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 aB-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.

Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration

“…To clarify whether low expression levels of Hsf-1 have a causative role in the accumulation of pathogenic AR in vivo, we depleted Hsf-1 in AR-97Q mice by crossing them with heterozygous Hsf-1-knockout mice 33 . As Hsf-1-null AR-97Q (AR-97Q Tg/ À , Hsf-1 À / À ) mice were not obtained, presumably owing to their early death during embryonic development, we performed immunohistochemistry on various tissues from wild-type…”

“…The present study also demonstrated the neuroprotective effects of the exogenous HSF-1 in the CNS of SBMA model mice. By contrast, the depletion of Hsf-1 shortens the lifespan of a mouse model of HD, although the associated histopathological and biochemical alterations were not thoroughly examined 33 . Taken together, our findings indicate that the Hsf-1-Hsp70 pathway exerts neuroprotective effects via the suppression of pathogenic protein accumulation in the pathogenesis of polyglutamine-induced neurodegeneration.…”

“…AR-97Q mice were generated by using the pCAGGS vector and maintained as described previously 25,40 . The AR-97Q and heterozygous Hsf-1-knockout AR-97Q mice, as well as the heterozygous Hsf-1-knockout wild-type and wild-type mice used in the experiments described here, were derived by crossing heterozygous Hsf-1-knockout C57BL6 mice with AR-97Q mice 33 . All of the experiments were performed on male mice derived from the cross described above.…”

“…All of the experiments were performed on male mice derived from the cross described above. The mice were genotyped by PCR on tail DNA 25,33 .…”

Heat stress induces epithelial plasticity and cell migration independent of heat shock factor 1

“…Both increased levels of HSF1 expression and activation have been correlated with more aggressive forms of human cancer, and HSF1 has consequently been proposed as an attractive therapeutic target for cancer (Whitesell and Lindquist 2009;Santagata et al 2011;Dai et al 2012). Moreover, recent studies have revealed that HSF1 regulates transcriptional targets that extend well beyond the induction of classical HSP genes, these include IL-6, MDR-1, NFATc2 and CXCL8/IL-8, with gene expression microarray and ChIP analysis providing evidence for many more (Maity et al 2011;Singh et al 2008;Vilaboa et al 2000;Page et al 2006;Hayashida et al 2010;Trinklein et al 2004). Consistent with its broad transcriptional landscape, HSF1 is known to have a diverse range of physiological functions, including the modulation of cell migration, inflammatory and metabolic pathway regulation (Ianaro et al 2001;O'Callaghan-Sunol and Sherman 2006;Dai et al 2007;Xiao et al 1999).…”