Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
Proc Natl Acad Sci U S A. 2013 May 28;110(22):8888-93. doi: 10.1073/pnas.1302792110. Epub 2013 May 13.
Inactivation of the ubiquitin ligase E6 associated protein (E6AP) encoded by the UBE3A gene has been associated with development of the Angelman syndrome. Recently, it was reported that in mice, loss of E6AP expression results in increased levels of the synaptic protein Arc and a concomitant impaired synaptic function, providing an explanation for some phenotypic features of Angelman syndrome patients. Accordingly, E6AP has been shown to negatively regulate activity-regulated cytoskeleton-associated protein (Arc) and it has been suggested that E6AP targets Arc for ubiquitination and degradation. In our study, we provide evidence that Arc is not a direct substrate for E6AP and binds only weakly to E6AP, if at all. Furthermore, we show that down-regulation of E6AP expression stimulates estradiol-induced transcription of the Arc gene. Thus, we propose that Arc protein levels are controlled by E6AP at the transcriptional rather than at the posttranslational level.
UBE3A 基因编码的泛素连接酶 E6 相关蛋白 (E6AP) 的失活与 Angelman 综合征的发展有关。最近有报道称，在小鼠中，E6AP 表达的缺失导致突触蛋白 Arc 的水平升高，同时突触功能受损，为 Angelman 综合征患者的一些表型特征提供了解释。因此，E6AP 被证明可负调控活性调节细胞骨架相关蛋白 (Arc)，并且有人提出 E6AP 将 Arc 作为泛素化和降解的靶标。在我们的研究中，我们提供的证据表明，Arc 不是 E6AP 的直接底物，并且仅与 E6AP 弱结合，如果有结合的话。此外，我们还表明，E6AP 表达的下调可刺激雌二醇诱导的 Arc 基因转录。因此，我们提出 Arc 蛋白水平受 E6AP 的转录调控，而不是翻译后调控。
