OTUD3 prevents ulcerative colitis by inhibiting microbiota-mediated STING activation
Bo Li, Taiki Sakaguchi, Haruka Tani, T Ito, Mari Murakami, Ryu Okumura, Masao Kobayashi, Daisuke Okuzaki, Daisuke Motooka, Hiroki Ikeuchi, Takayuki Ogino, Tsunekazu Mizushima, Seiichi Hirota, Yuriko Otake, 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
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.