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Suppression of the HSF 1‐mediated proteotoxic stress response by the metabolic stress sensor AMPK
Author(s) -
Dai Siyuan,
Tang Zijian,
Cao Junyue,
Zhou Wei,
Li Huawen,
Sampson Stephen,
Dai Chengkai
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201489062
Subject(s) - proteostasis , hsf1 , ampk , biology , unfolded protein response , microbiology and biotechnology , heat shock , proteotoxicity , cellular stress response , heat shock protein , protein aggregation , endoplasmic reticulum , phosphorylation , protein kinase a , fight or flight response , hsp70 , genetics , gene
Numerous extrinsic and intrinsic insults trigger the HSF 1‐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 HSF 1 at Ser121. Through AMPK activation, metabolic stress represses HSF 1, 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 HSF 1 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 HSF 1 that profoundly impacts stress resistance, proteostasis, and malignant growth.