OTUD3 prevents ulcerative colitis by inhibiting microbiota-mediated STING activation.
作者信息
Li Bo, Sakaguchi Taiki, Tani Haruka, Ito Takayoshi, Murakami Mari, Okumura Ryu, Kobayashi Masao, Okuzaki Daisuke, Motooka Daisuke, Ikeuchi Hiroki, Ogino Takayuki, Mizushima Tsunekazu, Hirota Seiichi, Otake-Kasamoto Yuriko, Kishikawa Toshihiro, Nakamura Shota, Kobiyama Kouji, Ishii Ken J, Hashiguchi Takao, Kawai Taro, Kuroda Etsushi, Shinzaki Shinichiro, Ise Wataru, Kurosaki Tomohiro, Kikuchi Akira, Tomofuji Yoshihiko, Okada Yukinori, Takeda Kiyoshi, Kayama Hisako
机构信息
Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.
Department of Gastroenterology, Endoscopy Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200136, China.
出版信息
Sci Immunol. 2025 Jul 18;10(109):eadm6843. doi: 10.1126/sciimmunol.adm6843.
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 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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