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SENP6 restricts the IFN-I-induced signaling pathway and antiviral activity by deSUMOylating USP8

Cellular & Molecular Immunology volume 21, pages 892–904 (2024)Cite this article

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Abstract

Type I interferon (IFN-I) exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections. In this study, we unveil SENP6 as a potent regulator of IFN-I antiviral activity. SENP6 does not impact the production of IFN-I induced by viruses but rather modulates IFN-I-activated signaling. Mechanistically, SENP6 constitutively interacts with USP8 and inhibits the SUMOylation of USP8, consequently restricting the interaction between USP8 and IFNAR2. The dissociation of USP8 from IFNAR2 enhances IFNAR2 ubiquitination and degradation, thus attenuating IFN-I antiviral activity. Correspondingly, the downregulation of SENP6 promotes the interaction between USP8 and IFNAR2, leading to a reduction in IFNAR2 ubiquitination and, consequently, an enhancement in IFN-I-induced signaling. This study deciphers a critical deSUMOylation-deubiquitination crosstalk that finely regulates the IFN-I response to viral infection.

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Acknowledgements

The authors thank Dr. F Zhou (Soochow University) and C Zheng (Fujian Medical University) for important reagents. This work is supported by grants from the National Natural Science Foundation of China (31970844, 32170927) to SDX.

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Authors and Affiliations

  1. Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, China

    Jing Guo, Hui Zheng & Sidong Xiong

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  1. Jing Guo
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  2. Hui Zheng
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  3. Sidong Xiong
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Contributions

JG performed the experiments. SDX, HZ, and JG designed experiments, analyzed data, and wrote the paper. SDX and HZ discussed the manuscript. SDX and HZ were responsible for research supervision, coordination, and strategy.

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Correspondence to Hui Zheng or Sidong Xiong.

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Guo, J., Zheng, H. & Xiong, S. SENP6 restricts the IFN-I-induced signaling pathway and antiviral activity by deSUMOylating USP8. Cell Mol Immunol 21, 892–904 (2024). https://doi.org/10.1038/s41423-024-01193-3

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