Quantitative Temporal Proteomic Analysis of Vaccinia Virus Infection Reveals Regulation of Histone Deacetylases by an Interferon Antagonist

Cell Rep. 2019 May 7;27(6):1920-1933.e7. doi: 10.1016/j.celrep.2019.04.042.

Abstract

Vaccinia virus (VACV) has numerous immune evasion strategies, including multiple mechanisms of inhibition of interferon regulatory factor 3 (IRF-3), nuclear factor κB (NF-κB), and type I interferon (IFN) signaling. Here, we use highly multiplexed proteomics to quantify ∼9,000 cellular proteins and ∼80% of viral proteins at seven time points throughout VACV infection. A total of 265 cellular proteins are downregulated >2-fold by VACV, including putative natural killer cell ligands and IFN-stimulated genes. Two-thirds of these viral targets, including class II histone deacetylase 5 (HDAC5), are degraded proteolytically during infection. In follow-up analysis, we demonstrate that HDAC5 restricts replication of both VACV and herpes simplex virus type 1. By generating a protein-based temporal classification of VACV gene expression, we identify protein C6, a multifunctional IFN antagonist, as being necessary and sufficient for proteasomal degradation of HDAC5. Our approach thus identifies both a host antiviral factor and a viral mechanism of innate immune evasion.

Keywords: histone deacetylase; host-pathogen interaction; immune evasion; innate immunity; interferon; poxvirus; quantitative proteomics; restriction factor; systems virology; tandem mass tag.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytomegalovirus / metabolism
  • Down-Regulation
  • Gene Expression Regulation, Viral
  • Herpesvirus 1, Human / metabolism
  • Histone Deacetylases / metabolism*
  • Host-Pathogen Interactions
  • Humans
  • Immune Evasion
  • Interferons / antagonists & inhibitors*
  • Interferons / metabolism
  • Membrane Proteins / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Proteomics*
  • Time Factors
  • Vaccinia / metabolism*
  • Vaccinia / virology*
  • Vaccinia virus / genetics
  • Vaccinia virus / immunology
  • Vaccinia virus / metabolism*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism

Substances

  • Membrane Proteins
  • Viral Proteins
  • Interferons
  • Proteasome Endopeptidase Complex
  • Histone Deacetylases