Control of translation initiation factor eIF2 alpha phosphorylation by the human papillomavirus-18E6oncoprotein: Implication in eIF-2 alpha-dependent gene expression and cell death.

Shirin Kazemi, Stavroula Papadopoulou, Qiaozhu Su, Antonis E Koromilas

Research output: Contribution to journalArticle

Abstract

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 eIF2a phosphorylation by an inducibledimerization form of the IFN-inducible protein kinase PKR. Herein, we demonstrate that HPV type 18 E6 protein synthesis is rapidly repressed upon eIF2a 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 eIF2a dephosphorylation. Inhibition of eIF2a phosphorylation by E6 mitigates eIF2a-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 eIF2a phosphorylation. The functional interaction between E6 and the eIF2a phosphorylation pathway may have important implications for HPV infection and associated pathogenesis.
Original languageEnglish
Article numberPMID: 15060162
Pages (from-to)3415-29
Number of pages15
JournalMolecular and Cellular Biology
Volume24
Issue number8
DOIs
Publication statusPublished - Apr 2004

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