Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation

  1. Xu Zheng
  2. Joanna Krakowiak
  3. Nikit Patel
  4. Ali Beyzavi
  5. Jideofor Ezike
  6. Ahmad S Khalil  Is a corresponding author
  7. David Pincus  Is a corresponding author
  1. Whitehead Institute for Biomedical Research, United States
  2. Boston University, United States
  3. Massachusetts Institute of Technology, United States

Abstract

Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. Here we show that in budding yeast, Hsf1 basally associates with the chaperone Hsp70 and this association is transiently disrupted by heat shock, providing the first evidence that a chaperone repressor directly regulates Hsf1 activity. We develop and experimentally validate a mathematical model of Hsf1 activation by heat shock in which unfolded proteins compete with Hsf1 for binding to Hsp70. Surprisingly, we find that Hsf1 phosphorylation, previously thought to be required for activation, in fact only positively tunes Hsf1 and does so without affecting Hsp70 binding. Our work reveals two uncoupled forms of regulation - an ON/OFF chaperone switch and a tunable phosphorylation gain - that allow Hsf1 to flexibly integrate signals from the proteostasis network and cell signaling pathways.

Article and author information

Author details

  1. Xu Zheng

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Joanna Krakowiak

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nikit Patel

    Department of Biomedical Engineering, Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ali Beyzavi

    David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jideofor Ezike

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ahmad S Khalil

    Department of Biomedical Engineering, Boston University, Boston, United States
    For correspondence
    akhalil@bu.edu
    Competing interests
    The authors declare that no competing interests exist.
  7. David Pincus

    Whitehead Institute for Biomedical Research, Cambridge, United States
    For correspondence
    pincus@wi.mit.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

NIH Office of the Director (DP5 OD017941-01)

  • David Pincus

National Science Foundation (MCB-1350949)

  • Ahmad S Khalil

Alexander and Margaret Stewart Trust (Fellowship)

  • 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

Publication history

  1. Received: June 9, 2016
  2. Accepted: November 1, 2016
  3. Accepted Manuscript published: November 10, 2016 (version 1)
  4. Version of Record published: November 29, 2016 (version 2)
  5. Version of Record updated: August 8, 2017 (version 3)

Copyright

© 2016, Zheng 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. Xu Zheng
  2. Joanna Krakowiak
  3. Nikit Patel
  4. Ali Beyzavi
  5. Jideofor Ezike
  6. Ahmad S Khalil
  7. David Pincus
(2016)
Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation
eLife 5:e18638.
https://doi.org/10.7554/eLife.18638

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