The human papillomavirus oncoprotein E7 attenuates NF-kappa B activation by targeting the Ikappa B kinase complex.
Infection with high-risk human papillomaviruses (HPV) can lead to the development of cervical carcinomas. This process critically depends on the virus-encoded E6 and E7 oncoproteins, which stimulate proliferation by manipulating the function of a variety of host key regulatory proteins. Here we show that both viral proteins dose-dependently interfere with the transcriptional activity of NF-kappaB. A variety of experimental approaches revealed that a fraction of the E7 proteins is found in association with the IkappaB kinase complex and attenuates induced kinase activity of IkappaB kinase alpha (IKKalpha) and IKKbeta, thus resulting in impaired IkappaBalpha phosphorylation and degradation. Indirect immunofluorescence shows that E7 impairs TNFalpha-induced nuclear translocation of NF-kappaB, thus preventing NF-kappaB from binding to its cognate DNA. While E7 obviates IKK activation in the cytoplasm, the E6 protein reduces NF-kappaB p65-dependent transcriptional activity within the nucleus. We suggest that HPV oncogene-mediated suppression of NF-kappaB activity contributes to HPV escape from the immune system.
Spitkovsky
Dimitry
D
Institute for Vegetative Physiology, University of Cologne, Robert-Koch-Strasse 39, Germany.
Hehner
Steffen P
SP
Hofmann
Thomas G
TG
Möller
Andreas
A
Schmitz
M Lienhard
ML
D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D051550:I-kappa B Kinase; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D014158:Transcription, Genetic / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human