Modulation of heat shock factor 1 activity through silencing of Ser303/Ser307 phosphorylation supports a metabolic program leading to age-related obesity and insulin resistance

Xiongjie Jin, Aijun Qiao, Dimitrios Moskofidis, Nahid F. Mivechia

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Activation of the adaptive response to cellular stress orchestrated by heat shock factor 1 (HSF1), which is an evolutionarily conserved transcriptional regulator of chaperone response and cellular bioenergetics in diverse model systems, is a central feature of organismal defense from environmental and cellular stress. HSF1 activity, induced by proteostatic, metabolic, and growth factor signals, is regulated by posttranscriptional modifications, yet the mechanisms that regulate HSF1 and particularly the functional significance of these modifications in modulating its biological activity in vivo remain unknown. HSF1 phosphorylation at both Ser303 (S303) and Ser307 (S307) has been shown to repress HSF1 transcriptional activity under normal physiological growth conditions. To determine the biological relevance of these HSF1 phosphorylation events, we generated a knock-in mouse model in which S303 and S307 were replaced with alanine (HSF1303A/307A). Our results confirmed that loss of phosphorylation in HSF1303A/307A cells and tissues increases protein stability but also markedly sensitizes HSF1 activation under normal and heat- or nutrient-induced stress conditions. Interestingly, the enhanced HSF1 activation in HSF1303A/307A mice activates a supportive metabolic program that aggravates the development of age-dependent obesity, fatty liver diseases, and insulin resistance. Thus, these findings highlight the importance of a posttranslational mechanism (through phosphorylation at S303 and S307 sites) of regulation of the HSF1-mediated transcriptional program that moderates the severity of nutrient-induced metabolic diseases.

Original languageEnglish (US)
Article numbere00095-18
JournalMolecular and Cellular Biology
Volume38
Issue number18
DOIs
StatePublished - Sep 1 2018

Keywords

  • Insulin resistance
  • Knock-in mouse model
  • Obesity
  • Phosphorylation of HSF1 (Ser303A/Ser307A)
  • Posttranslational HSF1 regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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