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


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 ?B-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.

SUBMITTER: Hayashida N 

PROVIDER: S-EPMC2964172 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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

Hayashida Naoki N   Fujimoto Mitsuaki M   Tan Ke K   Prakasam Ramachandran R   Shinkawa Toyohide T   Li Liangping L   Ichikawa Hitoshi H   Takii Ryosuke R   Nakai Akira A  

The EMBO journal 20100910 20


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,  ...[more]

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