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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...

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Detalles Bibliográficos
Autores principales: Zheng, Xu, Krakowiak, Joanna, Patel, Nikit, Beyzavi, Ali, Ezike, Jideofor, Khalil, Ahmad S, Pincus, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2016
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
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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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