USP25 augments XIAP-mediated signaling to safeguard intestinal homeostasis.

Nucleotide-binding oligomerization domain containing 2 (NOD2) recognizes conserved bacterial components in the cytoplasm to initiate innate immune responses, and its mutations are closely associated with Crohn's disease (CD). Here, we discover that the NOD2 signaling is regulated by the deubiquitinase USP25. Macrophages lacking USP25 exhibit impaired NOD2 signaling and are defective in cytokine production upon stimulation with muramyl dipeptide (MDP). USP25 enhances NOD2-initiated signal transduction by increasing the expression and recruitment of X-linked inhibitor of apoptosis protein (XIAP). In mice, USP25 deficiency exacerbates intestinal inflammation induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS), whereas USP25 overexpression alleviates TNBS-induced colitis. Moreover, USP25 deficiency leads to spontaneous intestinal inflammation in aged mice. Importantly, a known single nucleotide polymorphism associated with human inflammatory bowel disease compromises USP25 expression, and lower USP25 expression is detected in patients with CD. Thus, USP25 plays a critical role in NOD2 signaling and may represent a potential therapeutic target for CD.