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Heat shock factor 1 ameliorates proteotoxicity in cooperation with the transcription factor NFAT

Item Type:Article
Title:Heat shock factor 1 ameliorates proteotoxicity in cooperation with the transcription factor NFAT
Creators Name:Hayashida, N. and Fujimoto, M. and Tan, K. and Prakasam, R. and Shinkawa, T. and Li, L. and Ichikawa, H. and Takii, R. and Nakai, A.
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.
Keywords:Heat Shock, HSF, NFAT, Polyglutamine, Protein Homeostasis, Animals, Mice
Source:EMBO Journal
Publisher:Nature Publishing Group
Page Range:3459-3469
Date:20 October 2010
Official Publication:https://doi.org/10.1038/emboj.2010.225
PubMed:View item in PubMed

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