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Journal of Virology, March 2007, p. 2221-2230, Vol. 81, No. 5
0022-538X/07/$08.00+0     doi:10.1128/JVI.02151-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Cellular Protein P58^IPK Regulates Influenza Virus mRNA Translation and Replication through a PKR-Mediated Mechanism

Department of Microbiology,¹ Graduate Program in Bioengineering, University of Washington,² Washington National Primate Research Center, Seattle, Washington 98195,⁶ Department of Medicine,³ Department of Microbiology, University of Minnesota, Minneapolis, Minnesota 55455,⁵ Department of Microbiology and Immunology, University of Miami, Miami, Florida 33136⁴

Received 29 September 2006/ Accepted 3 December 2006

We previously hypothesized that efficient translation of influenza virus mRNA requires the recruitment of P58^IPK, the cellular inhibitor of PKR, an interferon-induced kinase that targets the eukaryotic translation initiation factor eIF2. P58^IPK also inhibits PERK, an eIF2 kinase that is localized in the endoplasmic reticulum (ER) and induced during ER stress. The ability of P58^IPK to interact with and inhibit multiple eIF2 kinases suggests it is a critical regulator of both cellular and viral mRNA translation. In this study, we sought to definitively define the role of P58^IPK during viral infection of mammalian cells. Using mouse embryo fibroblasts from P58^IPK–/– mice, we demonstrated that the absence of P58^IPK led to an increase in eIF2 phosphorylation and decreased influenza virus mRNA translation. The absence of P58^IPK also resulted in decreased vesicular stomatitis virus replication but enhanced reovirus yields. In cells lacking the P58^IPK target, PKR, the trends were reversed—eIF2 phosphorylation was decreased, and influenza virus mRNA translation was increased. Although P58^IPK also inhibits PERK, the presence or absence of this kinase had little effect on influenza virus mRNA translation, despite reduced levels of eIF2 phosphorylation in cells lacking PERK. Finally, we showed that influenza virus protein synthesis and viral mRNA levels decrease in cells that express a constitutively active, nonphosphorylatable eIF2. Taken together, our results support a model in which P58^IPK regulates influenza virus mRNA translation and infection through a PKR-mediated mechanism which is independent of PERK.

Published ahead of print on 13 December 2006.

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