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Hsf1 on a leash - controlling the heat shock response by chaperone titration.
Experimental Cell Research ( IF 3.3 ) Pub Date : 2020-08-27 , DOI: 10.1016/j.yexcr.2020.112246
Anna E Masser 1 , Michela Ciccarelli 1 , Claes Andréasson 1
Affiliation  

Heat shock factor 1 (Hsf1) is an ancient transcription factor that monitors protein homeostasis (proteostasis) and counteracts disturbances by triggering a transcriptional programme known as the heat shock response (HSR). The HSR is transiently activated and upregulates the expression of core proteostasis genes, including chaperones. Dysregulation of Hsf1 and its target genes are associated with disease; cancer cells rely on a constitutively active Hsf1 to promote rapid growth and malignancy, whereas Hsf1 hypoactivation in neurodegenerative disorders results in formation of toxic aggregates. These central but opposing roles highlight the importance of understanding the underlying molecular mechanisms that control Hsf1 activity. According to current understanding, Hsf1 is maintained latent by chaperone interactions but proteostasis perturbations titrate chaperone availability as a result of chaperone sequestration by misfolded proteins. Liberated and activated Hsf1 triggers a negative feedback loop by inducing the expression of key chaperones. Until recently, Hsp90 has been highlighted as the central negative regulator of Hsf1 activity. In this review, we focus on recent advances regarding how the Hsp70 chaperone controls Hsf1 activity and in addition summarise several additional layers of activity control.



中文翻译:

皮带上的Hsf1-通过伴侣滴定法控制热激反应。

热休克因子1(Hsf1)是一种古老的转录因子,它通过触发称为热休克反应(HSR)的转录程序来监视蛋白质稳态(蛋白稳态)并抵消干扰。HSR被短暂激活并上调核心蛋白稳态基因(包括伴侣蛋白)的表达。Hsf1及其靶基因的失调与疾病有关。癌细胞依赖于组成型活性的Hsf1来促进快速生长和恶性肿瘤,而神经退行性疾病中的Hsf1过度活化会导致毒性聚集物的形成。这些中心但相对的作用突出了理解控制Hsf1活性的潜在分子机制的重要性。根据目前的理解,Hsf1通过伴侣之间的相互作用而保持潜伏,但是由于伴侣蛋白被错误折叠的蛋白螯合,蛋白稳态扰动使伴侣蛋白的利用率升高。释放并激活的Hsf1通过诱导关键伴侣分子的表达触发负反馈循环。直到最近,Hsp90一直是Hsf1活性的中央负调控因子。在这篇综述中,我们重点介绍有关Hsp70分子伴侣如何控制Hsf1活性的最新进展,此外,还总结了几个其他的活性控制层。

更新日期:2020-09-02
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