Zhou Ruochen, Cui Yuanyuan, Wang Weihao, Qu Yidan, Zhang Gaojie, Wang Xue, Sun Yili, Li Jia
Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Int Immunopharmacol. 2025 Sep 23;162:115099. doi: 10.1016/j.intimp.2025.115099. Epub 2025 Jun 19.
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.
肠上皮细胞物理屏障的破坏是溃疡性结肠炎（UC）的一个标志。去泛素化酶（DUBs）通过去除泛素链来改变底物的稳定性、定位或活性，已参与到UC的发展过程中。然而，DUBs在肠上皮细胞（IECs）中的生物学作用尚未得到广泛研究。在这项研究中，我们发现USP2是葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠结肠中差异表达最显著的DUB，且主要在肠上皮中下调。值得注意的是，USP2的表达与紧密连接（TJ）蛋白的水平相关。此外，我们发现DSS诱导的急性结肠炎小鼠肠道以及LPS刺激的IECs中USP2表达均降低。USP2的过表达恢复了LPS诱导的TJPs减少。机制上，USP2可能通过减少肿瘤坏死因子受体相关因子6（TRAF6）上K63连接的多聚泛素链来减弱NF-κB的激活和肌球蛋白轻链的磷酸化。在体内，小鼠结肠特异性过表达USP2可改善DSS诱导的屏障损伤。总之，我们的研究提出USP2是一种新的去泛素化酶分子，参与UC病程，在UC进展过程中调节IECs的功能。
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