In the absence of stress HSF1 is predominantly monomeric and is thought to be repressed in its inactive monomeric state by the following mechanisms:
- interaction with chaperone proteins such as HSP90 (Zou J et al.1998; Guo Y et al. 2001)
- intramolecular coiled-coil interactions between a hydrophobic leucine zipper domain in the carboxyl-terminus of the protein and three amino-terminal leucine zippers, which are required for homotrimerization and transcriptional activation (Rabindran SK et al. 1993; Zuo J et al. 1995)
- post-translation modifications that include protein acetylation, sumoylation and phosphorylation may also contribute to HSF1 repression (Knauf U et al. 1996; Hietakangas V et al. 2003; Batista-Nascimento L et al. 2011)
The accumulation of misfolded proteins upon proteotoxic stresses leads to the release of HSF1 from the HSP90-containing multichaperone complex and results in HSF1 self-association to form homotrimers (Baler R et al. 1993). There is also evidence showing that HDAC6 senses the accumulation of misfolded, ubiquitinated protein aggregates in cells and induces dissociation of a repressive HDAC6:HSF1:HSP90 complex and subsequent HSF1 activation (Boyault C et al. 2007).