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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2016-11-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/18638 |
| _version_ | 1811180414542282752 |
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| author | Xu Zheng Joanna Krakowiak Nikit Patel Ali Beyzavi Jideofor Ezike Ahmad S Khalil David Pincus |
| author_facet | Xu Zheng Joanna Krakowiak Nikit Patel Ali Beyzavi Jideofor Ezike Ahmad S Khalil David Pincus |
| author_sort | Xu Zheng |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T09:02:45Z |
| format | Article |
| id | doaj.art-613e7a8ddce344988492e2faa4361c85 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:02:45Z |
| publishDate | 2016-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-613e7a8ddce344988492e2faa4361c852022-12-22T04:32:43ZengeLife Sciences Publications LtdeLife2050-084X2016-11-01510.7554/eLife.18638Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylationXu Zheng0Joanna Krakowiak1Nikit Patel2Ali Beyzavi3Jideofor Ezike4Ahmad S Khalil5David Pincus6https://orcid.org/0000-0002-9651-6858Whitehead Institute for Biomedical Research, Cambridge, United StatesWhitehead Institute for Biomedical Research, Cambridge, United StatesDepartment of Biomedical Engineering and Biological Design Center, Boston University, Boston, United StatesDepartment of Mechanical Engineering, Boston University, Boston, United StatesWhitehead Institute for Biomedical Research, Cambridge, United StatesDepartment of Biomedical Engineering and Biological Design Center, Boston University, Boston, United States; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, United StatesWhitehead Institute for Biomedical Research, Cambridge, United StatesHeat 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.https://elifesciences.org/articles/18638heat shockHsf1Hsp70phosphorylationchaperonesystems modeling |
| spellingShingle | Xu Zheng Joanna Krakowiak Nikit Patel Ali Beyzavi Jideofor Ezike Ahmad S Khalil David Pincus Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation eLife heat shock Hsf1 Hsp70 phosphorylation chaperone systems modeling |
| 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 | heat shock Hsf1 Hsp70 phosphorylation chaperone systems modeling |
| url | https://elifesciences.org/articles/18638 |
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