title: Increased susceptibility to DNA virus infection in mice with a GCN2 mutation.
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.
authors: Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors: Sungyong
authors: S
authors: Won
authors: Celine
authors: C
authors: Eidenschenk
authors: Carrie N
authors: CN
authors: Arnold
authors: Owen M
authors: OM
authors: Siggs
authors: Lei
authors: L
authors: Sun
authors: Katharina
authors: K
authors: Brandl
authors: Tina-Marie
authors: TM
authors: Mullen
authors: Glen R
authors: GR
authors: Nemerow
authors: Eva Marie Y
authors: EM
authors: Moresco
authors: Bruce
authors: B
authors: Beutler
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004266:DNA Virus Infections / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases