The Human Papillomavirus Oncoprotein E7 Attenuates NF-κB Activation by Targeting the IκB 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-κB. A variety of experimental approaches revealed that a fraction of the E7 proteins is found in association with the IκB kinase complex and attenuates induced kinase activity of IκB kinase α (IKKα) and IKKβ, thus resulting in impaired IκBα phosphorylation and degradation. Indirect immunofluorescence shows that E7 impairs TNFα-induced nuclear translocation of NF-κB, thus preventing NF-κB from binding to its cognate DNA. While E7 obviates IKK activation in the cytoplasm, the E6 protein reduces NF-κB p65-dependent transcriptional activity within the nucleus. We suggest that HPV oncogene-mediated suppression of NF-κB activity contributes to HPV escape from the immune system.