Vaccinia E5 is a major inhibitor of the DNA sensor cGAS

Nat Commun. 2023 May 22;14(1):2898. doi: 10.1038/s41467-023-38514-5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dendritic Cells* / immunology
  • Dendritic Cells* / virology
  • Female
  • HEK293 Cells
  • Humans
  • Interferon Type I / immunology
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleotidyltransferases* / immunology
  • Proteasome Endopeptidase Complex
  • T-Lymphocytes / immunology
  • Ubiquitination
  • Vaccinia virus* / pathogenicity
  • Viral Proteins* / genetics
  • Viral Proteins* / immunology
  • Virulence Factors / immunology

Substances

  • cGAS protein, mouse
  • Nucleotidyltransferases
  • Virulence Factors
  • E5R protein, Vaccinia virus
  • Viral Proteins
  • Proteasome Endopeptidase Complex
  • Interferon Type I
  • Sting1 protein, mouse
  • Membrane Proteins