The deubiquitinase USP2 preserves intestinal barrier through the TRAF6/NF-κB/MLCK/MLC signaling in ulcerative colitis

Disruption of the physical barrier of intestinal epithelial cells is a hallmark of ulcerative colitis (UC). Deubiquitinating enzymes (DUBs), which modify the stability, localization, or activity of substrates by removing ubiquitin chains, have been involved in the development of UC. However, the biological role of DUBs in intestinal epithelial cells (IECs) has yet to be extensively investigated. In this work, we revealed that USP2 as the most differentially expressed DUB in the colon of mice with dextran sodium sulfate (DSS)-induced colitis and was downregulated mainly in the intestinal epithelium. Notably, the expression of USP2 was correlated with the levels of tight junction (TJ) proteins. Furthermore we showed that USP2 expression was reduced in the intestine of mice with acute colitis induced by DSS, as well as in IECs stimulated with LPS. Overexpression of USP2 restored the LPS-induced the reduction of TJPs. Mechanistically, USP2 attenuates the activation of NF-κB and the phosphorylation of the myosin light chain, possibly by reducing the K63-linked polyubiquitin chain on the tumour necrosis factor receptor-associated factor 6 (TRAF6). In vivo, colonic-specific overexpression of USP2 in mice ameliorated DSS-induced barrier damage. Together, our study proposed USP2 as a new deubiquitinating enzyme molecule involved in the course of UC regulating the function of IECs during the progression of UC.