Human papillomavirus E6 proteins mediate resistance to interferon-induced growth arrest through inhibition of p53 acetylation.
The high-risk human papillomavirus (HPV) E6 and E7 proteins act cooperatively to mediate multiple activities in viral pathogenesis. For instance, E7 acts to increase p53 levels while E6 accelerates its rate of turnover through the binding of the cellular ubiquitin ligase E6AP. Interferons are important antiviral agents that modulate both the initial and persistent phases of viral infection. The expression of HPV type 16 E7 was found to sensitize keratinocytes to the growth-inhibitory effects of interferon, while coexpression of E6 abrogates this inhibition. Treatment of E7-expressing cells with interferon ultimately resulted in cellular senescence through a process that is dependent upon acetylation of p53 by p300/CBP at lysine 382. Cells expressing mutant forms of E6 that are unable to bind p300/CBP or bind p53 failed to block acetylation of p53 at lysine 382 and were sensitive to growth arrest by interferon. In contrast, mutant forms of E6 that are unable to bind E6AP remain resistant to the effects of interferon, demonstrating that the absolute levels of p53 are not the major determinants of this activity. Finally, p53 acetylation at lysine 382 was found not to be an essential determinant of other types of senescence such as that induced by overexpression of Ras in human fibroblasts. This study identifies an important physiological role for E6 binding to p300/CBP in blocking growth arrest of human keratinocytes in the presence of interferon and so contributes to the persistence of HPV-infected cells.
Hebner
Christy
C
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 320 E. Superior St., Chicago, IL 60611, USA.
Beglin
Melanie
M
Laimins
Laimonis A
LA
D000107:Acetylation; D002453:Cell Cycle / Q000276:immunology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000821:virology; D052162:Human papillomavirus 16 / Q000276:immunology*; D006801:Humans; D007372:Interferons / Q000276:immunology*; D015603:Keratinocytes / Q000166:cytology / Q000821:virology; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology*; D050725:Papillomavirus E7 Proteins; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; D007372:Interferons; D050880:p300-CBP Transcription Factors; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases