Increased susceptibility to DNA virus infection in mice with a GCN2 mutation

J Virol. 2012 Feb;86(3):1802-8. doi: 10.1128/JVI.05660-11. Epub 2011 Nov 23.

Abstract

The downregulation of translation through eIF2α phosphorylation is a cellular response to diverse stresses, including viral infection, and is mediated by the GCN2 kinase, protein kinase R (PKR), protein kinase-like endoplasmic reticulum kinase (PERK), and heme-regulated inhibitor kinase (HRI). Although PKR plays a major role in defense against viruses, other eIF2α kinases also may respond to viral infection and contribute to the shutdown of protein synthesis. Here we describe the recessive, loss-of-function mutation atchoum (atc) in Eif2ak4, encoding GCN2, which increased susceptibility to infection by the double-stranded DNA viruses mouse cytomegalovirus (MCMV) and human adenovirus. This mutation was identified by screening macrophages isolated from mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. Cells from Eif2ak4(atc/atc) mice failed to phosphorylate eIF2α in response to MCMV. Importantly, homozygous Eif2ak4(atc) mice showed a modest increase in susceptibility to MCMV infection, demonstrating that translational arrest dependent on GCN2 contributes to the antiviral response in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • DNA Primers
  • DNA Virus Infections / genetics*
  • Genetic Predisposition to Disease*
  • Mice
  • Mice, Inbred C57BL
  • Mutation*
  • Protein-Serine-Threonine Kinases / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • DNA Primers
  • Eif2ak4 protein, mouse
  • Protein-Serine-Threonine Kinases