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

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Overview

related to degree

  • Siggs, Owen Marc, D.Phil. in Biology, University of Oxford , Joint graduate program with The Scripps Research Institute 2007 - 2012
  • Siggs, Owen Marc, Ph.D. in Biology, Scripps Research , Joint graduate program with Oxford University 2007 - 2012

authors

  • Won, S.
  • Eidenschenk, C.
  • Arnold, C. N.
  • Siggs, Owen Marc
  • Sun, L.
  • Brandl, K.
  • Mullen, T. M.
  • Nemerow, Glen
  • Moresco, E. M. Y.
  • Beutler, Bruce

publication date

  • February 2012

journal

  • Journal of Virology  Journal

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.

subject areas

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

PubMed Central ID

  • PMC3264364

International Standard Serial Number (ISSN)

  • 0022-538X

Digital Object Identifier (DOI)

  • 10.1128/jvi.05660-11

PubMed ID

  • 22114338
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Additional Document Info

start page

  • 1802

end page

  • 1808

volume

  • 86

issue

  • 3

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