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

Heller, Corina; Weisser, Tanja GND; Mueller-Schickert, A.; Rufer, Elke GND; Hoh, Alexander GND; Leonhardt, Ralf Max GND; Knittler, Michael R. GND

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

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Heller, Corina / Weisser, Tanja / Mueller-Schickert, A. / et al: Identification of Key Amino Acid Residues That Determine the Ability of High Risk HPV16-E7 to Dysregulate Major Histocompatibility Complex Class I Expression. 2011.

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