International immunopharmacology · 2025
CYLD inhibits ubiquitin-mediated degradation of IRE1 to promote inflammatory injury in ulcerative colitis.
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Zhou Jianming, Xie Ruyi, Wang Ting, Xu Yuan, Zhang Bei
Аннотация
BACKGROUND: Previous studies have shown that elevated inositol-requiring enzyme 1 (IRE1) protein levels exacerbate ulcerative colitis (UC). However, the mechanism underlying the increase in IRE1 protein levels in UC remains unclear. Deubiquitinating enzymes (DUBs) have been demonstrated to play a key role in regulating intestinal inflammation. This study aimed to investigate the DUB that influenced IRE1 levels in UC and its specific regulatory mechanisms.
METHODS: The Ubibrowser 2.0 database was used to screen out IRE1-related DUBs. The combination of DUBs and IRE1 was verified by Co-IP detection. Dextran sulfate sodium (DSS)-induced UC mice and lipopolysaccharide (LPS)-induced intestinal epithelial cells (IECs) were utilized to explore the specific mechanism by which cylindromatosis lysine 63 deubiquitinase (CYLD) influence UC inflammatory injury. Moreover, the intestinal mucosa injury degree in mice were observed by HE staining, while cell activity and apoptosis in IECs were evaluated by CCK-8 and flow cytometry.
RESULTS: IRE1 knockdown prevented weight loss, decreased disease activity index score, increased colon length and reduced colon tissue inflammatory damage in UC mice. Furthermore, the ubiquitination level of IRE1 was significantly reduced in the colon tissues of UC mice. Subsequently, CYLD, a DUB, was identified as having the strongest correlation with IRE1 and was confirmed to bind directly to IRE1 in LPS-induced IECs. Mechanistically, CYLD knockdown decreased IRE1 protein level in LPS-induced IECs by promoting its ubiquitin-mediated degradation. Functionally, CYLD knockdown alleviated inflammatory damage in LPS-induced IECs and UC mice. The protective effects of CYLD knockdown were virtually eliminated by IRE1 overexpression in UC models.
CONCLUSION: In summary, CYLD inhibited the ubiquitin-mediated degradation of IRE1 to increase its protein level, promoting the development of colon tissue inflammatory damage in UC.
METHODS: The Ubibrowser 2.0 database was used to screen out IRE1-related DUBs. The combination of DUBs and IRE1 was verified by Co-IP detection. Dextran sulfate sodium (DSS)-induced UC mice and lipopolysaccharide (LPS)-induced intestinal epithelial cells (IECs) were utilized to explore the specific mechanism by which cylindromatosis lysine 63 deubiquitinase (CYLD) influence UC inflammatory injury. Moreover, the intestinal mucosa injury degree in mice were observed by HE staining, while cell activity and apoptosis in IECs were evaluated by CCK-8 and flow cytometry.
RESULTS: IRE1 knockdown prevented weight loss, decreased disease activity index score, increased colon length and reduced colon tissue inflammatory damage in UC mice. Furthermore, the ubiquitination level of IRE1 was significantly reduced in the colon tissues of UC mice. Subsequently, CYLD, a DUB, was identified as having the strongest correlation with IRE1 and was confirmed to bind directly to IRE1 in LPS-induced IECs. Mechanistically, CYLD knockdown decreased IRE1 protein level in LPS-induced IECs by promoting its ubiquitin-mediated degradation. Functionally, CYLD knockdown alleviated inflammatory damage in LPS-induced IECs and UC mice. The protective effects of CYLD knockdown were virtually eliminated by IRE1 overexpression in UC models.
CONCLUSION: In summary, CYLD inhibited the ubiquitin-mediated degradation of IRE1 to increase its protein level, promoting the development of colon tissue inflammatory damage in UC.