Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1

• Main Authors: Anna E Masser, Wenjing Kang, Joydeep Roy, Jayasankar Mohanakrishnan Kaimal, Jany Quintana-Cordero, Marc R Friedländer, Claes Andréasson
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2019-09-01
• Series: eLife
• Subjects: Hsf1; heat shock response; heat shock protein; Hsp70; chaperone
• Online Access: https://elifesciences.org/articles/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.