Heterotrimerization of Heat-Shock Factors 1 and 2 Provides a Transcriptional Switch in Response to Distinct Stimuli

Abstract

Organisms respond to circumstances threatening the cellular protein homeostasis by activation of heat-shock transcription factors (HSFs), which play important roles in stress resistance, development, and longevity. Of the four HSFs in vertebrates (HSF1-4), HSF1 is activated by stress, whereas HSF2 lacks intrinsic stress responsiveness. The mechanism by which HSF2 is recruited to stress-inducible promoters and how HSF2 is activated is not known. However, changes in the HSF2 expression occur, coinciding with the functions of HSF2 in development. Here, we demonstrate that HSF1 and HSF2 form heterotrimers when bound to satellite III DNA in nuclear stress bodies, subnuclear structures in which HSF1 induces transcription. By depleting HSF2, we show that HSF1-HSF2 heterotrimerization is a mechanism regulating transcription. Upon stress, HSF2 DNA binding is HSF1 dependent. Intriguingly, when the elevated expression of HSF2 during development is mimicked, HSF2 binds to DNA and becomes transcriptionally competent. HSF2 activation leads to activation of also HSF1, revealing a functional interdependency that is mediated through the conserved trimerization domains of these factors. We propose that heterotrimerization of HSF1 and HSF2 integrates transcriptional activation in response to distinct stress and developmental stimuli.

Regulation of transcription of hypoxia-inducible factor-1α (HIF-1α) by heat shock factors HSF2 and HSF4

“…Figures 1 and 3)-suggesting that HSF4 actions on HIF-1a expression are more complex than simple transcriptional repression. Individual HSFs are known to function in concert with, or in opposition to, other members of the HSF family (Mathew et al, 2001;Pirkkala et al, 2001;Chi and Karliner, 2004;Xing et al, 2005;Loison et al, 2006;Akerfelt et al, 2007;Ostling et al, 2007;Sandqvist et al, 2009;Yamamoto et al, 2009), and we hypothesized that HSF4 may participate with another HSF family member in the regulation of HIF-1a transcription. To investigate this possibility, we tested the effects of downregulation of two other HSF proteins known to be produced in human cells (that is, HSF1 and HSF2) (Fujimoto and Nakai, 2010).…”

Genomic Heat Shock Element Sequences Drive Cooperative Human Heat Shock Factor 1 DNA Binding and Selectivity

“…It is important to note that the correlation between in vitro and in vivo binding is not perfect, particularly for HSEs found in the promoters of genes such as DARS and HSPA1A. This observation suggests that another layer of complexity exists in HSF1 binding in vivo, which could be attributed to the previously reported heteromultimerization of HSF1 with HSF2, chromatin environments, post-translational modifications, and other factors (18,(32)(33)(34). However, our results suggest that when HSF1 is presented with a given array of accessible HSEs, it will prefer cooperatively oriented HSEs.…”

Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability

“…It was found that inactivation of HSF1 does not alter proteasome expression (Taylor et al, 2005) and our data are in accordance with this report as we show that Hsf1 À/À iMEFs exhibit a slight but not significant decrease in proteasome subunit expression. However, this slight decrease could be explained by the interdependence between HSF2 and HSF1 (Loison et al, 2006;Sandqvist et al, 2009). Thus, one could hypothesize that the lack of HSF1 would affect HSF2 binding and consequently reduce HSF2 activity.…”

“…Nevertheless, to add to the complexity of this proteotoxic response, our group showed that an HSF1/HSF2 heterocomplex was present on the promoter of the chaperone gene clusterin, following proteasome inhibition (Loison et al, 2006). The existence of the HSF1/ HSF2 heterotrimer was recently confirmed (Sandqvist et al, 2009) and it was shown that HSF2 can act as a modulator of HSF1 activity in response to proteotoxic insults (Ostling et al, 2007). Hence, the respective roles of HSF1 and HSF2 remain unclear when cells are exposed to proteasome inhibitors.…”