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

Sungyong Won, Celine Eidenschenk, Carrie N. Arnold, Owen M. Siggs, Lei Sun, Katharina Brandl, Tina Marie Mullen, Glen R. Nemerow, Eva Marie Y Moresco, Bruce Beutler

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

The downre gulation 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-offunction 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 Eif2ak4atc/atc mice failed to phosphorylate eIF2α in response to MCMV. Importantly, homozygous Eif2ak4atc mice showed a modest increase in susceptibility to MCMV infection, demonstrating that translational arrest dependent on GCN2 contributes to the antiviral response in vivo.

Original languageEnglish (US)
Pages (from-to)1802-1808
Number of pages7
JournalJournal of virology
Volume86
Issue number3
DOIs
StatePublished - Feb 1 2012

    Fingerprint

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Won, S., Eidenschenk, C., Arnold, C. N., Siggs, O. M., Sun, L., Brandl, K., Mullen, T. M., Nemerow, G. R., Moresco, E. M. Y., & Beutler, B. (2012). Increased susceptibility to DNA virus infection in mice with a GCN2 mutation. Journal of virology, 86(3), 1802-1808. https://doi.org/10.1128/JVI.05660-11