Heat Shock Factor 1 Is a Direct Antagonist of AMP-Activated Protein Kinase

Author:

Su,Kuo-Hui

Dai, Siyuan

Tang,Zijian

Xu,Meng

Dai,Chengkai
Author Address

Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA., Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, MA 01655, USA., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA; Graduate programs, Department of Molecular & Biomedical Sciences, The University of Maine, Orono, ME 04469, USA., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA. Electronic address: chengkai.dai@nih.gov.,

Abstract:

Through transcriptional control of the evolutionarily conserved heat shock, or proteotoxic stress, response, heat shock factor 1 (HSF1) preserves proteomic stability. Here, we show that HSF1, a physiological substrate for AMP-activated protein kinase (AMPK), constitutively suppresses this central metabolic sensor. By physically evoking conformational switching of AMPK, HSF1 impairs AMP binding to the gamma subunits and enhances the PP2A-mediated de-phosphorylation, but it impedes the LKB1-mediated phosphorylation of Thr172, and retards ATP binding to the catalytic alpha subunits. These immediate and manifold regulations empower HSF1 to both repress AMPK under basal conditions and restrain its activation by diverse stimuli, thereby promoting lipogenesis, cholesterol synthesis, and protein cholesteroylation. In vivo, HSF1 antagonizes AMPK to control body fat mass and drive the lipogenic phenotype and growth of melanomas independently of its intrinsic transcriptional action. Thus, the physical AMPK-HSF1 interaction epitomizes a reciprocal kinase-substrate regulation whereby lipid metabolism and proteomic stability intertwine.

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