title: Resistance to vesicular stomatitis virus infection requires a functional cross talk between the eukaryotic translation initiation factor 2alpha kinases PERK and PKR.
abstract: Phosphorylation of the alpha (alpha) subunit of the eukaryotic translation initiation factor 2 (eIF2) leads to the inhibition of protein synthesis in response to diverse stress conditions, including viral infection. The eIF2alpha kinase PKR has been shown to play an essential role against vesicular stomatitis virus (VSV) infection. We demonstrate here that another eIF2alpha kinase, the endoplasmic reticulum-resident protein kinase PERK, contributes to cellular resistance to VSV infection. We demonstrate that mouse embryonic fibroblasts (MEFs) from PERK(-/-) mice are more susceptible to VSV-mediated apoptosis than PERK(+/+) MEFs. The higher replication capacity of VSV in PERK(-/-) MEFs results from their inability to attenuate viral protein synthesis due to an impaired eIF2alpha phosphorylation. We also show that VSV-infected PERK(-/-) MEFs are unable to fully activate PKR, suggesting a cross talk between the two eIF2alpha kinases in virus-infected cells. These findings further implicate PERK in virus infection, and provide evidence that the antiviral and antiapoptotic roles of PERK are mediated, at least in part, via the activation of PKR.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte-Ste-Catherine St., Montreal, Quebec H3T 1E2, Canada.
authors.forename: Dionissios
authors.initials: D
authors.lastname: Baltzis
authors.forename: Li-Ke
authors.initials: LK
authors.lastname: Qu
authors.forename: Stavroula
authors.initials: S
authors.lastname: Papadopoulou
authors.forename: Jaime D
authors.initials: JD
authors.lastname: Blais
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
mesh_terms: D000818:Animals; D017209:Apoptosis; D053454:Caspase 12; D020169:Caspases / Q000096:biosynthesis; D002460:Cell Line; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D014721:Vesicular stomatitis Indiana virus / Q000502:physiology*; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000502:physiology*
chemical_list: D053454:Caspase 12; D020169:Caspases; D015852:Eukaryotic Initiation Factor-2; D019892:eIF-2 Kinase; C506444:CASP12 protein, human; C506440:Casp12 protein, mouse