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Volume 271, Number 45, Issue of November 8, 1996 pp. 28660-28666
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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The 58-kDa Cellular Inhibitor of the Double Stranded RNA-dependent Protein Kinase Requires the Tetratricopeptide Repeat 6 and DnaJ Motifs to Stimulate Protein Synthesis in Vivo

(Received for publication, April 15, 1996, and in revised form, July 26, 1996)

From the Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington 98195

Double stranded RNA-dependent protein kinase (PKR) is a double stranded RNA-activated, interferon-induced serine-threonine kinase that participates in both the antiviral and antiproliferative properties of interferon. We previously found that influenza virus inhibited PKR function by recruiting or activating a cellular inhibitor termed P58^IPK. The present study was undertaken to complement our earlier analyses, which demonstrated that P58^IPK efficiently inhibited PKR autophosphorylation and activity in vitro. We now report that P58^IPK down-regulates PKR and, in turn, stimulates protein synthetic rates inside the cell. Using transfection analysis, we show that P58^IPK stimulates translation of secreted embryonic alkaline phosphatase reporter gene mRNA. Furthermore, we found that at least two regions of the P58^IPK molecule were required for PKR inhibitory activity in COS-1 cells: (i) the DnaJ similarity region at the carboxyl terminus (amino acids 391-504); and (ii) the tetratricopeptide repeat 6 (TPR6) domain (amino acids 222-255) located in the middle of the P58^IPK protein and within the eukaryotic protein synthesis initiation factor 2 homology region. P58^IPK variants lacking either one of these regions were unable to stimulate secreted embryonic alkaline phosphatase protein synthetic rates. Consistent with this data is the observation that the TPR6 mutant (the P58^IPK variant lacking the TPR6 motif) failed to block PKR activity in vitro. Based on these data and our earlier in vitro functional and PKR-P58^IPK binding analyses, a revised model of PKR regulation by P58^IPK is presented.

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