Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK

• Siyuan Dai ^[1] ; Zijian Tang ^[2] ; Junyue Cao ^[1] ; Wei Zhou ^[1] ; Huawen Li ^[1] ; Stephen Sampson ^[1] ; Chengkai Dai ^[1]
  1. [1] 1 The Jackson Laboratory Bar Harbor, ME, USA
  2. [2] 1 The Jackson Laboratory Bar Harbor, ME, USA; 2 Graduate Programs, Department of Molecular & Biomedical Sciences, The University of Maine Orono, ME, USA
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 34, Nº. 3, 2014, págs. 275-293
• Idioma: inglés
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• Resumen

  • 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.