Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1
- Stockholm University, Sweden
Abstract
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 on-going translation in the cytosol. Pushing the boundaries of the regulatory system unveils a genetic hyper-stress 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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE78136.
Article and author information
Author details
Funding
The Swedish Cancer Society (CAN2018/711)
- Claes Andréasson
The Swedish Cancer Society (CAN2016/361)
- Claes Andréasson
Swedish Research Council (2015-05094)
- Claes Andréasson
Knut och Alice Wallenbergs Stiftelse (2017)
- Claes Andréasson
European Research Council (Starting Grant 758397)
- Marc R Friedländer
Swedish Research Council (2015-04611)
- Marc R Friedländer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Tricia R Serio, The University of Massachusetts, Amherst, United States
Version history
- Received: April 18, 2019
- Accepted: September 24, 2019
- Accepted Manuscript published: September 25, 2019 (version 1)
- Version of Record published: October 7, 2019 (version 2)
Copyright
© 2019, Masser et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1
eLife 8:e47791.
https://doi.org/10.7554/eLife.47791
Further reading
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