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The yeast Hsp70 Ssa1 is a sensor for activation of the heat shock response by thiol-reactive compounds

The heat shock transcription factor HSF1 governs the response to heat shock, oxidative stresses, and xenobiotics through unknown mechanisms. We demonstrate that diverse thiol-reactive molecules potently activate budding yeast Hsf1. Hsf1 activation by thiol-reactive compounds is not consistent with t...

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Autores principales: Wang, Yanyu, Gibney, Patrick A., West, James D., Morano, Kevin A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469052/
https://www.ncbi.nlm.nih.gov/pubmed/22809627
http://dx.doi.org/10.1091/mbc.E12-06-0447
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author Wang, Yanyu
Gibney, Patrick A.
West, James D.
Morano, Kevin A.
author_facet Wang, Yanyu
Gibney, Patrick A.
West, James D.
Morano, Kevin A.
author_sort Wang, Yanyu
collection PubMed
description The heat shock transcription factor HSF1 governs the response to heat shock, oxidative stresses, and xenobiotics through unknown mechanisms. We demonstrate that diverse thiol-reactive molecules potently activate budding yeast Hsf1. Hsf1 activation by thiol-reactive compounds is not consistent with the stresses of misfolding of cytoplasmic proteins or cytotoxicity. Instead, we demonstrate that the Hsp70 chaperone Ssa1, which represses Hsf1 in the absence of stress, is hypersensitive to modification by a thiol-reactive probe. Strikingly, mutation of two conserved cysteine residues to serine in Ssa1 rendered cells insensitive to Hsf1 activation and subsequently induced thermotolerance by thiol-reactive compounds, but not by heat shock. Conversely, substitution with the sulfinic acid mimic aspartic acid resulted in constitutive Hsf1 activation. Cysteine 303, located within the nucleotide-binding domain, was found to be modified in vivo by a model organic electrophile, demonstrating that Ssa1 is a direct target for thiol-reactive molecules through adduct formation. These findings demonstrate that Hsp70 is a proximal sensor for Hsf1-mediated cytoprotection and can discriminate between two distinct environmental stressors.
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spelling pubmed-34690522012-11-16 The yeast Hsp70 Ssa1 is a sensor for activation of the heat shock response by thiol-reactive compounds Wang, Yanyu Gibney, Patrick A. West, James D. Morano, Kevin A. Mol Biol Cell Articles The heat shock transcription factor HSF1 governs the response to heat shock, oxidative stresses, and xenobiotics through unknown mechanisms. We demonstrate that diverse thiol-reactive molecules potently activate budding yeast Hsf1. Hsf1 activation by thiol-reactive compounds is not consistent with the stresses of misfolding of cytoplasmic proteins or cytotoxicity. Instead, we demonstrate that the Hsp70 chaperone Ssa1, which represses Hsf1 in the absence of stress, is hypersensitive to modification by a thiol-reactive probe. Strikingly, mutation of two conserved cysteine residues to serine in Ssa1 rendered cells insensitive to Hsf1 activation and subsequently induced thermotolerance by thiol-reactive compounds, but not by heat shock. Conversely, substitution with the sulfinic acid mimic aspartic acid resulted in constitutive Hsf1 activation. Cysteine 303, located within the nucleotide-binding domain, was found to be modified in vivo by a model organic electrophile, demonstrating that Ssa1 is a direct target for thiol-reactive molecules through adduct formation. These findings demonstrate that Hsp70 is a proximal sensor for Hsf1-mediated cytoprotection and can discriminate between two distinct environmental stressors. The American Society for Cell Biology 2012-09-01 /pmc/articles/PMC3469052/ /pubmed/22809627 http://dx.doi.org/10.1091/mbc.E12-06-0447 Text en © 2012 Wang et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell BD; are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Wang, Yanyu
Gibney, Patrick A.
West, James D.
Morano, Kevin A.
The yeast Hsp70 Ssa1 is a sensor for activation of the heat shock response by thiol-reactive compounds
title The yeast Hsp70 Ssa1 is a sensor for activation of the heat shock response by thiol-reactive compounds
title_full The yeast Hsp70 Ssa1 is a sensor for activation of the heat shock response by thiol-reactive compounds
title_fullStr The yeast Hsp70 Ssa1 is a sensor for activation of the heat shock response by thiol-reactive compounds
title_full_unstemmed The yeast Hsp70 Ssa1 is a sensor for activation of the heat shock response by thiol-reactive compounds
title_short The yeast Hsp70 Ssa1 is a sensor for activation of the heat shock response by thiol-reactive compounds
title_sort yeast hsp70 ssa1 is a sensor for activation of the heat shock response by thiol-reactive compounds
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469052/
https://www.ncbi.nlm.nih.gov/pubmed/22809627
http://dx.doi.org/10.1091/mbc.E12-06-0447
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