The human papillomavirus 16 E6 protein binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis.

Filippova M, Song H, Connolly JL, Dermody TS, Duerksen-Hughes PJ
J Biol Chem. 2002 277 (24): 21730-9

PMID: 11934887 · DOI:10.1074/jbc.M200113200

High risk strains of human papillomavirus (HPV), such as HPV 16, cause human cervical carcinoma. The E6 protein of HPV 16 mediates the rapid degradation of p53, although this is not the only function of E6 and cannot completely explain its transforming potential. Previous work in our laboratory has demonstrated that transfection of HPV 16 E6 into the tumor necrosis factor (TNF)-sensitive LM cell line protects expressing cells from TNF-induced apoptosis in a p53-independent manner, and the purpose of this study was to determine the molecular mechanism underlying this protection. Caspase 3 and caspase 8 activation were significantly reduced in E6-expressing cells, indicating that E6 acts early in the TNF apoptotic pathway. In fact, E6 binds directly to TNF R1, as shown both by co-immunoprecipitation and mammalian two-hybrid approaches. E6 requires the same C-terminal portion of TNF R1 for binding as does TNF R1-associated death domain, and TNF R1/TNF R1-associated death domain interactions are decreased in the presence of E6. HA-E6 also blocked cell death triggered by transfection of the death domain of TNF R1. Together, these results provide strong support for a model in which HPV E6 binding to TNF R1 interferes with formation of the death-inducing signaling complex and thus with transduction of proapoptotic signals. They also demonstrate that HPV, like several other viruses, has developed a method for evading the TNF-mediated host immune response.

MeSH Terms (37)

3T3 Cells Animals Antigens, CD Apoptosis Caspase 3 Caspase 8 Caspase 9 Caspases Cell Death Cell Survival Ceramides Enzyme-Linked Immunosorbent Assay Enzyme Activation Genes, p53 Genes, Reporter Humans Immunoblotting Mice Mitomycin Oncogene Proteins, Viral Plasmids Precipitin Tests Protein Binding Proteins Protein Structure, Tertiary Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Repressor Proteins Signal Transduction Time Factors TNF Receptor-Associated Factor 1 Transfection Tumor Cells, Cultured Tumor Necrosis Factor-alpha Tumor Suppressor Protein p53 Two-Hybrid System Techniques U937 Cells

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