et al. . NEDD4 is involved in inflammation development during keloid formation. J Invest Dermatol. (2019) 139:333–41. 10.1016/j.jid.2018.07.044 [Abstract] [CrossRef] [Google Scholar]

124. Zhu F, Wu B, Li P, Wang J, Tang H, Liu Y, et al. . Association study confirmed susceptibility loci with keloid in the Chinese Han population. PloS One. (2013) 8:e62377. 10.1371/journal.pone.0062377 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

125. Wang G, Yuan J, Cai X, Xu Z, Wang J, Ocansey DKW, et al. . HucMSC-exosomes carrying miR-326 inhibit neddylation to relieve inflammatory bowel disease in mice. Clin Transl Med. (2020) 10:e113. 10.1002/ctm2.113 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

126. Qi LL, Fan ZY, Mao HG, Wang JB. The Therapeutic Efficacy of Adipose Tissue-Derived Mesenchymal Stem Cell Conditioned Medium on Experimental Colitis Was Improved by the Serum From Colitis Rats [published correction appears in Front Bioeng Biotechnol. Front Bioeng Biotechnol. (2021) 9:694908. 10.3389/fbioe.2021.694908 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

127. Zuo D, Tang Q, Fan H, Shou Z, Liu X, Cao D, et al. . Modulation of nuclear factor-κB-mediated pro-inflammatory response is associated with exogenous administration of bone marrow-derived mesenchymal stem cells for treatment of experimental colitis. Mol Med Rep. (2015) 11:2741–8. 10.3892/mmr.2014.3038 [Abstract] [CrossRef] [Google Scholar]

128. Nata T, Fujiya M, Ueno N, Moriichi K, Konishi H, Tanabe H, et al. . MicroRNA-146b improves intestinal injury in mouse colitis by activating nuclear factor-κB and improving epithelial barrier function. J Gene Med. (2013) 15:249–60. 10.1002/jgm.2717 [Abstract] [CrossRef] [Google Scholar]

129. Liu J, Chen Y, Liu D, Liu W, Hu S, Zhou N, et al. . Ectopic expression of SIGIRR in the colon ameliorates colitis in mice by downregulating TLR4/NF-κB overactivation. Immunol Lett. (2017) 183:52–61. 10.1016/j.imlet.2017.01.015 [Abstract] [CrossRef] [Google Scholar]

130. Wu G, McBride DW, Zhang JH. Axl activation attenuates neuroinflammation by inhibiting the TLR/TRAF/NF-κB pathway after MCAO in rats. Neurobiol Dis. (2018) 110:59–67. 10.1016/j.nbd.2017.11.009 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

131. Lin SC, Lo YC, Wu H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature. (2010) 465:885–90. 10.1038/nature09121 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

132. Cohen P. The TLR and IL-1 signalling network at a glance. J Cell Sci. (2014) 127:2383–90. 10.1242/jcs.149831 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

133. Lee YS, Park JS, Kim JH, Jung SM, Lee JY, Kim SJ, et al. . Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling. Nat Commun. (2011) 2:460. 10.1038/ncomms1469 [Abstract] [CrossRef] [Google Scholar]

134. Wang C, Chen T, Zhang J, Yang M, Li N, Xu X, et al. . The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated production of type I interferon. Nat Immunol. (2009) 10:744–52. 10.1038/ni.1742 [Abstract] [CrossRef] [Google Scholar]

135. Yu W, Venkatraman A, Menden HL, Martinez M, Umar S, Sampath V. Short-chain fatty acids ameliorate necrotizing enterocolitis-like intestinal injury through enhancing Notch1-mediated single immunoglobulin interleukin-1-related receptor, toll-interacting protein, and A20 induction. Am J Physiol Gastrointest Liver Physiol. (2023) 324:G24–37. 10.1152/ajpgi.00057.2022 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

136. Parvatiyar K, Barber GN, Harhaj EW. TAX1BP1 and A20 inhibit antiviral signaling by targeting TBK1-IKKi kinases. J Biol Chem. (2010) 285:14999–5009. 10.1074/jbc.M110.109819 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

137. Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, et al. . SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. (2003) 4:920–7. 10.1038/ni968 [Abstract] [CrossRef] [Google Scholar]

138. Jiang M, Gao T, Liu Y, Cao X, Li Y, Li J, et al. . CD14 dictates differential activation of mesenchymal stromal cells through AKT, NF-κB and P38 signals. Biosci Rep. (2019) 39:BSR20190807. 10.1042/BSR20190807 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

139. Duan S, Lou X, Chen S, Jiang H, Chen D, Yin R, et al. . Macrophage LMO7 deficiency facilitates inflammatory injury via metabolic-epigenetic reprogramming. Acta Pharm Sin B. (2023) 13:4785–800. 10.1016/j.apsb.2023.09.012 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

140. Liotta F, Angeli R, Cosmi L, Filì L, Manuelli C, Frosali F, et al. . Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells. (2008) 26:279–89. 10.1634/stemcells.2007-0454 [Abstract] [CrossRef] [Google Scholar]

141. Niu GC, Liu L, Zheng L, Zhang H, Shih DQ, Zhang X. Mesenchymal stem cell transplantation improves chronic colitis-associated complications through inhibiting the activity of toll-like receptor-4 in mice. BMC Gastroenterol. (2018) 18:127. 10.1186/s12876-018-0850-7 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

142. Liu H, Liang Z, Wang F, Zhou C, Zheng X, Hu T, et al. . Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanism. JCI Insight. (2019) 4:e131273. 10.1172/jci.insight.131273 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

143. Cao L, Xu H, Wang G, Liu M, Tian D, Yuan Z. Extracellular vesicles derived from bone marrow mesenchymal stem cells attenuate dextran sodium sulfate-induced ulcerative colitis by promoting M2 macrophage polarization. Int Immunopharmacol. (2019) 72:264–74. 10.1016/j.intimp.2019.04.020 [Abstract] [CrossRef] [Google Scholar]

144. Deng D, Li X, Zhang JJ, Yin Y, Tian Y, Gan D, et al. . Biotin-avidin system-based delivery enhances the therapeutic performance of MSC-derived exosomes. ACS Nano. (2023) 17:8530–50. 10.1021/acsnano.3c00839 [Abstract] [CrossRef] [Google Scholar]

145. Chen L, Cao SQ, Lin ZM, He SJ, Zuo JP. NOD-like receptors in autoimmune diseases. Acta Pharmacol Sin. (2021) 42:1742–56. 10.1038/s41401-020-00603-2 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

146. Mukherjee T, Hovingh ES, Foerster EG, Abdel-Nour M, Philpott DJ, Girardin SE. NOD1 and NOD2 in inflammation, immunity and disease. Arch Biochem Biophys. (2019) 670:69–81. 10.1016/j.abb.2018.12.022 [Abstract] [CrossRef] [Google Scholar]

147. Kim YK, Shin JS, Nahm MH. NOD-like receptors in infection, immunity, and diseases. Yonsei Med J. (2016) 57:5–14. 10.3349/ymj.2016.57.1.5 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

148. Liu P, Lu Z, Liu L, Li R, Liang Z, Shen M, et al. . NOD-like receptor signaling in inflammation-associated cancers: From functions to targeted therapies. Phytomedicine. (2019) 64:152925. 10.1016/j.phymed.2019.152925 [Abstract] [CrossRef] [Google Scholar]

149. Emmerich CH, Bakshi S, Kelsall IR, Ortiz-Guerrero J, Shpiro N, Cohen P. Lys63/Met1-hybrid ubiquitin chains are commonly formed during the activation of innate immune signalling. Biochem Biophys Res Commun. (2016) 474:452–61. 10.1016/j.bbrc.2016.04.141 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

150. Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Núñez G, et al. . A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J. (2008) 27:373–83. 10.1038/sj.emboj.7601962 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

151. Kanayama A, Seth RB, Sun L, Ea CK, Hong M, Shaito A, et al. . TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Mol Cell. (2004) 15:535–48. 10.1016/j.molcel.2004.08.008 [Abstract] [CrossRef] [Google Scholar]

