OTUD3 prevents ulcerative colitis by inhibiting microbiota-mediated STING activation

IF 16.3 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-07-18 DOI:10.1126/sciimmunol.adm6843

Bo Li, Taiki Sakaguchi, Haruka Tani, Takayoshi Ito, Mari Murakami, Ryu Okumura, Masao Kobayashi, Daisuke Okuzaki, Daisuke Motooka, Hiroki Ikeuchi, Takayuki Ogino, Tsunekazu Mizushima, Seiichi Hirota, Yuriko Otake-Kasamoto, Toshihiro Kishikawa, Shota Nakamura, Kouji Kobiyama, Ken J. Ishii, Takao Hashiguchi, Taro Kawai, Etsushi Kuroda, Shinichiro Shinzaki, Wataru Ise, Tomohiro Kurosaki, Akira Kikuchi, Yoshihiko Tomofuji, Yukinori Okada, Kiyoshi Takeda, Hisako Kayama

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Abstract

Ulcerative colitis (UC) develops through a complicated interaction between the host and microbiota. Intestinal fibroblasts are believed to play crucial roles in the pathogenesis of UC, but the influence of the host-microbiota interaction on the pathophysiology of intestinal fibroblasts remains poorly understood. Here, we demonstrate that OTU deubiquitinase 3 (OTUD3) suppresses pathologic activation of fibroblasts exposed to microbial cyclic GMP-AMP (3′3’-cGAMP) in the colon by deubiquitinating stimulator of interferon genes (STING). Mice harboring a UC risk missense variant in the Otud3 gene showed pathological features of UC in the colon after transplantation of a fecal microbiota with the potential to produce excessive cGAMP from patients with UC. Collectively, these results highlight a mechanism of the interaction between OTUD3 in host fibroblasts and STING-activating microbiota in UC development.

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OTUD3通过抑制微生物介导的STING激活来预防溃疡性结肠炎

溃疡性结肠炎（UC）通过宿主和微生物群之间复杂的相互作用而发展。肠成纤维细胞被认为在UC的发病机制中起着至关重要的作用，但宿主-微生物群相互作用对肠成纤维细胞病理生理的影响尚不清楚。在这里，我们证明OTU去泛素酶3 （OTUD3）通过干扰素基因的去泛素刺激剂（STING）抑制结肠中暴露于微生物环GMP-AMP （3 ' 3 ' -cGAMP）的成纤维细胞的病理激活。携带Otud3基因UC风险错义变体的小鼠在移植UC患者的粪便微生物群后显示出UC的病理特征，这些微生物群有可能产生过量的UC患者的cGAMP。总之，这些结果突出了宿主成纤维细胞中的OTUD3与UC发育中sting激活微生物群之间相互作用的机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.