OTUD5 maintains STAT1/2 stability and promotes IFNγ-driven intestinal inflammation
TL;DR
Using an intestinal epithelial cell -specific Otud5 KO mouse model, it is shown that Otud5 deficiency significantly alleviated the IFNγ-dependent colitis induced by dextran sulfate sodium, as evidenced by reduced weight loss and diminished infiltration of Ly6C+ inflammatory monocytes.
Abstract
Inflammatory bowel disease is characterized by unresolved mucosal inflammation driven mainly by TNFα and/or interferon gamma (IFNγ). While anti-TNFα biologics are a clinical mainstay, therapeutic resistance remains a significant hurdle. The molecular mechanisms that sustain inflammation in anti-TNFα nonresponders are not fully understood. In human colon biopsies, we identified significant upregulation of the deubiquitinase OTUD5 in nonresponders compared to responders, suggesting its involvement in therapy resistance. Using an intestinal epithelial cell -specific Otud5 KO mouse model, we show that Otud5 deficiency significantly alleviated the IFNγ-dependent colitis induced by dextran sulfate sodium, as evidenced by reduced weight loss and diminished infiltration of Ly6C+ inflammatory monocytes. Mechanistically, IFNγ induces OTUD5 expression through a nontranscriptional mechanism; in turn, OTUD5 stabilizes STAT1 and STAT2 by preventing their ubiquitination and subsequent degradation. This sustains IFNγ-ISGF3 signaling, which directly drives the expression of CCL8, a critical chemokine for monocyte recruitment. Targeting this pathway with a newly identified small-molecule inhibitor, CT1170, which exhibits potent activity against OTUD5, blocked the IFNγ-ISGF3-CCL8 axis, halted colitis progression, and suppressed colitis-elicited tumorigenesis. These findings were validated in human inflammatory bowel disease organoids, where CT1170 effectively disrupted IFNγ-driven inflammatory signaling.