Vaccinia E5 is a major inhibitor of the DNA sensor cGAS

Ning Yang (), Yi Wang, Peihong Dai, Tuo Li, Christian Zierhut, Adrian Tan, Tuo Zhang, Jenny Zhaoying Xiang, Alban Ordureau, Hironori Funabiki, Zhijian Chen and Liang Deng ()
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Ning Yang: Memorial Sloan Kettering Cancer Center
Yi Wang: Memorial Sloan Kettering Cancer Center
Peihong Dai: Memorial Sloan Kettering Cancer Center
Tuo Li: University of Texas Southwestern Medical Center
Christian Zierhut: The Rockefeller University
Adrian Tan: Weill Cornell Medical College
Tuo Zhang: Weill Cornell Medical College
Jenny Zhaoying Xiang: Weill Cornell Medical College
Alban Ordureau: Memorial Sloan Kettering Cancer Center
Hironori Funabiki: The Rockefeller University
Zhijian Chen: University of Texas Southwestern Medical Center
Liang Deng: Memorial Sloan Kettering Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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 not well understood. In this study, we screened 80 vaccinia 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. E5 is responsible for abolishing cGAMP production during vaccinia virus (Western Reserve strain) infection of dendritic cells. E5 localizes to the cytoplasm and nucleus of infected cells. Cytosolic E5 triggers ubiquitination of cGAS and proteasome-dependent degradation via interacting with cGAS. 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, and thereby improves antigen-specific T cell responses.

Date: 2023
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DOI: 10.1038/s41467-023-38514-5

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