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Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK
Numerous extrinsic and intrinsic insults trigger the HSF1-mediated proteotoxic stress response (PSR), an ancient transcriptional program that is essential to proteostasis and survival under such conditions. In contrast to its well-recognized mobilization by proteotoxic stress, little is known about...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BlackWell Publishing Ltd
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339117/ https://www.ncbi.nlm.nih.gov/pubmed/25425574 http://dx.doi.org/10.15252/embj.201489062 |
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author | Dai, Siyuan Tang, Zijian Cao, Junyue Zhou, Wei Li, Huawen Sampson, Stephen Dai, Chengkai |
author_facet | Dai, Siyuan Tang, Zijian Cao, Junyue Zhou, Wei Li, Huawen Sampson, Stephen Dai, Chengkai |
author_sort | Dai, Siyuan |
collection | PubMed |
description | Numerous extrinsic and intrinsic insults trigger the HSF1-mediated proteotoxic stress response (PSR), an ancient transcriptional program that is essential to proteostasis and survival under such conditions. In contrast to its well-recognized mobilization by proteotoxic stress, little is known about how this powerful adaptive mechanism reacts to other stresses. Surprisingly, we discovered that metabolic stress suppresses the PSR. This suppression is largely mediated through the central metabolic sensor AMPK, which physically interacts with and phosphorylates HSF1 at Ser121. Through AMPK activation, metabolic stress represses HSF1, rendering cells vulnerable to proteotoxic stress. Conversely, proteotoxic stress inactivates AMPK and thereby interferes with the metabolic stress response. Importantly, metformin, a metabolic stressor and popular anti-diabetic drug, inactivates HSF1 and provokes proteotoxic stress within tumor cells, thereby impeding tumor growth. Thus, these findings uncover a novel interplay between the metabolic stress sensor AMPK and the proteotoxic stress sensor HSF1 that profoundly impacts stress resistance, proteostasis, and malignant growth. |
format | Online Article Text |
id | pubmed-4339117 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BlackWell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-43391172015-03-10 Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK Dai, Siyuan Tang, Zijian Cao, Junyue Zhou, Wei Li, Huawen Sampson, Stephen Dai, Chengkai EMBO J Articles Numerous extrinsic and intrinsic insults trigger the HSF1-mediated proteotoxic stress response (PSR), an ancient transcriptional program that is essential to proteostasis and survival under such conditions. In contrast to its well-recognized mobilization by proteotoxic stress, little is known about how this powerful adaptive mechanism reacts to other stresses. Surprisingly, we discovered that metabolic stress suppresses the PSR. This suppression is largely mediated through the central metabolic sensor AMPK, which physically interacts with and phosphorylates HSF1 at Ser121. Through AMPK activation, metabolic stress represses HSF1, rendering cells vulnerable to proteotoxic stress. Conversely, proteotoxic stress inactivates AMPK and thereby interferes with the metabolic stress response. Importantly, metformin, a metabolic stressor and popular anti-diabetic drug, inactivates HSF1 and provokes proteotoxic stress within tumor cells, thereby impeding tumor growth. Thus, these findings uncover a novel interplay between the metabolic stress sensor AMPK and the proteotoxic stress sensor HSF1 that profoundly impacts stress resistance, proteostasis, and malignant growth. BlackWell Publishing Ltd 2015-02-03 2014-11-25 /pmc/articles/PMC4339117/ /pubmed/25425574 http://dx.doi.org/10.15252/embj.201489062 Text en © 2014 The Authors. Published under the terms of the CC BY NC ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Dai, Siyuan Tang, Zijian Cao, Junyue Zhou, Wei Li, Huawen Sampson, Stephen Dai, Chengkai Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK |
title | Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK |
title_full | Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK |
title_fullStr | Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK |
title_full_unstemmed | Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK |
title_short | Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK |
title_sort | suppression of the hsf1-mediated proteotoxic stress response by the metabolic stress sensor ampk |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339117/ https://www.ncbi.nlm.nih.gov/pubmed/25425574 http://dx.doi.org/10.15252/embj.201489062 |
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