152. Tigno-Aranjuez JT, Abbott DW. Ubiquitination and phosphorylation in the regulation of NOD2 signaling and NOD2-mediated disease. Biochim Biophys Acta. (2012) 1823:2022–8. 10.1016/j.bbamcr.2012.03.017 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

153. Sorbara MT, Ellison LK, Ramjeet M, Travassos LH, Jones NL, Girardin SE, et al. . The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner [published correction appears in Immunity. Immunity. (2013) 39:858–73. 10.1016/j.immuni.2013.10.013 [Abstract] [CrossRef] [Google Scholar]

154. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. (2002) 10:417–26. 10.1016/S1097-2765(02)00599-3 [Abstract] [CrossRef] [Google Scholar]

155. Nazari S, Pourmand SM, Motevaseli E, Hassanzadeh G. Mesenchymal stem cells (MSCs) and MSC-derived exosomes in animal models of central nervous system diseases: Targeting the NLRP3 inflammasome. IUBMB Life. (2023) 75:794–810. 10.1002/iub.2759 [Abstract] [CrossRef] [Google Scholar]

156. Varghese GP, Uporova L, Halfvarson J, Sirsjö A, Fransén K. Polymorphism in the NLRP3 inflammasome-associated EIF2AK2 gene and inflammatory bowel disease. Mol Med Rep. (2015) 11:4579–84. 10.3892/mmr.2015.3236 [Abstract] [CrossRef] [Google Scholar]

157. Wu K, Yuan Y, Yu H, Dai X, Wang S, Sun Z, et al. . The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice. Blood. (2020) 136:501–15. 10.1182/blood.2019003990 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

158. Xu T, Yu W, Fang H, Wang Z, Chi Z, Guo X, et al. . Ubiquitination of NLRP3 by gp78/Insig-1 restrains NLRP3 inflammasome activation. Cell Death Differ. (2022) 29:1582–95. 10.1038/s41418-022-00947-8 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

159. Mai CT, Wu MM, Wang CL, Su ZR, Cheng YY, Zhang XJ. Palmatine attenuated dextran sulfate sodium (DSS)-induced colitis via promoting mitophagy-mediated NLRP3 inflammasome inactivation. Mol Immunol. (2019) 105:76–85. 10.1016/j.molimm.2018.10.015 [Abstract] [CrossRef] [Google Scholar]

160. Song H, Liu B, Huai W, Yu Z, Wang W, Zhao J, et al. . The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3. Nat Commun. (2016) 7:13727. 10.1038/ncomms13727 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

161. Zheng Y, Wang S, Zhong Y, Huang C, Wu X. A20 affects macrophage polarization through the NLRP3 inflammasome signaling pathway and promotes breast cancer progression. Exp Ther Med. (2023) 25:147. 10.3892/etm.2023.11846 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

162. Cai X, Zhang ZY, Yuan JT, Ocansey DKW, Tu Q, Zhang X, et al. . hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis. Stem Cell Res Ther. (2021) 12:416. 10.1186/s13287-021-02492-6 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

163. Ocansey DKW, Zhang Z, Xu X, Liu L, Amoah S, Chen X, et al. . Mesenchymal stem cell-derived exosome mitigates colitis via the modulation of the gut metagenomics-metabolomics-farnesoid X receptor axis. Biomater Sci. (2022) 10:4822–36. 10.1039/D2BM00559J [Abstract] [CrossRef] [Google Scholar]

164. Garcia-Irigoyen O, Moschetta A. A novel protective role for FXR against inflammasome activation and endotoxemia. Cell Metab. (2017) 25:763–4. 10.1016/j.cmet.2017.03.014 [Abstract] [CrossRef] [Google Scholar]

165. Al-Shaibi AA, Abdel-Motal UM, Hubrack SZ, Bullock AN, Al-Marri AA, Agrebi N, et al. . Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease [published correction appears in Cell Mol Gastroenterol Hepatol. Cell Mol Gastroenterol Hepatol. (2021) 12:1809–30. 10.1016/j.jcmgh.2021.07.001 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

166. Wlodarska M, Luo C, Kolde R, d'Hennezel E, Annand JW, Heim CE, et al. . Indoleacrylic acid produced by commensal peptostreptococcus species suppresses inflammation. Cell Host Microbe. (2017) 22:25–37.e6. 10.1016/j.chom.2017.06.007 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

167. Goto Y, Kiyono H. Epithelial barrier: an interface for the cross-communication between gut flora and immune system. Immunol Rev. (2012) 245:147–63. 10.1111/j.1600-065X.2011.01078.x [Abstract] [CrossRef] [Google Scholar]

168. Giuffrida P, Corazza GR, Di Sabatino A. Old and new lymphocyte players in inflammatory bowel disease. Dig Dis Sci. (2018) 63:277–88. 10.1007/s10620-017-4892-4 [Abstract] [CrossRef] [Google Scholar]

169. Kmieć Z, Cyman M, Ślebioda TJ. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease. Adv Med Sci. (2017) 62:1–16. 10.1016/j.advms.2016.09.001 [Abstract] [CrossRef] [Google Scholar]

170. Ye M, Joosse ME, Liu L, Sun Y, Dong Y, Cai C, et al. . Deletion of IL-6 exacerbates colitis and induces systemic inflammation in IL-10-deficient mice. J Crohn's colitis. (2020) 14:831–40. 10.1093/ecco-jcc/jjz176 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

171. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. (2016) 39:98–106. 10.1097/COC.0000000000000239 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

172. Chen RY, Zhu Y, Shen YY, Xu QY, Tang HY, Cui NX, et al. . The role of PD-1 signaling in health and immune-related diseases. Front Immunol. (2023) 14:1163633. 10.3389/fimmu.2023.1163633 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

173. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, et al. . CTLA-4 can function as a negative regulator of T cell activation. Immunity. (1994) 1:405–13. 10.1016/1074-7613(94)90071-X [Abstract] [CrossRef] [Google Scholar]

174. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. (1995) 182:459–65. 10.1084/jem.182.2.459 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

175. Wang C, Thudium KB, Han M, Wang XT, Huang H, Feingersh D, et al. . In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. (2014) 2:846–56. 10.1158/2326-6066.CIR-14-0040 [Abstract] [CrossRef] [Google Scholar]

176. Rajabian Z, Kalani F, Taghiloo S, Tehrani M, Rafiei A, Hosseini-Khah Z, et al. . Over-expression of immunosuppressive molecules, PD-L1 and PD-L2, in ulcerative colitis patients. Iran J Immunol. (2019) 16:62–70. 10.22034/IJI.2019.39407 [Abstract] [CrossRef] [Google Scholar]

177. Krummey SM, Ford ML. Braking bad: novel mechanisms of CTLA-4 inhibition of T cell responses. Am J Transplant. (2014) 14:2685–90. 10.1111/ajt.12938 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

178. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. . CTLA-4 control over Foxp3+ regulatory T cell function. Science. (2008) 322:271–5. 10.1126/science.1160062 [Abstract] [CrossRef] [Google Scholar]

179. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, et al. . Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. (2000) 192:303–10. 10.1084/jem.192.2.303 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

180. Ma Y, Wang Z, Zhang A, Xu F, Zhao N, Xue J, et al. . Human placenta-derived mesenchymal stem cells ameliorate GVHD by modulating Th17/Tr1 balance via expression of PD-L2. Life Sci. (2018) 214:98–105. 10.1016/j.lfs.2018.10.061 [Abstract] [CrossRef] [Google Scholar]

181. Lohr NJ, Molleston JP, Strauss KA, Torres-Martinez W, Sherman EA, Squires RH, et al. . Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease. Am J Hum Genet. (2010) 86:447–53. 10.1016/j.ajhg.2010.01.028 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

182. Ramon HE, Riling CR, Bradfield J, Yang B, Hakonarson H, Oliver PM. The ubiquitin ligase adaptor Ndfip1 regulates T cell-mediated gastrointestinal inflammation and inflammatory bowel disease susceptibility. Mucosal Immunol. (2011) 4:314–24. 10.1038/mi.2010.69 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

183. Huang X, Zhang Q, Lou Y, Wang J, Zhao X, Wang L, et al. . USP22 deubiquitinates CD274 to suppress anticancer immunity. Cancer Immunol Res. (2019) 7:1580–90. 10.1158/2326-6066.CIR-18-0910 [Abstract] [CrossRef] [Google Scholar]

184. Mao R, Tan X, Xiao Y, Wang X, Wei Z, Wang J, et al. . Ubiquitin C-terminal hydrolase L1 promotes expression of programmed cell death-ligand 1 in non-small-cell lung cancer cells. Cancer Sci. (2020) 111:3174–83. 10.1111/cas.14529 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

185. Cotton AD, Nguyen DP, Gramespacher JA, Seiple IB, Wells JA. Development of antibody-based PROTACs for the degradation of the cell-surface immune checkpoint protein PD-L1. J Am Chem Soc. (2021) 143:593–8. 10.1021/jacs.0c10008 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

186. Fujiwara M, Anstadt EJ, Clark RB. Cbl-b deficiency mediates resistance to programmed death-ligand 1/programmed death-1 regulation. Front Immunol. (2017) 8:42. 10.3389/fimmu.2017.00042 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

187. Augustin RC, Bao R, Luke JJ. Targeting Cbl-b in cancer immunotherapy. J immunotherapy Cancer. (2023) 11:e006007. 10.1136/jitc-2022-006007 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

188. Gavali S, Liu J, Li X, Paolino M. Ubiquitination in T-cell activation and checkpoint inhibition: new avenues for targeted cancer immunotherapy. Int J Mol Sci. (2021) 22:10800. 10.3390/ijms221910800 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

189. Xu AT, Lu JT, Ran ZH, Zheng Q. Exosome in intestinal mucosal immunity. J Gastroenterol Hepatol. (2016) 31:1694–9. 10.1111/jgh.13413 [Abstract] [CrossRef] [Google Scholar]

190. Chen QQ, Yan L, Wang CZ, Wang WH, Shi H, Su BB, et al. . Mesenchymal stem cells alleviate TNBS-induced colitis by modulating inflammatory and autoimmune responses. World J Gastroenterol. (2013) 19:4702–17. 10.3748/wjg.v19.i29.4702 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

191. Chao K, Zhang S, Qiu Y, Chen X, Zhang X, Cai C, et al. . Human umbilical cord-derived mesenchymal stem cells protect against experimental colitis via CD5(+) B regulatory cells [published correction appears in Stem Cell Res Ther. Stem Cell Res Ther. (2016) 7:109. 10.1186/s13287-016-0376-2 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

192. Tian J, Zhu Q, Zhang Y, Bian Q, Hong Y, Shen Z, et al. . Olfactory ecto-mesenchymal stem cell-derived exosomes ameliorate experimental colitis via modulating th1/th17 and treg cell responses. Front Immunol. (2020) 11:598322. 10.3389/fimmu.2020.598322 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

193. Wakefield LM, Hill CS. Beyond TGFβ: roles of other TGFβ superfamily members in cancer. Nat Rev Cancer. (2013) 13:328–41. 10.1038/nrc3500 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

194. Perez LG, Kempski J, McGee HM, Pelzcar P, Agalioti T, Giannou A, et al. . TGF-β signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer [published correction appears in Nat Commun. Nat Commun. (2020) 11:2608. 10.1038/s41467-020-16363-w [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

195. Ihara S, Hirata Y, Koike K. TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota. J Gastroenterol. (2017) 52:777–87. 10.1007/s00535-017-1350-1 [Abstract] [CrossRef] [Google Scholar]

196. de Ceuninck van Capelle C, Spit M, Ten Dijke P. Current perspectives on inhibitory SMAD7 in health and disease. Crit Rev Biochem Mol Biol. (2020) 55:691–715. 10.1080/10409238.2020.1828260 [Abstract] [CrossRef] [Google Scholar]

197. Tang Y, Reissig S, Glasmacher E, Regen T, Wanke F, Nikolaev A, et al. . Alternative splice forms of CYLD mediate ubiquitination of SMAD7 to prevent TGFB signaling and promote colitis. Gastroenterology. (2019) 156:692–707.e7. 10.1053/j.gastro.2018.10.023 [Abstract] [CrossRef] [Google Scholar]

198. Shearwin-Whyatt L, Dalton HE, Foot N, Kumar S. Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins. Bioessays. (2006) 28:617–28. 10.1002/bies.20422 [Abstract] [CrossRef] [Google Scholar]

199. Li H, Seth A. An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein. Oncogene. (2004) 23:1801–8. 10.1038/sj.onc.1207319 [Abstract] [CrossRef] [Google Scholar]

200. Zhang H, Wang L, Li C, Yu Y, Yi Y, Wang J, et al. . Exosome-induced regulation in inflammatory bowel disease. Front Immunol. (2019) 10:1464. 10.3389/fimmu.2019.01464 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

201. Cai Z, Zhang W, Yang F, Yu L, Yu Z, Pan J, et al. . Immunosuppressive exosomes from TGF-β1 gene-modified dendritic cells attenuate Th17-mediated inflammatory autoimmune disease by inducing regulatory T cells. Cell Res. (2012) 22:607–10. 10.1038/cr.2011.196 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

202. Ma ZJ, Wang YH, Li ZG, Wang Y, Li BY, Kang HY, et al. . Immunosuppressive effect of exosomes from mesenchymal stromal cells in defined medium on experimental colitis. Int J Stem Cells. (2019) 12:440–8. 10.15283/ijsc18139 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

203. Zheng W, Bian S, Qiu S, Bishop CE, Wan M, Xu N, et al. . Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis. Inflammation Regen. (2023) 43:47. 10.1186/s41232-023-00297-z [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

204. Zhou Q, Cheng C, Wei Y, Yang J, Zhou W, Song Q, et al. . USP15 potentiates NF-κB activation by differentially stabilizing TAB2 and TAB3. FEBS J. (2020) 287:3165–83. 10.1111/febs.15202 [Abstract] [CrossRef] [Google Scholar]

205. Wang F, Ning S, Yu B, Wang Y. USP14: structure, function, and target inhibition. Front Pharmacol. (2022) 12:801328. 10.3389/fphar.2021.801328 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

206. Li H, Quan J, Zhao X, Ling J, Chen W. USP14 negatively regulates RIG-I-mediated IL-6 and TNF-α production by inhibiting NF-κB activation. Mol Immunol. (2021) 130:69–76. 10.1016/j.molimm.2020.12.022 [Abstract] [CrossRef] [Google Scholar]

207. Lei CQ, Wu X, Zhong X, Jiang L, Zhong B, Shu HB. USP19 inhibits TNF-α- and IL-1β-triggered NF-κB activation by deubiquitinating TAK1. J Immunol. (2019) 203:259–68. 10.4049/jimmunol.1900083 [Abstract] [CrossRef] [Google Scholar]

208. Tsuchida T, Zou J, Saitoh T, Kumar H, Abe T, Matsuura Y, et al. . The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA. Immunity. (2010) 33:765–76. 10.1016/j.immuni.2010.10.013 [Abstract] [CrossRef] [Google Scholar]

209. Corcoran K, Jabbour M, Bhagwandin C, Deymier MJ, Theisen DL, Lybarger L. Ubiquitin-mediated regulation of CD86 protein expression by the ubiquitin ligase membrane-associated RING-CH-1 (MARCH1). J Biol Chem. (2011) 286:37168–80. 10.1074/jbc.M110.204040 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

210. Tze LE, Horikawa K, Domaschenz H, Howard DR, Roots CM, Rigby RJ, et al. . CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation. J Exp Med. (2011) 208:149–65. 10.1084/jem.20092203 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

211. Baravalle G, Park H, McSweeney M, Ohmura-Hoshino M, Matsuki Y, Ishido S, et al. . Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells. J Immunol. (2011) 187:2966–73. 10.4049/jimmunol.1101643 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

212. Sun W, Tan X, Shi Y, Xu G, Mao R, Gu X, et al. . USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha. Cell Signal. (2010) 22:386–94. 10.1016/j.cellsig.2009.10.008 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

