Abstract
The activity and stability of the adapter protein MAVS (also known as VISA, Cardif and IPS-1), which critically mediates cellular antiviral responses, are extensively regulated by ubiquitination. However, the process whereby MAVS is deubiquitinated is unclear. Here, we report that the ovarian tumor family deubiquitinase 4 (OTUD4) targets MAVS for deubiquitination. Viral infection leads to the IRF3/7-dependent upregulation of OTUD4 which interacts with MAVS to remove K48-linked polyubiquitin chains, thereby maintaining MAVS stability and promoting innate antiviral signaling. Knockout or knockdown of OTUD4 impairs RNA virus-triggered activation of IRF3 and NF-κB, expression of their downstream target genes, and potentiates VSV replication in vitro and in vivo. Consistently, Cre-ER Otud4fl/fl or Lyz2-Cre Otud4fl/fl mice produce decreased levels of type I interferons and proinflammatory cytokines and exhibit increased sensitivity to VSV infection compared to their control littermates. In addition, reconstitution of MAVS into OTUD4-deficient cells restores virus-induced expression of downstream genes and cellular antiviral responses. Together, our findings uncover an essential role of OTUD4 in virus-triggered signaling and contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses.
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Acknowledgements
We would like to thank Drs. Hong-Bing Shu (Wuhan University) and Chen Dong (Tsinghua University) for reagents, members of Zhong lab and the core facilities of Medical Research Institute for technical help. This study was supported by grants from the Ministry of Science and Technology of China (2014CB542601), Natural Science Foundation of China (31521091, 31601131, 31671454 and 31622036), National Natural Science Foundation of Hubei Province (2018CFA016), Wuhan University (2042017kf0199 and 2042017kf0242) and State Key Laboratory of Veterinary Etiological Biology (SKLVEB2017KFKT004).
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B.Z. designed and supervised the study. T.L. designed and performed the major experiments; K.Y., L.Y., M.Z. and Z.C. helped with the animal studies; Z.Z. and Y.R. performed the ChIP analysis; Q.Z. provided reagents; B.Z., D.L. and T.L. wrote the paper. All authors analyzed data.
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Liuyu, T., Yu, K., Ye, L. et al. Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS. Cell Res 29, 67–79 (2019). https://doi.org/10.1038/s41422-018-0107-6
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DOI: https://doi.org/10.1038/s41422-018-0107-6
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