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.
Phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) 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 eIF2alpha 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 eIF2alpha 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 eIF2alpha dephosphorylation. Inhibition of eIF2alpha phosphorylation by E6 mitigates eIF2alpha-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 eIF2alpha phosphorylation. The functional interaction between E6 and the eIF2alpha phosphorylation pathway may have important implications for HPV infection and associated pathogenesis.
Kazemi
Shirin
S
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, Québec H3T 1E2, Canada.
Papadopoulou
Stavroula
S
Li
Suiyang
S
Su
Qiaozhu
Q
Wang
Shuo
S
Yoshimura
Akihiko
A
Matlashewski
Greg
G
Dever
Thomas E
TE
Koromilas
Antonis E
AE
D049933:Aminocoumarins; D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D003374:Coumarins / Q000378:metabolism; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000378:metabolism; D030361:Papillomavirus Infections; D010766:Phosphorylation; D014176:Protein Biosynthesis; D054645:Protein Phosphatase 1; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic; D051028:bcl-2-Associated X Protein; D019892:eIF-2 Kinase / Q000378:metabolism
D049933:Aminocoumarins; D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D003374:Coumarins; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D015852:Eukaryotic Initiation Factor-2; D016898:Interferon-alpha; D009856:Oncogene Proteins, Viral; D021122:Protein Subunits; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019892:eIF-2 Kinase; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1; C004628:coumermycin