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The vaccinia virus K3L gene product potentiates translation by inhibiting double-stranded-RNA-activated protein kinase and phosphorylation of the alpha subunit of eukaryotic initiation factor 2.

Genetics Institute, Cambridge, Massachusetts 02140-2387.

ABSTRACT

Interferon resistance of vaccinia virus is mediated by specific inhibition of phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha) by the double-stranded-RNA-activated (DAI) protein kinase. Vaccinia virus encodes a homolog of eIF-2 alpha, K3L, the deletion of which renders the virus sensitive to interferon treatment. We have studied the mechanism by which this protein product elicits interferon resistance in a transient DNA transfection system designed to evaluate regulators of eIF-2 alpha phosphorylation. In this system, translation of a reporter gene mRNA is inefficient because of eIF-2 phosphorylation mediated by the DAI protein kinase. Cotransfection of the K3L gene enhances translation of the reporter mRNA in this system. The K3L protein inhibits eIF-2 alpha phosphorylation and DAI kinase activation, apparently without being phosphorylated itself. Inhibition of protein synthesis, elicited by expression of a mutant Ser-51----Asp eIF-2 alpha designed to mimic a phosphorylated serine, is not relieved by the presence of K3L, suggesting that K3L cannot bypass a block imposed by eIF-2 alpha phosphorylation. The results suggest that K3L acts as a decoy of eIF-2 alpha to inhibit DAI kinase autophosphorylation and activation. Another vaccinia virus gene product, K1L, which is required for growth of vaccinia virus on human cells, does not enhance translation in this assay.

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• Patel, R. C., Sen, G. C. (1998). Requirement of PKR Dimerization Mediated by Specific Hydrophobic Residues for Its Activation by Double-Stranded RNA and Its Antigrowth Effects in Yeast. Mol. Cell. Biol. 18: 7009-7019 [Abstract] [Full Text]  
• Kumar, M., Carmichael, G. G. (1998). Antisense RNA: Function and Fate of Duplex RNA in Cells of Higher Eukaryotes. Microbiol. Mol. Biol. Rev. 62: 1415-1434 [Abstract] [Full Text]  
• Qian, W., Zhu, S., Sobolev, A. Y., Wek, R. C. (1996). Expression of Vaccinia Virus K3L Protein in Yeast Inhibits Eukaryotic Initiation Factor-2 Kinase GCN2 and the General Amino Acid Control Pathway. J. Biol. Chem. 271: 13202-13207 [Abstract] [Full Text]  
• Langland, J. O., Langland, L. A., Browning, K. S., Roth, D. A. (1996). Phosphorylation of Plant Eukaryotic Initiation Factor-2 by the Plant-encoded Double-stranded RNA-dependent Protein Kinase, pPKR, and Inhibition of Protein Synthesis in Vitro. J. Biol. Chem. 271: 4539-4544 [Abstract] [Full Text]  
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• Colamonici, O. R., Domanski, P., Sweitzer, S. M., Larner, A., Buller, R. M. L. (1995). Vaccinia Virus B18R Gene Encodes a Type I Interferon-binding Protein That Blocks Interferon [IMAGE] Transmembrane Signaling. J. Biol. Chem. 270: 15974-15978 [Abstract] [Full Text]  
• Karupiah, G, Xie, Q., Buller, R., Nathan, C, Duarte, C, MacMicking, J. (1993). Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science 261: 1445-1448 [Abstract]