A putative stimulatory role for activator turnover in gene expression
A putative stimulatory role for activator turnover in gene expression
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DOI：
10.1038/nature04098
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发表时间：
2005-11-03
期刊：
影响因子：
64.8
通讯作者：
Deshaies, RJ
中科院分区：
文献类型：
--
作者：
Lipford, JR;Smith, GT;Deshaies, RJ
泛素-蛋白酶体系统（UPS）通过将被26 S蛋白酶体识别的泛素链连接到靶蛋白上来促进靶蛋白的破坏（1）。UPS影响大多数细胞过程，其靶点包括作为基因表达主要决定因素的转录激活因子。新出现的证据表明UPS的非蛋白水解功能可能刺激转录活性（2，3）。在这里，我们表明，蛋白水解的一些转录激活因子的UPS可以刺激他们的功能。我们专注于UPS依赖性蛋白水解在酵母中诱导型转录激活因子功能中的作用，发现蛋白酶体的抑制（4）减少了激活因子Gcn 4、Gal 4和Ino 2/4的靶点的转录。此外，Gcn 4的泛素连接酶SCFCdc 4的突变（参考文献5）或阻止降解的泛素突变（6）也会损害Gcn 4靶点的转录。尽管同源启动子上Gcn 4的丰度增加，但这些转录缺陷仍表现出来。蛋白酶体抑制也降低了RNA聚合酶II与Gcn 4、Gal 4和Ino 2/4靶点的关联，Gcn 4靶点的SCFCdc 4突变也是如此。Gcn 4稳定磷酸化位点突变体的表达（参考文献7）或靶向Gcn 4进行转换的激酶的破坏（5，7）减轻了Gcn 4活性对UPS缺陷的敏感性。
The ubiquitin - proteasome system (UPS) promotes the destruction of target proteins by attaching to them a ubiquitin chain that is recognized by the 26S proteasome(1). The UPS influences most cellular processes, and its targets include transcriptional activators that are primary determinants of gene expression. Emerging evidence indicates that non-proteolytic functions of the UPS might stimulate transcriptional activity(2,3). Here we show that the proteolysis of some transcriptional activators by the UPS can stimulate their function. We focused on the role of UPS-dependent proteolysis in the function of inducible transcriptional activators in yeast, and found that inhibition of the proteasome(4) reduced transcription of the targets of the activators Gcn4, Gal4 and Ino2/4. In addition, mutations in SCFCdc4, the ubiquitin ligase for Gcn4 (ref. 5), or mutations in ubiquitin that prevent degradation(6), also impaired the transcription of Gcn4 targets. These transcriptional defects were manifested despite the enhanced abundance of Gcn4 on cognate promoters. Proteasome inhibition also decreased the association of RNA polymerase II with Gcn4, Gal4 and Ino2/4 targets, as did mutations in SCFCdc4 for Gcn4 targets. Expression of a stable phospho-site mutant of Gcn4 ( ref. 7) or disruption of the kinases that target Gcn4 for turnover(5,7) alleviated the sensitivity of Gcn4 activity to defects in the UPS.