Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1.

Masser AE, Kang W, Roy J, Mohanakrishnan Kaimal J, Quintana-Cordero J, Friedländer MR, Andréasson C

Elife 8 (-) - [2019-09-25; online 2019-09-25]

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.

Bioinformatics Compute and Storage [Service]

NGI Stockholm (Genomics Applications) [Service]

NGI Stockholm (Genomics Production) [Service]

National Genomics Infrastructure [Service]

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PubMed 31552827

DOI 10.7554/eLife.47791

Crossref 10.7554/eLife.47791

GEO GSE78136

47791

pmc PMC6779467