Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1.
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.
Westerheide
Sandy D
SD
Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, 60208, USA.
Anckar
Julius
J
Stevens
Stanley M
SM
Sistonen
Lea
L
Morimoto
Richard I
RI
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D034741:RNA, Small Interfering; D014157:Transcription Factors; D004247:DNA; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins