The interferon induced serine/threonine protein kinase, PKR, is regulated by the influenza virus activated protein, P58IPK, and the molecular chaperones, Hsp40 and Hsp70

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The interferon induced serine/threonine protein kinase, PKR, is regulated by the influenza virus activated protein, P58IPK, and the molecular chaperones, Hsp40 and Hsp70

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Title: The interferon induced serine/threonine protein kinase, PKR, is regulated by the influenza virus activated protein, P58IPK, and the molecular chaperones, Hsp40 and Hsp70
Author: Melville, Mark Wallace
Abstract: P58IPK is a TPR-containing protein with homology to the J-domain of DnaJ. P58IPK was first recognized for its ability to inhibit the interferon-induced double-stranded RNA-activated serine/threonine protein kinase, PKR, in cells infected with influenza virus. PKR is activated in response to viral infection and downregulates translation initiation via phosphorylation of eukaryotic initiation factor 2 on the alpha-subunit. Many viruses have developed mechanisms to inhibit the kinase, but only influenza virus has taken advantage of the cellular inhibitor of PKR, p58IPK . P58IPK inhibits PKR through direct protein-protein interaction and prevents dimerization of the kinase. Influenza virus infection activates P58IPK by dissociating it from its own inhibitor, originally termed I-P58IPK.We now show that I-P58IPK is the molecular chaperone, heat shock protein 40 (Hsp40). P58IPK and Hsp40 bind in vitro and in vivo, but dissociate upon infection with influenza virus, consistent with our hypothesis that P58IPK is activated by dissociation from its inhibitor. Hsp40 is a mammalian homolog of the DnaJ protein of E. coli, and assists its cognate partner, Hsp70, in folding and refolding nascent and denatured proteins. We now speculate that P58IPK recruits the molecular chaperone Hsp70 to refold (i.e. inactivate) the kinase. We show here that P58IPK binds specifically to the N-terminal half of Hsp70 (the ATPase domain). Furthermore, P58IPK regulates the ATPase activity and refolding activity of Hsp70 in in vitro assays. These findings support a model of P58IPK inhibition of PKR in which P58IPK stimulates Hsp70 to alter the conformation of PKR.
Description: Thesis (Ph. D.)--University of Washington, 1998
URI: http://hdl.handle.net/1773/11489

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