Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1

Elife. 2019 Sep 25;8:e47791. doi: 10.7554/eLife.47791.


Hsf1 is an ancient transcription factor that responds to protein folding stress by inducing the heat-shock response (HSR) that restore perturbed proteostasis. Hsp70 chaperones negatively regulate the activity of Hsf1 via stress-responsive mechanisms that are poorly understood. Here, we have reconstituted budding yeast Hsf1-Hsp70 activation complexes and find that surplus Hsp70 inhibits Hsf1 DNA-binding activity. Hsp70 binds Hsf1 via its canonical substrate binding domain and Hsp70 regulates Hsf1 DNA-binding activity. During heat shock, Hsp70 is out-titrated by misfolded proteins derived from ongoing translation in the cytosol. Pushing the boundaries of the regulatory system unveils a genetic hyperstress program that is triggered by proteostasis collapse and involves an enlarged Hsf1 regulon. The findings demonstrate how an apparently simple chaperone-titration mechanism produces diversified transcriptional output in response to distinct stress loads.

Keywords: Hsf1; Hsp70; S. cerevisiae; cell biology; chaperone; heat shock protein; heat shock response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA, Fungal / metabolism
  • DNA-Binding Proteins / biosynthesis*
  • Gene Expression Regulation, Fungal*
  • HSP70 Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins / biosynthesis*
  • Hot Temperature
  • Protein Binding
  • Protein Folding
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae / radiation effects
  • Saccharomyces cerevisiae Proteins / biosynthesis*
  • Transcription Factors / biosynthesis*


  • DNA, Fungal
  • DNA-Binding Proteins
  • HSF1 protein, S cerevisiae
  • HSP70 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors

Associated data

  • GEO/GSE78136