title: Suppression of the HSF1-mediated proteotoxic stress response by the metabolic stress sensor AMPK.
abstract: 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Dai
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA Graduate Programs, Department of Molecular & Biomedical Sciences, The University of Maine, Orono, ME, USA.
authors.forename: Zijian
authors.initials: Z
authors.lastname: Tang
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Junyue
authors.initials: J
authors.lastname: Cao
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Huawen
authors.initials: H
authors.lastname: Li
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Sampson
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA Chengkai.Dai@jax.org.
authors.forename: Chengkai
authors.initials: C
authors.lastname: Dai
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D000076249:Heat Shock Transcription Factors; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D007004:Hypoglycemic Agents; D009363:Neoplasm Proteins; D014157:Transcription Factors; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: AMPK; HSF1; metformin; proteostasis; tumorigenesis