Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1

Science. 2009 Feb 20;323(5917):1063-6. doi: 10.1126/science.1165946.

Abstract

Heat shock factor 1 (HSF1) is essential for protecting cells from protein-damaging stress associated with misfolded proteins and regulates the insulin-signaling pathway and aging. Here, we show that human HSF1 is inducibly acetylated at a critical residue that negatively regulates DNA binding activity. Activation of the deacetylase and longevity factor SIRT1 prolonged HSF1 binding to the heat shock promoter Hsp70 by maintaining HSF1 in a deacetylated, DNA-binding competent state. Conversely, down-regulation of SIRT1 accelerated the attenuation of the heat shock response (HSR) and release of HSF1 from its cognate promoter elements. These results provide a mechanistic basis for the requirement of HSF1 in the regulation of life span and establish a role for SIRT1 in protein homeostasis and the HSR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Animals
  • Cellular Senescence / physiology*
  • Chromatin Immunoprecipitation
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • HSP70 Heat-Shock Proteins / genetics*
  • HeLa Cells
  • Heat Shock Transcription Factors
  • Heat-Shock Response*
  • Homeostasis
  • Humans
  • Mice
  • Molecular Sequence Data
  • Promoter Regions, Genetic*
  • RNA, Small Interfering
  • Sirtuin 1
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Stress, Psychological*
  • Transcription Factors / metabolism*
  • Transfection

Substances

  • DNA-Binding Proteins
  • HSF1 protein, human
  • HSP70 Heat-Shock Proteins
  • Heat Shock Transcription Factors
  • RNA, Small Interfering
  • Transcription Factors
  • DNA
  • SIRT1 protein, human
  • Sirtuin 1
  • Sirtuins