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

  • Cell Death Differ. 2023 Mar 17. doi: 10.1038/s41418-023-01148-7.
Xin Liu  1  2 ,  Yi Fang  1 ,  Xinting Lv  2 ,  Chenghong Hu  1 ,  Guorong Chen  3 ,  Lingxi Zhang  1 ,  Bo Jin  1 ,  Lijiang Huang  4 ,  Wu Luo  1 ,  Guang Liang  2 ,  Yi Wang  5  6  7
Affiliations
  • 1. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2. Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 3. Department of Pathology, the Affiliated Quzhou Hospital of Wenzhou Medical University, Quzhou, Zhejiang, China.
  • 4. Department of Gastroenterology, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China.
  • 5. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China. [email protected].
  • 6. Department of Gastroenterology, the Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China. [email protected].
  • 7. School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, China. [email protected].
PMID: 36932155 DOI: 10.1038/s41418-023-01148-7
Abstract

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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