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OTUD3 prevents ulcerative colitis by inhibiting microbiota-mediated STING activation
Bo Li1,2, Taiki Sakaguchi1, Haruka Tani1,3
1Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.
OTU deubiquitinase 3 (OTUD3) in intestinal fibroblasts prevents ulcerative colitis (UC) by regulating the host-microbiota interaction. This mechanism involves OTUD3 deubiquitinating stimulator of interferon genes (STING) in response to microbial signals.
Area of Science:
- Gastroenterology
- Immunology
- Microbiology
Background:
- Ulcerative colitis (UC) involves complex host-microbiota interactions.
- Intestinal fibroblasts are key in UC pathogenesis, but their response to host-microbiota signaling is unclear.
Purpose of the Study:
- To investigate the role of OTU deubiquitinase 3 (OTUD3) in intestinal fibroblast response to microbial stimuli in UC.
- To elucidate the mechanism by which OTUD3 influences the host-microbiota interaction in UC.
Main Methods:
- Investigated OTUD3's function in deubiquitinating stimulator of interferon genes (STING).
- Utilized a mouse model with a UC risk variant in the Otud3 gene.
- Transplanted fecal microbiota from UC patients into mice.
Main Results:
- OTUD3 suppresses the pathologic activation of colonic fibroblasts exposed to microbial cyclic GMP-AMP (3'3'-cGAMP).
- Mice with an Otud3 variant exhibited UC pathology after receiving UC patient-derived microbiota.
- Demonstrated OTUD3's role in modulating STING-dependent responses to microbial products.
Conclusions:
- OTUD3 acts as a critical regulator in host fibroblasts, mitigating adverse responses to STING-activating microbiota.
- Highlights a novel mechanism linking fibroblast function, host-microbiota crosstalk, and UC development.
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