213. Kit Leng Lui S, Iyengar PV, Jaynes P, Isa ZFBA, Pang B, Tan TZ, et al. . USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7 [published correction appears in EMBO Rep. EMBO Rep. (2017) 18:797–808. 10.15252/embr.201643270 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar] Retracted

214. Cao Y, Sun Y, Chang H, Sun X, Yang S. The E3 ubiquitin ligase RNF182 inhibits TLR-triggered cytokine production through promoting p65 ubiquitination and degradation. FEBS Lett. (2019) 593:3210–9. 10.1002/1873-3468.13583 [Abstract] [CrossRef] [Google Scholar]

215. Yu JS, Huang T, Zhang Y, Mao XT, Huang LJ, Li YN, et al. . Substrate-specific recognition of IKKs mediated by USP16 facilitates autoimmune inflammation. Sci Adv. (2021) 7:eabc4009. 10.1126/sciadv.abc4009 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

216. Li Y, Wang C, Xi HM, Li WT, Liu YJ, Feng S, et al. . Chorionic villus-derived mesenchymal stem cells induce E3 ligase TRIM72 expression and regulate cell behaviors through ubiquitination of p53 in trophoblasts. FASEB J. (2021) 35:e22005. 10.1096/fj.202100801R [Abstract] [CrossRef] [Google Scholar]

217. Shahrokh S, Baradaran Ghavami S, Asadzadeh Aghdaei H, Parigi TL, Farmani M, Danese S, et al. . High prevalence of SARS-Coronavirus-2 in patients with inflammatory bowel disease and the role of soluble angiotensin converting Enzyme2. Arch Physiol Biochem. (2024) 130:325–32. 10.1080/13813455.2022.2080228 [Abstract] [CrossRef] [Google Scholar]

218. Bednash JS, Johns F, Farkas D, Elhance A, Adair J, Cress K, et al. . Inhibiting the deubiquitinase UCHL1 reduces SARS-coV-2 viral uptake by ACE2. Am J Respir Cell Mol Biol. (2023) 68:566–76. 10.1165/rcmb.2022-0331OC [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

219. Jin S, He X, Ma L, Zhuang Z, Wang Y, Lin M, et al. . Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy. Nat Commun. (2022) 13:5204. 10.1038/s41467-022-32957-y [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

220. Bulek K, Zhao J, Liao Y, Rana N, Corridoni D, Antanaviciute A, et al. . Epithelial-derived gasdermin D mediates nonlytic IL-1β release during experimental colitis. J Clin Invest. (2020) 130:4218–34. 10.1172/JCI138103 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

221. Saadh MJ, Mikhailova MV, Rasoolzadegan S, Falaki M, Akhavanfar R, Gonzáles JLA, et al. . Therapeutic potential of mesenchymal stem/stromal cells (MSCs)-based cell therapy for inflammatory bowel diseases (IBD) therapy. Eur J Med Res. (2023) 28:47. 10.1186/s40001-023-01008-7 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

222. Guo G, Tan Z, Liu Y, Shi F, She J. The therapeutic potential of stem cell-derived exosomes in the ulcerative colitis and colorectal cancer. Stem Cell Res Ther. (2022) 13:138. 10.1186/s13287-022-02811-5 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

223. Ocansey DKW, Zhang L, Wang Y, Yan Y, Qian H, Zhang X, et al. . Exosome-mediated effects and applications in inflammatory bowel disease. Biol Rev Camb Philos Soc. (2020) 95:1287–307. 10.1111/brv.12608 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

224. Schirmer M, Garner A, Vlamakis H, Xavier RJ. Microbial genes and pathways in inflammatory bowel disease. Nat Rev Microbiol. (2019) 17:497–511. 10.1038/s41579-019-0213-6 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

225. Prockop DJ, Olson SD. Clinical trials with adult stem/progenitor cells for tissue repair: let's not overlook some essential precautions. Blood. (2007) 109:3147–51. 10.1182/blood-2006-03-013433 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

226. Bhoj VG, Chen ZJ. Ubiquitylation in innate and adaptive immunity. Nature. (2009) 458:430–7. 10.1038/nature07959 [Abstract] [CrossRef] [Google Scholar]