1. Cell Biology
  2. Computational and Systems Biology

Transcriptional regulation of Sis1 promotes fitness but not feedback in the heat shock response

  1. Rania Garde
  2. Abhyudai Singh  Is a corresponding author
  3. Asif Ali
  4. David Pincus  Is a corresponding author
  1. University of Chicago, United States
  2. University of Delaware, United States
https://doi.org/10.7554/eLife.79444
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  1. Rania Garde
  2. Abhyudai Singh
  3. Asif Ali
  4. David Pincus
(2023)
Transcriptional regulation of Sis1 promotes fitness but not feedback in the heat shock response
eLife 12:e79444.
https://doi.org/10.7554/eLife.79444
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Abstract

The heat shock response (HSR) controls expression of molecular chaperones to maintain protein homeostasis. Previously, we proposed a feedback loop model of the HSR in which heat-denatured proteins sequester the chaperone Hsp70 to activate the HSR, and subsequent induction of Hsp70 deactivates the HSR (Krakowiak et al., 2018; Zheng et al., 2016). However, recent work has implicated newly synthesized proteins (NSPs) - rather than unfolded mature proteins - and the Hsp70 co-chaperone Sis1 in HSR regulation, yet their contributions to HSR dynamics have not been determined. Here we generate a new mathematical model that incorporates NSPs and Sis1 into the HSR activation mechanism, and we perform genetic decoupling and pulse-labeling experiments to demonstrate that Sis1 induction is dispensable for HSR deactivation. Rather than providing negative feedback to the HSR, transcriptional regulation of Sis1 by Hsf1 promotes fitness by coordinating stress granules and carbon metabolism. These results support an overall model in which NSPs signal the HSR by sequestering Sis1 and Hsp70, while induction of Hsp70 - but not Sis1 - attenuates the response.

Data availability

All data presented in the paper and custom analysis software are deposited in Dryad and Zenodo, respectively, with the following accessions: https://doi.org/doi:10.5061/dryad.b2rbnzsm6https://doi.org/10.5281/zenodo.7860686

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

Article and author information

Author details

  1. Rania Garde

    Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Abhyudai Singh

    Department of Electrical and Computer Engineering, University of Delaware, Delaware, United States
    For correspondence
    absingh@udel.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1451-2838

  3. Asif Ali

    Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. David Pincus

    Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, United States
    For correspondence
    pincus@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9651-6858

Funding

National Institutes of Health (GM124446)

  • Abhyudai Singh

National Science Foundation (OMA-2121044)

  • David Pincus

National Institutes of Health (GM138689)

  • David Pincus

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Tony Hunter, Salk Institute for Biological Studies, United States

Version history

  1. Received: April 19, 2022
  2. Preprint posted: April 28, 2022 (view preprint)
  3. Accepted: April 26, 2023
  4. Accepted Manuscript published: May 9, 2023 (version 1)
  5. Version of Record published: May 17, 2023 (version 2)

Copyright

© 2023, Garde 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. Rania Garde
  2. Abhyudai Singh
  3. Asif Ali
  4. David Pincus
(2023)
Transcriptional regulation of Sis1 promotes fitness but not feedback in the heat shock response
eLife 12:e79444.
https://doi.org/10.7554/eLife.79444

Share this article

https://doi.org/10.7554/eLife.79444

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