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Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation
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 t...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127643/ https://www.ncbi.nlm.nih.gov/pubmed/27831465 http://dx.doi.org/10.7554/eLife.18638 |
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author | Zheng, Xu Krakowiak, Joanna Patel, Nikit Beyzavi, Ali Ezike, Jideofor Khalil, Ahmad S Pincus, David |
author_facet | Zheng, Xu Krakowiak, Joanna Patel, Nikit Beyzavi, Ali Ezike, Jideofor Khalil, Ahmad S Pincus, David |
author_sort | Zheng, Xu |
collection | PubMed |
description | 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. DOI: http://dx.doi.org/10.7554/eLife.18638.001 |
format | Online Article Text |
id | pubmed-5127643 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-51276432016-11-30 Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation Zheng, Xu Krakowiak, Joanna Patel, Nikit Beyzavi, Ali Ezike, Jideofor Khalil, Ahmad S Pincus, David eLife Cell Biology 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. DOI: http://dx.doi.org/10.7554/eLife.18638.001 eLife Sciences Publications, Ltd 2016-11-10 /pmc/articles/PMC5127643/ /pubmed/27831465 http://dx.doi.org/10.7554/eLife.18638 Text en © 2016, Zheng et al http://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (http://creativecommons.org/publicdomain/zero/1.0/) . |
spellingShingle | Cell Biology Zheng, Xu Krakowiak, Joanna Patel, Nikit Beyzavi, Ali Ezike, Jideofor Khalil, Ahmad S Pincus, David Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation |
title | Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation |
title_full | Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation |
title_fullStr | Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation |
title_full_unstemmed | Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation |
title_short | Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation |
title_sort | dynamic control of hsf1 during heat shock by a chaperone switch and phosphorylation |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127643/ https://www.ncbi.nlm.nih.gov/pubmed/27831465 http://dx.doi.org/10.7554/eLife.18638 |
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