Heat shock factor 1 ameliorates proteotoxicity in cooperation with the transcription factor NFAT
Heat shock factor 1 ameliorates proteotoxicity in cooperation with the transcription factor NFAT
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DOI：
10.1038/emboj.2010.225
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发表时间：
2010-10-20
期刊：
影响因子：
11.4
通讯作者：
Nakai, Akira
中科院分区：
文献类型：
--
作者：
Hayashida, Naoki;Fujimoto, Mitsuaki;Nakai, Akira
热休克转录因子1（HSF 1）是一种重要的蛋白质稳态调节因子，通过控制促进蛋白质折叠的主要热休克蛋白（Hsps）的表达。然而，目前还不清楚是否其他蛋白质代谢途径是由HSF 1介导的。在这里，我们确定了哺乳动物细胞中HSF 1的新靶点，其抑制聚谷氨酰胺（polyQ）蛋白的聚集。其中，我们表明，活化T细胞（NFAT）蛋白的核因子之一，NFATc 2，显着抑制polyQ聚集在细胞中，是所需的HSF 1介导的抑制polyQ聚集。NFAT缺乏加速疾病进展，包括突变的polyQ-亨廷顿蛋白的聚集和R6/2亨廷顿病小鼠寿命的缩短。此外，我们发现HSF 1和NFAT协同诱导支架蛋白PDZK 3和α B-晶状体蛋白的表达，这有助于polyQ蛋白的降解。这些结果显示了HSF 1对蛋白质稳态具有比单个Hsp或不同Hsp的组合更深刻的影响的观察的第一个机制基础，并提出了改善蛋白质错误折叠疾病的新途径。The EMBO Journal（2010）29，3459-3469. doi：10.1038/daj.2010.225; Published online 10 September 2010主题分类：信号转导;染色质和转录;蛋白质
Heat shock transcription factor 1 (HSF1) is an important regulator of protein homeostasis (proteostasis) by controlling the expression of major heat shock proteins (Hsps) that facilitate protein folding. However, it is unclear whether other proteostasis pathways are mediated by HSF1. Here, we identified novel targets of HSF1 in mammalian cells, which suppress the aggregation of polyglutamine (polyQ) protein. Among them, we show that one of the nuclear factor of activated T cells (NFAT) proteins, NFATc2, significantly inhibits polyQ aggregation in cells and is required for HSF1-mediated suppression of polyQ aggregation. NFAT deficiency accelerated disease progression including aggregation of a mutant polyQ-huntingtin protein and shortening of lifespan in R6/2 Huntington's disease mice. Furthermore, we found that HSF1 and NFAT cooperatively induce the expression of the scaffold protein PDZK3 and alpha B-crystallin, which facilitate the degradation of polyQ protein. These results show the first mechanistic basis for the observation that HSF1 has a much more profound effect on proteostasis than individual Hsp or combination of different Hsps, and suggest a new pathway for ameliorating protein-misfolding diseases. The EMBO Journal (2010) 29, 3459-3469. doi:10.1038/emboj.2010.225; Published online 10 September 2010 Subject Categories: signal transduction; chromatin & transcription; proteins