title: Identification of key amino acid residues that determine the ability of high risk HPV16-E7 to dysregulate major histocompatibility complex class I expression.
abstract: High risk human Papillomavirus (HPV) types are the major causative agents of cervical cancer. Reduced expression of major histocompatibility complex class I (MHC I) on HPV-infected cells might be responsible for insufficient T cell response and contribute to HPV-associated malignancy. The viral gene product required for subversion of MHC I synthesis is the E7 oncoprotein. Although it has been suggested that high and low risk HPVs diverge in their ability to dysregulate MHC I expression, it is not known what sequence determinants of HPV-E7 are responsible for this important functional difference. To investigate this, we analyzed the capability to affect MHC I of a set of chimeric E7 variants containing sequence elements from either high risk HPV16 or low risk HPV11. HPV16-E7, but not HPV11-E7, causes significant diminution of mRNA synthesis and surface presentation of MHC I, which depend on histone deacetylase activity. Our experiments demonstrate that the C-terminal region within the zinc finger domain of HPV-E7 is responsible for the contrasting effects of HPV11- and HPV16-E7 on MHC I. By using different loss- and gain-of-function mutants of HPV11- and HPV16-E7, we identify for the first time a residue variation at position 88 that is highly critical for HPV16-E7-mediated suppression of MHC I. Furthermore, our studies suggest that residues at position 78, 80, and 88 build a minimal functional unit within HPV16-E7 required for binding and histone deacetylase recruitment to the MHC I promoter. Taken together, our data provide new insights into how high risk HPV16-E7 dysregulates MHC I for immune evasion.
authors.affiliation: Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Institute of Immunology, Tuebingen, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Heller
authors.forename: Tanja
authors.initials: T
authors.lastname: Weisser
authors.forename: Antje
authors.initials: A
authors.lastname: Mueller-Schickert
authors.forename: Elke
authors.initials: E
authors.lastname: Rufer
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoh
authors.forename: Ralf M
authors.initials: RM
authors.lastname: Leonhardt
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knittler
mesh_terms: D005786:Gene Expression Regulation; D057809:HEK293 Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006655:Histone Deacetylases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D052140:Human papillomavirus 11 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C493190:E7 protein, human papillomavirus 11; D015395:Histocompatibility Antigens Class I; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D006655:Histone Deacetylases