Cellular response to heat stress

At the same time, heat shock-induced phosphorylation of translation initiation factor eIF2alpha leads to the shutdown of the nascent polypeptide synthesis reducing the burden on the chaperone system that has to deal with the increased amount of misfolded and thermally denatured proteins (Duncan RF & Hershey JWB 1989; Sarkar A et al. 2002; Spriggs KA et al. 2010).

The induction of HS gene expression primarily occurs at the level of transcription and is mediated by heat shock transcription factor HSF1(Sarge KD et al. 1993; Baler R et al. 1993). Human cells express five members of HSF protein family: HSF1, HSF2, HSF4, HSFX and HSFY. HSF1 is the master regulator of the heat inducible gene expression (Zuo J et al. 1995; Akerfelt M et al. 2010). HSF2 is activated in response to certain developmental stimuli in addition to being co-activated with HSF1 to provide promoter-specific fine-tuning of the HS response by forming heterotrimers with HSF1 (Ostling P et al. 2007; Sandqvist A et al. 2009). HSF4 lacks the transcription activation domain and acts as a repressor of certain genes during HS (Nakai A et al. 1997; Tanabe M et al. 1999; Kim SA et al. 2012). Two additional family members HSFX and HSFY, which are located on the X and Y chromosomes respectively, remain to be characterized (Bhowmick BK et al. 2006; Shinka T et al. 2004; Kichine E et al. 2012).

Under normal conditions HSF1 is present in both cytoplasm and nucleus in the form of an inactive monomer. The monomeric state of HSF1 is maintained by an intricate network of protein-protein interactions that include the association with HSP90 multichaperone complex, HSP70/HSP40 chaperone machinery, as well as intramolecular interaction of two conserved hydrophobic repeat regions. Monomeric HSF1 is constitutively phosphorylated on Ser303 and Ser 307 by (Zou J et al. 1998; Knauf U et al. 1996; Kline MP & Moromoto RI 1997; Guettouche T et al. 2005). This phosphorylation plays an essential role in ensuring cytoplasmic localization of at least a subpopulation of HSF1 molecules under normal conditions (Wang X et al. 2004).

Exposure to heat and other proteotoxic stimuli results in the release of HSF1 from the inhibitory complex with chaperones and its subsequent trimerization, which is promoted by its interaction with translation elongation factor eEF1A1 (Baler R et al. 1993; Shamovsky I et al. 2006; Herbomel G et al 2013). The trimerization is believed to involve intermolecular interaction between hydrophobic repeats 1-3 leading to the formation of a triple coil structure. Additional stabilization of the HSF1 trimer is provided by the formation of intermolecular S-S bonds between Cys residues in the DNA binding domain (Lu M et al.2008). Trimeric HSF1 is predominantly localized in the nucleus where it binds the specific sequence in the promoter of hsp genes (Sarge KD et al. 1993; Wang Y and Morgan WD 1994). The binding sequence for HSF1 (HSE, heat shock element) contains series of inverted repeats nGAAn in head-to-tail orientation, with at least three elements being required for the high affinity binding. Binding of the HSF1 trimer to the promoter is not sufficient to induce transcription of the gene (Cotto J et al. 1996). In order to do so, HSF1 needs to undergo inducible phosphorylation on specific Ser residues such as Ser230, Ser326. This phosphorylated form of HSF1 trimer is capable of increasing the promoter initiation rate. HSF1 bound to DNA promotes recruiting components of the transcription mediator complex and relieving promoter-proximal pause of RNA polymerase II through its interaction with TFIIH transcription factor (Yuan CX & Gurley WB 2000).

HSF1 activation is regulated in a precise and tight manner at multiple levels (Zuo J et al. 1995; Cotto J et al. 1996). This allows fast and robust activation of HS response to minimize proteotoxic effects of the stress. The exact set of HSF1 inducible genes is probably cell type specific. Moreover, cells in different pathophysiological states will display different but overlapping profile of HS inducible genes.