The transcriptional regulator of the chaperone response HSF1 controls hepatic bioenergetics and protein homeostasis.
Metabolic energy reprogramming facilitates adaptations to a variety of stress conditions and cellular dysfunction, but how the energetic demands are monitored and met in response to physiological stimuli remains elusive. Our data support a model demonstrating that heat shock factor 1 (HSF1), a master transcriptional regulator of the chaperone response, has been coopted from its role as a critical protein quality-control regulator to having a central role in systemic energy sensing and for metabolic adaptation to nutrient availability. We found that in the absence of HSF1, levels of NAD+and ATP are not efficiently sustained in hepatic cells, largely because of transcriptional repression of nicotinamide phosphoribosyltransferase in the NAD+salvage pathway. Mechanistically, the defect in NAD+and ATP synthesis linked to a loss of NAD+-dependent deacetylase activity, increased protein acetylation, and impaired mitochondrial integrity. Remarkably, the drop in ATP level caused by HSF1 loss invoked an adaptive response featuring the inhibition of energetically demanding processes, including gluconeogenesis, translation, and lipid synthesis. Our work identifies HSF1 as a central regulator of cellular bioenergetics and protein homeostasis that benefits malignant cell progression and exacerbates development of metabolic diseases.
Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912.|Georgia Cancer Center, Augusta University, Augusta, GA 30912.
Aijun
0000-0001-7545-3395
A
Qiao
Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912.|Georgia Cancer Center, Augusta University, Augusta, GA 30912.
Xiongjie
X
Jin
Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912.|Georgia Cancer Center, Augusta University, Augusta, GA 30912.
Junfeng
J
Pang
Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912 nmivechi@augusta.edu dmoskofidis@augusta.edu.|Georgia Cancer Center, Augusta University, Augusta, GA 30912.|Department of Medicine, Augusta University, Augusta, GA 30912.
Demetrius
D
Moskophidis
Molecular Chaperone Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912 nmivechi@augusta.edu dmoskofidis@augusta.edu.|Georgia Cancer Center, Augusta University, Augusta, GA 30912.|Department of Radiology, Augusta University, Augusta, GA 30912.
Nahid F
0000-0002-3510-9968
NF
Mivechi
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics; D018869:Heat-Shock Response / Q000235:genetics; D006706:Homeostasis / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000235:genetics*; D009243:NAD / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*
D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D018832:Molecular Chaperones; D014157:Transcription Factors; D009243:NAD; D000255:Adenosine Triphosphate