The role of the ubiquitin ligase E6-AP in human papillomavirus E6-mediated degradation of PDZ domain-containing proteins.
The E6 oncoprotein of human papillomaviruses associated with cervical cancer targets the tumor suppressor p53 and several other cellular proteins including the human homologs of Dlg and Scribble for degradation via the ubiquitin-proteasome system. Similar to p53 degradation, E6-induced degradation of Scribble is mediated by the ubiquitin ligase E6-AP. In contrast, degradation of Dlg in vitro and within cells has been reported to be independent of E6-AP, suggesting that the E6 oncoprotein has the ability to interact with ubiquitin ligases other than E6-AP. Furthermore, the ability of the E6 oncoprotein to interact with these yet unidentified ubiquitin ligases may be shared by the E6 protein of so-called low risk human papillomaviruses that are not associated with cervical cancer. In this study, we used the RNA interference technology and mouse embryo fibroblasts derived from E6-AP-deficient mice to obtain information about the identity of the ubiquitin ligase(s) involved in E6-mediated degradation of Dlg. We report that, within cells, E6-mediated degradation of Dlg depends on the presence of functional E6-AP and provide evidence that the E6 protein of low risk human papillomaviruses functionally interacts with E6-AP. Based on these data, we propose that, in general, the proteolytic properties of human papillomavirus E6 proteins are mediated by interaction with E6-AP.
Kuballa
Petric
P
Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
Matentzoglu
Konstantin
K
Scheffner
Martin
M
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*
C469553:E6 protein, Human papillomavirus type 11; D009856:Oncogene Proteins, Viral; D034741:RNA, Small Interfering; D025801:Ubiquitin; C471639:UBE3A protein, human; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases