Kuballa Petric, Matentzoglu Konstantin, Scheffner Martin
Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
J Biol Chem. 2007 Jan 5;282(1):65-71. doi: 10.1074/jbc.M605117200. Epub 2006 Nov 3.
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.
与宫颈癌相关的人乳头瘤病毒E6癌蛋白靶向肿瘤抑制因子p53以及其他几种细胞蛋白，包括Dlg和Scribble的人类同源物，通过泛素-蛋白酶体系统将它们降解。与p53降解类似，E6诱导的Scribble降解由泛素连接酶E6-AP介导。相比之下，据报道Dlg在体外和细胞内的降解不依赖于E6-AP，这表明E6癌蛋白有能力与E6-AP以外的泛素连接酶相互作用。此外，所谓的低风险人乳头瘤病毒（与宫颈癌无关）的E6蛋白可能也具有与这些尚未明确的泛素连接酶相互作用的能力。在本研究中，我们使用RNA干扰技术以及源自E6-AP缺陷小鼠的小鼠胚胎成纤维细胞，以获取有关参与E6介导的Dlg降解的泛素连接酶身份的信息。我们报告称，在细胞内，E6介导的Dlg降解依赖于功能性E6-AP的存在，并提供证据表明低风险人乳头瘤病毒的E6蛋白与E6-AP存在功能上的相互作用。基于这些数据，我们提出，一般来说，人乳头瘤病毒E6蛋白的蛋白水解特性是通过与E6-AP相互作用介导的。
