Vaccinia E5 is a major inhibitor of the DNA sensor cGAS

Yang, N.; Wang, Y.; Dai, P.; Li, T.; Zierhut, C.; Tan, A.; Zhang, T.; Pan, H.; Li, Z.; Ordureau, A.; Xiang, J. Z.; Hendrickson, R. C.; Funabiki, H.; Chen, Z.; Deng, L.

doi:10.1101/2021.10.25.465197

bioRxiv · 10.1101/2021.10.25.465197

Vaccinia E5 is a major inhibitor of the DNA sensor cGAS

Yang, N.·Wang, Y.·Dai, P.·Li, T.·Zierhut, C.·Tan, A.·Zhang, T.·Pan, H.·Li, Z.·Ordureau, A.·Xiang, J. Z.·Hendrickson, R. C.·Funabiki, H.·Chen, Z.·Deng, L.

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Abstract

The DNA sensor cyclic GMP-AMP synthase (cGAS) is critical in host antiviral immunity. Vaccinia virus (VACV) is a large cytoplasmic DNA virus that belongs to the poxvirus family. How vaccinia virus antagonizes the cGAS-mediated cytosolic DNA-sensing pathway is largely unknown. In this study, we screened 82 vaccinia viral genes to identify potential viral inhibitors of the cGAS/Stimulator of interferon gene (STING) pathway. We discovered that vaccinia E5 is a virulence factor and a major inhibitor of cGAS that elicits proteasome-dependent cGAS degradation. E5 localizes to the cytoplasm and nuclei of infected cells. Cytosolic E5 triggers K48-linked ubiquitination of cGAS and proteasome-dependent degradation via interacting with cGAS. E5 itself also undergoes ubiquitination and degradation. Deleting the E5R gene from the Modified vaccinia virus Ankara (MVA) genome strongly induces type I IFN production by dendritic cells (DCs) and promotes DC maturation, thereby improving the immunogenicity of the viral vector.

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Yang, N., Wang, Y., Dai, P., Li, T., Zierhut, C., Tan, A., Zhang, T., Pan, H., Li, Z., Ordureau, A., Xiang, J. Z., Hendrickson, R. C., Funabiki, H., Chen, Z., Deng, L.. 2021-10-26. Vaccinia E5 is a major inhibitor of the DNA sensor cGAS. https://doi.org/10.1101/2021.10.25.465197

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