The inactive HSF1 was reported to constitutively shuttle between the nucleus and the cytoplasm in mammalian cells (Vujanac M et al. 2005). There is no consensus on whether inactive HSF1 monomers localize in the nucleus or in the cytosol (Sarge KD et al. 1993; Zuo J et al. 1995; Mercier PA et al. 1999; Vujanac M et al. 2005). This event shows stress-induced activation of HSF1 in the nucleus.
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).