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OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING

Cellular & Molecular Immunology volume 18, pages 1945–1955 (2021)Cite this article

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Abstract

Stimulator of interferon genes (STING) is an adaptor protein that is critical for effective innate antiviral and antitumor immunity. The activity of STING is heavily regulated by protein ubiquitination, which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases. Here, we report that the deubiquitinase OTUD5 interacts with STING, cleaves its K48-linked polyubiquitin chains, and promotes its stability. Consistently, knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation. More importantly, Lyz2-Cre Otud5fl/Y mice and CD11-Cre Otud5fl/Y mice showed more susceptibility to herpes simplex virus type 1 (HSV-1) infection and faster development of melanomas than their corresponding control littermates, indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity. Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.

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All data generated or analyzed during this study are included in Figs. 1–6 and Supplementary Figs. S1–S5. Additional data sets that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (31730026, 81930039, and 81525012).

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Author notes

  1. These authors contributed equally: Yunyun Guo, Fei Jiang

Authors and Affiliations

  1. Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Biomedical Sciences, Shandong University, 250012, Jinan, Shandong, People’s Republic of China

    Yunyun Guo, Fei Jiang, Lingli Kong, Haifeng Wu, Honghai Zhang, Xiaorong Chen, Jian Zhao, Baoshan Cai, Yanqi Li, Chunhong Ma, Lei Zhang, Bingyu Liu, Yi Zheng & Chengjiang Gao

  2. Department of Pharmacology, School of Biomedical Sciences, Shandong University, 250012, Jinan, Shandong, People’s Republic of China

    Fan Yi

  3. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 100850, Beijing, People’s Republic of China

    Lingqiang Zhang

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  1. Yunyun Guo
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Contributions

C.G. conceived and designed the research; Y.G., F.J., L.K., J.Z., B.C., and Y.L. performed the research; H.W., H.Z., and X.C. provided reagents; C.M., F.Y., L.Z., B.L., and Y.Z. provided discussions; L.Z. provided Otud5fl/Y mice; Y.G., F.J., and C.G. analyzed the data; and C.G., Y.Z., and Y.G. wrote the paper.

Corresponding authors

Correspondence to Lingqiang Zhang or Chengjiang Gao.

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Guo, Y., Jiang, F., Kong, L. et al. OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING. Cell Mol Immunol 18, 1945–1955 (2021). https://doi.org/10.1038/s41423-020-00531-5

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