Deubiquitinase OTUD6A in macrophages promotes intestinal inflammation and colitis via deubiquitination of NLRP3

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, which has been shown to increase the incidence of colorectal Cancer. Recent studies have highlighted the role of ubiquitination, a post-translational modification, in the occurrence and development of colonic inflammation. Ovarian tumor Deubiquitinase 6 A (OTUD6A) is a deubiquitinating Enzyme, which regulates cell proliferation and tumorigenesis. In this study, we investigated the expression and role of OTUD6A in IBD. Wide-type or Otud6a^-/- mice were used to develop dextran sodium sulfate (DSS)- or 2,6,4-trinitrobenzene sulfonic acid (TNBS)-induced colitis model, as well as azoxymethane (AOM)/DSS-induced colitis-associated Cancer model. Bone marrow-derived macrophages (BMDMs) were isolated from wild-type and Otud6a^-/- mice to dissect molecular mechanisms. Our data show that OTUD6A deficiency attenuated DSS or TNBS-induced colitis, as well as AOM/DSS-induced colitis-related colon Cancer in vivo. Bone marrow transplantation experiments further revealed that OTUD6A in myeloid cells was responsible for exacerbation of DSS-induced colitis. Mechanistically, OTUD6A directly bound to NACHT domain of NLRP3 inflammasome and selectively cleaved K48-linked polyubiquitin chains from NLRP3 at K430 and K689 to enhance the stability of NLRP3, leading to increased IL-1β level and inflammation. Taken together, our research identifies a new function of OTUD6A in the pathogenesis of colitis by promoting NLRP3 inflammasome activation, suggesting that OTUD6A could be a potential target for the treatment of IBD.