Abstract Background Anti-TNF treatment has been widely used to treat ulcerative colitis (UC). However, a comparable proportion of patients are unable to achieve satisfactory therapeutic effect after infliximab (IFX) treatment, the widely used monoclonal antibody against TNF-α. Aberrantly excessive intestinal inflammation, independent on TNF-α, could be responsible for impaired therapeutic effect of anti-TNF treatment.Tripartite motif (TRIM) family proteins, most of which have E3 ubiquitin ligase activities due to the RING-finger domain, mediate the ubiquitination of numerous protein substrates to regulate diverse biological processes, including inflammatory diseases and carcinogenesis. Recent studies revealed that TRIM27 was identified as a key genetic factor involved in gut homeostasis and promoted colitis in Trim27-/- total knockout mice. Yet, the biological function and dysregulated mechanisms of TRIM27 during intestinal epithelial inflammation in UC remains largely undefined. Methods The functions and mechanism of TRIM27 in UC were detected in vitro and in Villin-Trim27flox/flox mice Results This study makes three conceptual advances in TRIM27’s fucntion and UC. First, our findings suggest that TRIM27 functions as a negative regulator of the IKK complex activation to promote the ubiquitination and subsequent degradation of TRAF6 and IKKα, revealing TRIM27 as an anti-inflammatory factor during the intestinal inflammation in an E3 ubiquitin ligase-dependent manner. Second, we discover the USP7/TRIM27-IKK double negative feedback loop involved in the regulation of intestinal inflammation. Phosphorylation and ubiquitination modification of TRIM27 are crucial for its stability. Phosphorylation of TRIM27 of S173 by IKKβ impairs its binding with USP7, which in turn suppresses subsequent USP7-mediated K48-linked deubiquitination, leading to decreased TRIM27 protein in response to intestinal inflammation. Therefore, our study reveals a new double negative feedback loop of IKK complex by USP7-TRIM27, highlighting the anti-inflammatory role of TRIM27 in UC. Third, our study highlights the therapeutic potential of TRIM27 overexpression to enhance the effect of TNF-α antagonists. Our findings suggest that overexpression of TRIM27 markedly enhance the therapeutic effect of IFX, which suggests that increased expression of TRIM27 could synergize with IFX to inhibit intestinal inflammation. Conclusion Overall, our study identifies epithelial TRIM27 as a bona fide negative modulator of intestinal inflammation and USP7/TRIM27-IKK as a new double negative feedback mechanism of the NF-κB pathway, which supports the use of TRIM27 replenishment as a potential therapeutic strategy for UC. Conflict of interest: Dr. Xu, Weimin: No conflict of interest Hua, Zhebin: No conflict of interest Dai, Zhujiang: No conflict of interest Liu, Chen-Ying: No conflict of interest Du, Peng: No conflict of interest
Xu et al. (Thu,) studied this question.
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