Abstract
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.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation
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HeLa Cells
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Heat Shock Transcription Factors
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Humans
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Huntingtin Protein
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Life Expectancy
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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Molecular Chaperones / genetics
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Molecular Chaperones / metabolism
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / metabolism*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Peptides / metabolism*
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Signal Transduction / physiology
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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alpha-Crystallin B Chain / genetics
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alpha-Crystallin B Chain / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cryab protein, mouse
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DNA-Binding Proteins
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HSF1 protein, human
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Heat Shock Transcription Factors
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Hsf1 protein, mouse
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Htt protein, mouse
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Huntingtin Protein
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Molecular Chaperones
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NFATC Transcription Factors
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Neoplasm Proteins
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Nerve Tissue Proteins
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Nfatc2 protein, mouse
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Nuclear Proteins
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Peptides
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Transcription Factors
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alpha-Crystallin B Chain
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polyglutamine