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

p58(IPK), a member of the tetratricopeptide repeat and J-domain protein fam ilies, was first recognized for its ability to inhibit the double-stranded RNA-activated protein kinase, PKR. PKR is part of the interferon-induced ho st defense against viral infection, and down-regulates translation initiati on via phosphorylation of eukaryotic initiation factor 2 on the alpha-subun it. P58(IPK) is activated in response to infection by influenza virus, and inhibits PKR through direct protein-protein interaction. Previously, we dem onstrated that the molecular chaperone heat shock protein 40 (hsp40) was a negative regulator of p58(IPK). We could now report that influenza virus ac tivates the p58(IPK) pathway by promoting the dissociation of hsp40 from p5 8(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 ev en 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). More over, like other J-domain proteins, p58(IPK) stimulated the ATPase activity of Hsc70, Taken together, our data suggest that p58(IPK) is a co-chaperone , possibly directing hsp/Hsc70 to refold, and thus inhibit kinase function.