Defining the Essential Function of Yeast Hsf1 Reveals a Compact Transcriptional Program for Maintaining Eukaryotic Proteostasis.
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.
Department of Molecular and Cellular Biology, Northwest Labs, Harvard University, Cambridge, MA 02138, USA; Systems Biology PhD Program, Harvard University, Cambridge, MA 02138, USA.
Eric J
EJ
Solís
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Jai P
JP
Pandey
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Xu
X
Zheng
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Dexter X
DX
Jin
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Piyush B
PB
Gupta
Department of Statistics, Harvard University, Cambridge, MA 02138, USA.
Edoardo M
EM
Airoldi
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: pincus@wi.mit.edu.
David
D
Pincus
Department of Molecular and Cellular Biology, Northwest Labs, Harvard University, Cambridge, MA 02138, USA. Electronic address: vdenic@mcb.harvard.edu.
Vladimir
V
Denic
D000818:Animals; D064113:CRISPR-Cas Systems; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response; D006706:Homeostasis; D057507:Mice, 129 Strain; D008808:Mice, Inbred CBA; D066329:Protein Aggregates; D060066:Protein Interaction Maps; D012331:RNA, Fungal / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; C067168:HSF1 protein, S cerevisiae; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D066329:Protein Aggregates; D012331:RNA, Fungal; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors