Deubiquitinase OTUD6A in macrophages promotes intestinal inflammation and colitis via deubiquitination of NLRP3
Deubiquitinase OTUD6A in macrophages promotes intestinal inflammation and colitis via deubiquitination of NLRP3
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DOI：
10.1038/s41418-023-01148-7
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发表时间：
2023-03-17
影响因子：
12.4
通讯作者：
Wang, Yi
中科院分区：
文献类型：
--
作者：
Liu, Xin;Fang, Yi;Wang, Yi
炎症性肠病（IBD）是一种胃肠道慢性炎症性疾病，已被证明会增加结直肠癌的发病率。最近的研究强调了泛素化（一种翻译后修饰）在结肠炎症发生和发展中的作用。卵巢肿瘤去泛素酶 6 A (OTUD6A) 是一种去泛素化酶，可调节细胞增殖和肿瘤发生。在本研究中，我们研究了 OTUD6A 在 IBD 中的表达和作用。 Widetype 或 Otud6a(-/-) 小鼠用于开发右旋糖酐硫酸钠 (DSS) 或 2,6,4-三硝基苯磺酸 (TNBS) 诱导的结肠炎模型，以及氧化偶氮甲烷 (AOM)/DSS 诱导的结肠炎相关癌症模型。从野生型和 Otud6a(-/-) 小鼠中分离骨髓源性巨噬细胞 (BMDM) 以剖析分子机制。我们的数据显示，OTUD6A 缺陷在体内减弱了 DSS 或 TNBS 诱导的结肠炎，以及 AOM/DSS 诱导的结肠炎相关结肠癌。骨髓移植实验进一步表明，骨髓细胞中的 OTUD6A 是 DSS 诱导的结肠炎恶化的原因。从机制上讲，OTUD6A直接与NLRP3炎症小体的NACHT结构域结合，并在K430和K689处选择性地从NLRP3上裂解K48连接的多聚泛素链，以增强NLRP3的稳定性，导致IL-1 ss水平增加和炎症。综上所述，我们的研究通过促进 NLRP3 炎症小体激活，确定了 OTUD6A 在结肠炎发病机制中的新功能，表明 OTUD6A 可能成为治疗 IBD 的潜在靶点。
IInflammatory 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. Widetype 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-1 ss 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.