1. Cell Biology

Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1

  1. Anna E Masser
  2. Wenjing Kang
  3. Joydeep Roy
  4. Jayasankar M Kaimal
  5. Jany Quintana-Cordero
  6. Marc R Friedländer
  7. Claes Andréasson  Is a corresponding author
  1. Stockholm University, Sweden
https://doi.org/10.7554/eLife.47791
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  1. Anna E Masser
  2. Wenjing Kang
  3. Joydeep Roy
  4. Jayasankar M Kaimal
  5. Jany Quintana-Cordero
  6. Marc R Friedländer
  7. Claes Andréasson
(2019)
Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1
eLife 8:e47791.
https://doi.org/10.7554/eLife.47791
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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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Anna E Masser

    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  2. Wenjing Kang

    Science for Life Laboratory, Department of Molecular Biosciences, Stockholm University, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  3. Joydeep Roy

    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  4. Jayasankar M Kaimal

    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  5. Jany Quintana-Cordero

    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  6. Marc R Friedländer

    Science for Life Laboratory, Department of Molecular Biosciences, Stockholm University, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  7. Claes Andréasson

    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
    For correspondence
    claes.andreasson@su.se
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8948-0685

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

  1. Tricia R Serio, The University of Massachusetts, Amherst, United States

Version history

  1. Received: April 18, 2019
  2. Accepted: September 24, 2019
  3. Accepted Manuscript published: September 25, 2019 (version 1)
  4. 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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  1. Anna E Masser
  2. Wenjing Kang
  3. Joydeep Roy
  4. Jayasankar M Kaimal
  5. Jany Quintana-Cordero
  6. Marc R Friedländer
  7. Claes Andréasson
(2019)
Cytoplasmic protein misfolding titrates Hsp70 to activate nuclear Hsf1
eLife 8:e47791.
https://doi.org/10.7554/eLife.47791

Share this article

https://doi.org/10.7554/eLife.47791

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