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PMID: 22114338 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

Journal of virology ·Vol. 86 ·No. 3 ·2012-02-00 ·Pages 1802-8

Won S, Eidenschenk C, Arnold CN, Siggs OM, Sun L, Brandl K, Mullen TM, Nemerow GR, Moresco EM, Beutler B

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.

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
Chemicals
DNA Primers Eif2ak4 protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Won Sungyong
Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Eidenschenk Celine
Arnold Carrie N
Siggs Owen M
Sun Lei
Brandl Katharina
Mullen Tina-Marie
Nemerow Glen R
Moresco Eva Marie Y
Beutler Bruce
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
1098-5514
DOI
10.1128/JVI.05660-11
Published
2012-02-00
Epub
2011-00-23
Pages
1802-8
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC3264364
Subset
IM
Grants
NIAID NIH HHS · P01 AI070167 · United States
NHLBI NIH HHS · R01 HL054352 · United States
NIGMS NIH HHS · R37 GM067759 · United States
NIAID NIH HHS · 2P01AI070167-06 · United States
External Links
PubMed source DOI: 10.1128/JVI.05660-11 PMC Full Text View journal details
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