title: Activation of cap-dependent translation by mucosal human papillomavirus E6 proteins is dependent on the integrity of the LXXLL binding motif.
abstract: The human papillomavirus (HPV) type 16 (HPV16) E6 protein can stimulate mechanistic target of rapamycin complex 1 (mTORC1) signaling and cap-dependent translation through activation of the PDK1 and mTORC2 kinases. Here we report that HPV18 E6 also enhances cap-dependent translation. The integrity of LXXLL and PDZ protein binding domains is important for activation of cap-dependent translation by high-risk mucosal HPV E6 proteins. Consistent with this model, low-risk mucosal HPV6b and HPV11 E6 proteins, which do not contain a PDZ protein binding motif, also activate cap-dependent translation and mTORC1, albeit at a lower efficiency than high-risk HPV E6 proteins. In contrast, cutaneous HPV5 and HPV8 E6 proteins, which lack LXXLL and PDZ motif protein binding, do not enhance cap-dependent translation. Mutagenic analyses of low-risk HPV E6 proteins revealed that association with the LXXLL motif containing ubiquitin ligase E6AP (UBE3A) correlates with activation of cap-dependent translation. Hence, activation of mTORC1 and cap-dependent translation may be important for the viral life cycle in specific epithelial tissue types and contribute to cellular transformation in cooperation with other biological activities of high-risk HPV E6-containing proteins.
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Spangle
authors.forename: Nayana
authors.initials: N
authors.lastname: Ghosh-Choudhury
authors.forename: Karl
authors.initials: K
authors.lastname: Munger
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D002460:Cell Line; D057809:HEK293 Cells; D052140:Human papillomavirus 11 / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000378:metabolism*; D052161:Human papillomavirus 18 / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D009092:Mucous Membrane / Q000821:virology; D046912:Multiprotein Complexes; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D054731:PDZ Domains; D014176:Protein Biosynthesis; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*
chemical_list: C493245:CRTC2 protein, human; C068651:E6 protein, Human papillomavirus type 16; D046912:Multiprotein Complexes; D009856:Oncogene Proteins, Viral; D011506:Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D064413:3-Phosphoinositide-Dependent Protein Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases