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Molecular and Cellular Biology, April 2004, p. 3415-3429, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3415-3429.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Control of Subunit of Eukaryotic Translation Initiation Factor 2 (eIF2) Phosphorylation by the Human Papillomavirus Type 18 E6 Oncoprotein: Implications for eIF2-Dependent Gene Expression and Cell Death

Shirin Kazemi,¹ Stavroula Papadopoulou,¹ Suiyang Li,^1, Qiaozhu Su,¹ Shuo Wang,¹ Akihiko Yoshimura,² Greg Matlashewski,³ Thomas E. Dever,⁴ and Antonis E. Koromilas^1*

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, Québec H3T 1E2,¹ Department of Microbiology and Immunology, McGill University, Montréal, Québec H3A 2B4, Canada,³ Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan,² Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892⁴

Received 10 October 2003/ Returned for modification 26 November 2003/ Accepted 12 January 2004

Phosphorylation of the subunit of eukaryotic translation initiation factor 2 (eIF2) at serine 51 inhibits protein synthesis in cells subjected to various forms of stress including virus infection. The human papillomavirus (HPV) E6 oncoprotein contributes to virus-induced pathogenicity through multiple mechanisms including the inhibition of apoptosis and the blockade of interferon (IFN) action. We have investigated a possible functional relationship between the E6 oncoprotein and eIF2 phosphorylation by an inducible-dimerization form of the IFN-inducible protein kinase PKR. Herein, we demonstrate that HPV type 18 E6 protein synthesis is rapidly repressed upon eIF2 phosphorylation caused by the conditional activation of the kinase. The remainder of E6, however, can rescue cells from PKR-mediated inhibition of protein synthesis and induction of apoptosis. E6 physically associates with GADD34/PP1 holophosphatase complex, which mediates translational recovery, and facilitates eIF2 dephosphorylation. Inhibition of eIF2 phosphorylation by E6 mitigates eIF2-dependent responses to transcription and translation of proapoptotic genes. These findings demonstrate, for the first time, a role of the oncogenic E6 in apoptotic signaling induced by PKR and eIF2 phosphorylation. The functional interaction between E6 and the eIF2 phosphorylation pathway may have important implications for HPV infection and associated pathogenesis.

Present address: Department of Biochemistry, McGill University, Montréal, Québec H3G 1Y6, Canada.

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