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.
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All data needed to evaluate the conclusions in this study are presented in this manuscript or the supplementary information. The materials described in this study are either commercially available or available upon reasonable request from the corresponding authors.
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We graciously thank Fuping You (Peking University, Beijing, China) for sharing Otud6a−/− mice. This study was supported by the National Natural Science Foundation of China (81970338 and 82170373 to YW), Medical and Health Research Project of Zhejiang Province (2023XY164 to LH), and Key Scientific Project of Wenzhou City (ZY2021021 to YW).
The authors declare no competing interests.
The study about the human colonic biopsy samples was approved by the Human Ethical Committee of the Quzhou People’s Hospital (Approval document #2022–0037). All animal studies were approved by the Institutional Animal Policy and Welfare Committee of Wenzhou Medical University (Approval document #wydw2022-0202).
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Liu, X., Fang, Y., Lv, X. et al. Deubiquitinase OTUD6A in macrophages promotes intestinal inflammation and colitis via deubiquitination of NLRP3. Cell Death Differ (2023). https://doi.org/10.1038/s41418-023-01148-7