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The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NF-κB signaling

Cellular & Molecular Immunology volume 19, pages 276–289 (2022)Cite this article

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Abstract

The E3 ubiquitin ligase (E3)-mediated ubiquitination and deubiquitinase (DUB)-mediated deubiquitination processes are closely associated with the occurrence and development of colonic inflammation. Ovarian tumor deubiquitinase 1 (OTUD1) is involved in immunoregulatory functions linked to infectious diseases. However, the effect of OTUD1 on intestinal immune responses during colonic inflammatory disorders such as inflammatory bowel disease (IBD) remains unclear. Here, we show that loss of OTUD1 in mice contributes to the pathogenesis of dextran sulfate sodium (DSS)-induced colitis via excessive release of proinflammatory cytokines. In addition, bone marrow transplantation experiments revealed that OTUD1 in hematopoietic cells plays a dominant role in protection against colitis. Mechanistically, OTUD1 physically interacts with receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and selectively cleaves K63-linked polyubiquitin chains from RIPK1 to inhibit the recruitment of NF-κB essential modulator (NEMO). Moreover, the expression of OTUD1 in mucosa samples from ulcerative colitis (UC) patients was lower than that in mucosa samples from healthy controls. Furthermore, we demonstrate that the UC-associated OTUD1 G430V mutation abolishes the ability of OTUD1 to inhibit RIPK1-mediated NF-κB activation and intestinal inflammation. Taken together, our study unveils a previously unexplored role of OTUD1 in moderating intestinal inflammation by inhibiting RIPK1-mediated NF-κB activation, suggesting that the OTUD1-RIPK1 axis could be a potential target for the treatment of IBD.

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Acknowledgements

We thank Ke Zhao (State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of LifeOmics, Beijing) for technical assistance in the mouse transplantation experiments and Tong Zhao (Institute of Microbiology, Chinese Academy of Sciences, Beijing) for helping with the flow cytometry data generation and analysis.

Funding

This work was jointly supported by the National Key Research and Development Project of China (2021YFA1300200), the Biosafety Special Project of China (19SWAQ17), the National Natural Science Foundation of China (31800746, 31830003 and 81825014), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29020000) and the State Key Laboratory of Proteomics (SKLP-K202001).

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Author notes

  1. These authors contributed equally: Bo Wu, Lihua Qiang, Yong Zhang, Yesheng Fu.

Authors and Affiliations

  1. State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China

    Bo Wu, Yong Zhang, Yesheng Fu, Yan-Ge Wei, Hongmiao Dai, Yingwei Ge, Mingqiu Liu, Xuemei Zhou, Zhiqiang Peng, Hongchang Li, Chun-Ping Cui & Lingqiang Zhang

  2. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China

    Lihua Qiang, Yong Zhang, Mengyuan Zhao, Zehui Lei, Zhe Lu, Jing Wang & Cui Hua Liu

  3. Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 101408, China

    Lihua Qiang, Mengyuan Zhao, Zehui Lei, Zhe Lu & Cui Hua Liu

  4. International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu, China

    Hui Zheng

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Contributions

CHL and LZ designed the research; BW, LQ, YZ and YF performed most experiments and analyzed the data; MZ, ZL, ML, XZ, ZP, HD, YW, YG and JW also performed experiments; HZ provided the Otud1−/− mice; HL helped with the animal experiments; BW, LQ and YZ wrote the paper; CHL and LZ read and approved the final version of the paper.

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Correspondence to Cui Hua Liu or Lingqiang Zhang.

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Wu, B., Qiang, L., Zhang, Y. et al. The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NF-κB signaling. Cell Mol Immunol 19, 276–289 (2022). https://doi.org/10.1038/s41423-021-00810-9

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