Heat shock factor 1 ameliorates proteotoxicity in cooperation with the transcription factor NFAT.
Heat shock transcription factor 1 (HSF1) is an important regulator of protein homeostasis (proteostasis) by controlling the expression of major heat shock proteins (Hsps) that facilitate protein folding. However, it is unclear whether other proteostasis pathways are mediated by HSF1. Here, we identified novel targets of HSF1 in mammalian cells, which suppress the aggregation of polyglutamine (polyQ) protein. Among them, we show that one of the nuclear factor of activated T cells (NFAT) proteins, NFATc2, significantly inhibits polyQ aggregation in cells and is required for HSF1-mediated suppression of polyQ aggregation. NFAT deficiency accelerated disease progression including aggregation of a mutant polyQ-huntingtin protein and shortening of lifespan in R6/2 Huntington's disease mice. Furthermore, we found that HSF1 and NFAT cooperatively induce the expression of the scaffold protein PDZK3 and αB-crystallin, which facilitate the degradation of polyQ protein. These results show the first mechanistic basis for the observation that HSF1 has a much more profound effect on proteostasis than individual Hsp or combination of different Hsps, and suggest a new pathway for ameliorating protein-misfolding diseases.
Hayashida
Naoki
N
Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Ube, Japan.
Fujimoto
Mitsuaki
M
Tan
Ke
K
Prakasam
Ramachandran
R
Shinkawa
Toyohide
T
Li
Liangping
L
Ichikawa
Hitoshi
H
Takii
Ryosuke
R
Nakai
Akira
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D000071058:Huntingtin Protein; D008017:Life Expectancy; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C525420:Cryab protein, mouse; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C494007:Nfatc2 protein, mouse; D009687:Nuclear Proteins; D010455:Peptides; D014157:Transcription Factors; D038203:alpha-Crystallin B Chain; C097188:polyglutamine