Identification of Key Amino Acid Residues That Determine the Ability of High Risk HPV16-E7 to Dysregulate Major Histocompatibility Complex Class I Expression

• Published in: The Journal of biological chemistry 2011-04, Vol.286 (13), p.10983-10997
• Main Authors: Heller, Corina, Weisser, Tanja, Mueller-Schickert, Antje, Rufer, Elke, Hoh, Alexander, Leonhardt, Ralf M., Knittler, Michael R.
• Format: Article
• Language: English
• Subjects: Antigen; Antigen Presentation; Cellular Immune Response; Gene Expression Regulation; HEK293 Cells; Histocompatibility Antigens Class I - biosynthesis; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Histone Deacetylases - genetics; Histone Deacetylases - immunology; Histone Deacetylases - metabolism; Human papillomavirus 11 - genetics; Human papillomavirus 11 - immunology; Human papillomavirus 11 - metabolism; Human papillomavirus 16 - genetics; Human papillomavirus 16 - immunology; Human papillomavirus 16 - metabolism; Humans; Immune Evasion; Immunology; MHC; Oncogene Proteins, Viral - genetics; Oncogene Proteins, Viral - immunology; Oncogene Proteins, Viral - metabolism; Papillomavirus E7 Proteins - genetics; Papillomavirus E7 Proteins - immunology; Papillomavirus E7 Proteins - metabolism; Promoter Regions, Genetic - genetics; Promoter Regions, Genetic - immunology; Protein Structure, Tertiary; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Messenger - immunology; Virus
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.199190

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.