OTUD3 prevents ulcerative colitis by inhibiting microbiota-mediated STING activation

Bo Li^{1

2}, Taiki Sakaguchi¹, Haruka Tani^{1

3}, Takayoshi Ito¹, Mari Murakami^{1

3}, Ryu Okumura^{1

3

4}, Masao Kobayashi¹, Daisuke Okuzaki^{3

4

5

6}, Daisuke Motooka^{3

4

5

7}, Hiroki Ikeuchi⁸, Takayuki Ogino⁹, Tsunekazu Mizushima^{9

10}, Seiichi Hirota¹¹, Yuriko Otake-Kasamoto¹², Toshihiro Kishikawa^{13

14}, Shota Nakamura^{3

4

5

7}, Kouji Kobiyama¹⁵, Ken J Ishii^{3

15}, Takao Hashiguchi¹⁶, Taro Kawai¹⁷, Etsushi Kuroda¹⁸, Shinichiro Shinzaki^{12

19}, Wataru Ise^{3

6}, Tomohiro Kurosaki³, Akira Kikuchi⁶, Yoshihiko Tomofuji^{13

20

21

22

23

24}, Yukinori Okada^{3

5

13

20

21

25}, Kiyoshi Takeda^{1

3

4

6}, Hisako Kayama^{1

3

26}

Affiliations

¹ Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.
² Department of Gastroenterology, Endoscopy Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200136, China.
³ WPI Immunology Frontier Research Center, University of Osaka, Suita, Osaka 565-0871, Japan.
⁴ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, University of Osaka, Suita, Osaka 565-0871, Japan.
⁵ Genome Information Research Center, Research Institute for Microbial Diseases, University of Osaka, Suita, Osaka 565-0871, Japan.
⁶ Center for Infectious Disease Education and Research, University of Osaka, Suita, Osaka 565-0871, Japan.
⁷ Department of Infection Metagenomics, Research Institute for Microbial Diseases, University of Osaka, Suita, Osaka 565-0871, Japan.
⁸ Department of Gastroenterological Surgery, Division of Inflammatory Bowel Disease Surgery, Hyogo Medical University, Nishinomiya, Hyogo 663-8501, Japan.
⁹ Department of Gastroenterological Surgery, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.
¹⁰ Department of Gastroenterological Surgery, Osaka Police Hospital, Osaka, Osaka 543-0035, Japan.
¹¹ Department of Surgical Pathology, Hyogo Medical University, Nishinomiya, Hyogo 663-8501, Japan.
¹² Department of Gastroenterology and Hepatology, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.
¹³ Department of Statistical Genetics, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.
¹⁴ Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan.
¹⁵ Division of Vaccine Science, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo (IMSUT), Tokyo 108-8639, Japan.
¹⁶ Institute for Life and Medical Sciences, Kyoto University, Kyoto, Kyoto 606-8507, Japan.
¹⁷ Laboratory of Molecular Immunobiology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), Ikoma, Nara 630-0192, Japan.
¹⁸ Department of Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo 663-8501, Japan.
¹⁹ Department of Gastroenterology, Hyogo Medical University, Nishinomiya, Hyogo 663-8501, Japan.
²⁰ Department of Genome Informatics, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
²¹ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
²² Center for Data Sciences, Brigham and Women's Hospital, Boston, MA 02115, USA.
²³ Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
²⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
²⁵ Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), University of Osaka, Suita, Osaka 565-0871, Japan.
²⁶ Institute for Advanced Co-Creation Studies, University of Osaka, Suita, Osaka 565-0871, Japan.

PMID: 40680146
DOI: 10.1126/sciimmunol.adm6843

OTUD3 prevents ulcerative colitis by inhibiting microbiota-mediated STING activation

Bo Li et al. Sci Immunol. 2025.

. 2025 Jul 18;10(109):eadm6843.

doi: 10.1126/sciimmunol.adm6843. Epub 2025 Jul 18.

Authors

Affiliations

¹ Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.
² Department of Gastroenterology, Endoscopy Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200136, China.
³ WPI Immunology Frontier Research Center, University of Osaka, Suita, Osaka 565-0871, Japan.
⁴ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, University of Osaka, Suita, Osaka 565-0871, Japan.
⁵ Genome Information Research Center, Research Institute for Microbial Diseases, University of Osaka, Suita, Osaka 565-0871, Japan.
⁶ Center for Infectious Disease Education and Research, University of Osaka, Suita, Osaka 565-0871, Japan.
⁷ Department of Infection Metagenomics, Research Institute for Microbial Diseases, University of Osaka, Suita, Osaka 565-0871, Japan.
⁸ Department of Gastroenterological Surgery, Division of Inflammatory Bowel Disease Surgery, Hyogo Medical University, Nishinomiya, Hyogo 663-8501, Japan.
⁹ Department of Gastroenterological Surgery, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.
¹⁰ Department of Gastroenterological Surgery, Osaka Police Hospital, Osaka, Osaka 543-0035, Japan.
¹¹ Department of Surgical Pathology, Hyogo Medical University, Nishinomiya, Hyogo 663-8501, Japan.
¹² Department of Gastroenterology and Hepatology, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.
¹³ Department of Statistical Genetics, Graduate School of Medicine, University of Osaka, Suita, Osaka 565-0871, Japan.
¹⁴ Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan.
¹⁵ Division of Vaccine Science, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo (IMSUT), Tokyo 108-8639, Japan.
¹⁶ Institute for Life and Medical Sciences, Kyoto University, Kyoto, Kyoto 606-8507, Japan.
¹⁷ Laboratory of Molecular Immunobiology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), Ikoma, Nara 630-0192, Japan.
¹⁸ Department of Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo 663-8501, Japan.
¹⁹ Department of Gastroenterology, Hyogo Medical University, Nishinomiya, Hyogo 663-8501, Japan.
²⁰ Department of Genome Informatics, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
²¹ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
²² Center for Data Sciences, Brigham and Women's Hospital, Boston, MA 02115, USA.
²³ Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
²⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
²⁵ Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), University of Osaka, Suita, Osaka 565-0871, Japan.
²⁶ Institute for Advanced Co-Creation Studies, University of Osaka, Suita, Osaka 565-0871, Japan.

PMID: 40680146
DOI: 10.1126/sciimmunol.adm6843

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.

PubMed Disclaimer

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Atypon
- Ovid Technologies, Inc.
Medical
- MedlinePlus Health Information
Molecular Biology Databases
- Mouse Genome Informatics (MGI)
Research Materials
- NCI CPTC Antibody Characterization Program

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

OTUD3 prevents ulcerative colitis by inhibiting microbiota-mediated STING activation

Affiliations

OTUD3 prevents ulcerative colitis by inhibiting microbiota-mediated STING activation

Authors

Affiliations

Abstract

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials