The cellular inhibitor of the PKR protein kinase, P58(IPK), is an influenza virus-activated co-chaperone that modulates heat shock protein 70 activity

Mark W. Melville, Seng Lai Tan, Marlene Wambach, Jaewhan Song, Richard I. Morimoto, Michael G. Katze*

*Corresponding author for this work

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

P58(IPK), a member of the tetratricopeptide repeat and J-domain protein families, was first recognized for its ability to inhibit the double-stranded RNA-activated protein kinase, PKR. PKR is part of the interferon-induced host defense against viral infection, and downregulates translation initiation via phosphorylation of eukaryotic initiation factor 2 on the α-subunit. P58(IPK) is activated in response to infection by influenza virus, and inhibits PKR through direct protein-protein interaction. Previously, we demonstrated that the molecular chaperone heat shock protein 40 (hsp40) was a negative regulator of P58(IPK). We could now report that influenza virus activates the P58(IPK) pathway by promoting the dissociation of hsp40 from P58(IPK) during infection. We also found that the P58(IPK)-hsp40 association was disrupted during recovery from heat shock, which suggested a regulatory role for P58(IPK) in the absence of virus infection. The PKR pathway is even more complex as we show in this report that the molecular chaperone, hsp/Hsc70, was a component of a trimeric complex with hsp40 and P58(IPK). Moreover, like other J-domain proteins, P58(IPK) stimulated the ATPase activity of Hsc70. Taken together, our data suggest that P58(IPK) is a cochaperone, possibly directing hsp/Hsc70 to refold, and thus inhibit kinase function.

Original languageEnglish (US)
Pages (from-to)3797-3803
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number6
DOIs
StatePublished - Feb 5 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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