Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc
Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc
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DOI：
10.1073/pnas.1302792110
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发表时间：
2013-05-28
影响因子：
11.1
通讯作者：
Scheffner, Martin
中科院分区：
文献类型：
--
作者：
Kuehnle, Simone;Mothes, Benedikt;Scheffner, Martin
UBE3A基因编码的泛素连接酶E6相关蛋白（E6AP）的失活与Angelman综合征的发生有关。最近，据报道，在小鼠中，E6AP表达的损失导致突触蛋白Arc水平的增加和伴随的突触功能受损，为Angelman综合征患者的一些表型特征提供了解释。因此，E6AP已经显示负调节活性调节的细胞凋亡相关蛋白（Arc），并且已经表明E6AP靶向Arc进行泛素化和降解。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，如果有的话。此外，我们表明，下调E6AP的表达刺激雌二醇诱导的转录的弧基因。因此，我们建议，弧蛋白水平的控制E6AP在转录，而不是在翻译后水平。
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.