The Cellular Protein P58IPK Regulates Influenza Virus mRNA Translation and Replication through a PKR-Mediated Mechanism

Alan G Goodman; Jennifer A Smith; Siddharth Balachandran; Olivia Perwitasari; Sean C Proll; Matthew J Thomas; Marcus J Korth; Glen N Barber; Leslie A Schiff; Michael G Katze

doi:10.1128/JVI.02151-06

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The Cellular Protein P58IPK Regulates Influenza Virus mRNA Translation and Replication through a PKR-Mediated Mechanism

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The Cellular Protein P58IPK Regulates Influenza Virus mRNA Translation and Replication through a PKR-Mediated Mechanism

Alan G Goodman, Jennifer A Smith, Siddharth Balachandran, Olivia Perwitasari, Sean C Proll, Matthew J Thomas, Marcus J Korth, Glen N Barber, Leslie A Schiff and Michael G Katze

Journal of virology, Vol.81(5), pp.2221-2230

03/2007

DOI: https://doi.org/10.1128/JVI.02151-06

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https://hdl.handle.net/2376/116056

PMCID: PMC1865913

PMID: 17166899

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Abstract

Cellular Response to Infection

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 eIF2α. P58 IPK also inhibits PERK, an eIF2α 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 eIF2α 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 eIF2α 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—eIF2α 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 eIF2α 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 eIF2α. 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.

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Title: The Cellular Protein P58IPK Regulates Influenza Virus mRNA Translation and Replication through a PKR-Mediated Mechanism
Creators: Alan G Goodman - Department of Microbiology
Jennifer A Smith - Department of Microbiology
Siddharth Balachandran - Department of Microbiology
Olivia Perwitasari - Department of Microbiology
Sean C Proll - Department of Microbiology
Matthew J Thomas - Department of Microbiology
Marcus J Korth - Department of Microbiology
Glen N Barber - Department of Microbiology
Leslie A Schiff - Department of Microbiology
Michael G Katze - Department of Microbiology
Publication Details: Journal of virology, Vol.81(5), pp.2221-2230
Academic Unit: Molecular Biosciences, School of
Publisher: American Society for Microbiology
Identifiers: 99900548080301842
Language: English
Resource Type: Journal article