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

Shirin Kazemi,1 Stavroula Papadopoulou,1 Suiyang Li,1,{dagger} Qiaozhu Su,1 Shuo Wang,1 Akihiko Yoshimura,2 Greg Matlashewski,3 Thomas E. Dever,4 and Antonis E. Koromilas1*

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 {alpha} subunit of eukaryotic translation initiation factor 2 (eIF2{alpha}) 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{alpha} 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{alpha} 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{alpha} dephosphorylation. Inhibition of eIF2{alpha} phosphorylation by E6 mitigates eIF2{alpha}-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{alpha} phosphorylation. The functional interaction between E6 and the eIF2{alpha} phosphorylation pathway may have important implications for HPV infection and associated pathogenesis.

* Corresponding author. Mailing address: Lady Davis Institute-McGill University, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Côte-Ste-Catherine Street, Montréal, Québec, Canada H3T 1E2. Phone: (514) 340-8260, ext. 3697. Fax: (514) 340-7576. E-mail: antonis.koromilas{at}mcgill.ca.

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

Molecular and Cellular Biology, April 2004, p. 3415-3429, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3415-3429.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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