Dissociation of cytosolic HSF1:HSP90:HDAC6:PTGES3 upon sensing protein aggregates

Stable Identifier
Reaction [transition]
Homo sapiens
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Proteotoxic stress results in an accumulation of misfolded proteins which tend to form insoluble protein aggregates. Histone deacetylase 6 (HDAC6) binds to ubiquitinated protein aggregates to regulate their degradation (Boyault C et al. 2006). HDAC6 was also found to interact with HSP90 and to regulate HSP90 chaperone complex activity via deacetylation of HSP90 (Kovacs JJ et al. 2005; Boyault C et al. 2007). Binding of HDAC6 to polyubiquitinted proteins triggers the dissociation of the HDAC6:HSP90:HSF1 complex resulting in the activation of HSF1 (Boyault C et al. 2007).

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)
Literature References
PubMed ID Title Journal Year
17785525 HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates

Garrido, C, Gilquin, B, Zhang, Y, Khochbin, S, Vourc'h, C, Matthias, P, Yao, TP, Fritah, S, Kwon, SH, Caron, C, Boyault, C

Genes Dev. 2007
Catalyst Activity

misfolded protein binding activity of HSF1:HSP90:HDAC6:VCP:PTGES3 [cytosol]

Orthologous Events
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