title: The human papillomavirus type 16 E6 oncoprotein activates mTORC1 signaling and increases protein synthesis.
abstract: The mammalian target of rapamycin (mTOR) kinase acts as a cellular rheostat that integrates signals from a variety of cellular signal transduction pathways that sense growth factor and nutrient availability as well as intracellular energy status. It was previously reported that the human papillomavirus type 16 (HPV16) E6 oncoprotein may activate the S6 protein kinase (S6K) through binding and E6AP-mediated degradation of the mTOR inhibitor tuberous sclerosis complex 2 (TSC2) (Z. Lu, X. Hu, Y. Li, L. Zheng, Y. Zhou, H. Jiang, T. Ning, Z. Basang, C. Zhang, and Y. Ke, J. Biol. Chem. 279:35664-35670, 2004; L. Zheng, H. Ding, Z. Lu, Y. Li, Y. Pan, T. Ning, and Y. Ke, Genes Cells 13:285-294, 2008). Our results confirmed that HPV16 E6 expression causes an increase in mTORC1 activity through enhanced phosphorylation of mTOR and activation of downstream signaling pathways S6K and eukaryotic initiation factor binding protein 1 (4E-BP1). However, we did not detect a decrease in TSC2 levels in HPV16 E6-expressing cells. We discovered, however, that HPV16 E6 expression causes AKT activation through the upstream kinases PDK1 and mTORC2 under conditions of nutrient deprivation. We show that HPV16 E6 expression causes an increase in protein synthesis by enhancing translation initiation complex assembly at the 5' mRNA cap and an increase in cap-dependent translation. The increase in cap-dependent translation likely results from HPV16 E6-induced AKT/mTORC1 activation, as the assembly of the translation initiation complex and cap-dependent translation are rapamycin sensitive. Lastly, coexpression of the HPV16 E6 and E7 oncoproteins does not affect HPV16 E6-induced activation of mTORC1 and cap-dependent translation. HPV16 E6-mediated activation of mTORC1 signaling and cap-dependent translation may be a mechanism to promote viral replication under conditions of limited nutrient supply in differentiated, HPV oncoprotein-expressing proliferating cells.
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital and Committee on Virology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Spangle
authors.forename: Karl
authors.initials: K
authors.lastname: Münger
mesh_terms: D002460:Cell Line; D054884:Host-Pathogen Interactions; D006801:Humans; D015603:Keratinocytes / Q000821:virology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt / Q000096:biosynthesis; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D010442:Peptide Chain Initiation, Translational; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D011506:Proteins; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C493245:CRTC2 protein, human; C068651:E6 protein, Human papillomavirus type 16; D046912:Multiprotein Complexes; D009856:Oncogene Proteins, Viral; C000631429:PDK1 protein, human; D011506:Proteins; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012097:Repressor Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases