Intestinal Epithelial‐Derived USP13 Alleviates Colonic Inflammation by Suppressing GRP78‐mediated Endoplasmic Reticulum Stress

Inflammatory bowel disease (IBD) is a chronic condition in which endoplasmic reticulum (ER) stress and subsequent apoptosis of intestinal epithelial cells play significant roles. E3 ubiquitin ligases and deubiquitinases are crucial in IBD pathophysiology by modulating protein ubiquitination. This study investigated the regulatory role of a deubiquitinase ubiquitin-specific peptidase 13 (USP13) in a DSS-induced colitis mouse model and explored the underlying mechanism. Intestinal epithelial-specific Usp13 knockout (USP13^IEKO) mice were treated with DSS to induce colitis. Adeno-associated virus serotype 9 (AAV9) was constructed to overexpress UPS13 in colonic tissues. The results show that intestinal epithelial-specific USP13 knockout exacerbated DSS-induced colitis, linked to increased ER stress and apoptosis. Mechanistically, USP13 interacted with GRP78, attenuating ER stress-induced apoptosis and maintaining intestinal barrier integrity by selectively removing K63-linked ubiquitin at lysine 327. Moreover, restoration of USP13 expression via AAV9 in USP13^IEKO mice attenuated DSS-induced colitis and preserved intestinal barrier integrity. Also, USP13 levels were reduced in ulcerative colitis patients compared to the healthy controls, highlighting its protective role in intestinal health. These findings underscore the protective role of the USP13-GRP78 axis in IBD and suggest that targeting USP13 through intestinal epithelial-specific gene therapy may be a potential therapeutic strategy for IBD.