Solís Eric J, Pandey Jai P, Zheng Xu, Jin Dexter X, Gupta Piyush B, Airoldi Edoardo M, Pincus David, Denic Vladimir
Department of Molecular and Cellular Biology, Northwest Labs, Harvard University, Cambridge, MA 02138, USA; Systems Biology PhD Program, Harvard University, Cambridge, MA 02138, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Mol Cell. 2016 Jul 7;63(1):60-71. doi: 10.1016/j.molcel.2016.05.014. Epub 2016 Jun 16.
Despite its eponymous association with the heat shock response, yeast heat shock factor 1 (Hsf1) is essential even at low temperatures. Here we show that engineered nuclear export of Hsf1 results in cytotoxicity associated with massive protein aggregation. Genome-wide analysis revealed that Hsf1 nuclear export immediately decreased basal transcription and mRNA expression of 18 genes, which predominately encode chaperones. Strikingly, rescuing basal expression of Hsp70 and Hsp90 chaperones enabled robust cell growth in the complete absence of Hsf1. With the exception of chaperone gene induction, the vast majority of the heat shock response was Hsf1 independent. By comparative analysis of mammalian cell lines, we found that only heat shock-induced but not basal expression of chaperones is dependent on the mammalian Hsf1 homolog (HSF1). Our work reveals that yeast chaperone gene expression is an essential housekeeping mechanism and provides a roadmap for defining the function of HSF1 as a driver of oncogenesis.
尽管酵母热休克因子1（Hsf1）与热休克反应同名相关，但即使在低温下它也是必不可少的。我们在此表明，工程化的Hsf1核输出会导致与大量蛋白质聚集相关的细胞毒性。全基因组分析显示，Hsf1核输出会立即降低18个基因的基础转录和mRNA表达，这些基因主要编码伴侣蛋白。引人注目的是，挽救Hsp70和Hsp90伴侣蛋白的基础表达能够在完全没有Hsf1的情况下实现强劲的细胞生长。除了伴侣蛋白基因诱导外，绝大多数热休克反应都不依赖于Hsf1。通过对哺乳动物细胞系的比较分析，我们发现只有热休克诱导的伴侣蛋白表达而非基础表达依赖于哺乳动物Hsf1同源物（HSF1）。我们的工作揭示了酵母伴侣蛋白基因表达是一种基本的看家机制，并为定义HSF1作为肿瘤发生驱动因子的功能提供了路线图。
