Interplay of Acetyltransferase EP300 and the Proteasome System in Regulating Heat Shock Transcription Factor 1
Interplay of Acetyltransferase EP300 and the Proteasome System in Regulating Heat Shock Transcription Factor 1
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DOI：
10.1016/j.cell.2014.01.055
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发表时间：
2014-02-27
期刊：
影响因子：
64.5
通讯作者：
Hartl, F. Ulrich
中科院分区：
文献类型：
--
作者：
Raychaudhuri, Swasti;Loew, Christian;Hartl, F. Ulrich
当暴露于蛋白毒性环境条件时，哺乳动物细胞激活胞质应激反应以恢复蛋白质稳态。这种反应的一个关键特征是分子伴侣的热休克转录因子1（HSF1）依赖性表达。在这里，我们描述了在HeLa细胞中的RNA干扰筛选的结果，以确定应激反应的诱导和衰减的调制器。调节蛋白定位于多个细胞区室中，染色质修饰剂和核蛋白质质量控制起着中心调节作用。我们发现，乙酰转移酶，EP300，控制可激活的HSF1的细胞水平。这涉及HSF 1在功能不需要的多个赖氨酸处的乙酰化，并导致HSF 1稳定以对抗蛋白酶体周转。在应激期间功能关键赖氨酸的乙酰化用于微调HSF 1活化。最后，核蛋白酶体系统通过以与错误折叠蛋白质的清除相关的方式降解活化的HSF 1来减弱应激反应。
When exposed to proteotoxic environmental conditions, mammalian cells activate the cytosolic stress response in order to restore protein homeostasis. A key feature of this response is the heat shock transcription factor 1 (HSF1)-dependent expression of molecular chaperones. Here, we describe the results of an RNA interference screen in HeLa cells to identify modulators of stress response induction and attenuation. The modulator proteins are localized in multiple cellular compartments, with chromatin modifiers and nuclear protein quality control playing a central regulatory role. We find that the acetyltransferase, EP300, controls the cellular level of activatable HSF1. This involves acetylation of HSF1 at multiple lysines not required for function and results in stabilization of HSF1 against proteasomal turnover. Acetylation of functionally critical lysines during stress serves to fine-tune HSF1 activation. Finally, the nuclear proteasome system functions in attenuating the stress response by degrading activated HSF1 in a manner linked with the clearance of misfolded proteins.