Chaperone regulation of the heat shock protein response.
The heat shock protein response appears to be triggered primarily by nonnative proteins accumulating in a stressed cell and results in increased expression of heat shock proteins (HSPs). Many heat shock proteins prevent protein aggregation and participate in refolding or elimination of misfolded proteins in their capacity as chaperones. Even though several mechanisms exist to regulate the abundance of cytosolic and nuclear chaperones, activation of heat shock transcription factor 1 (HSF1) is an essential aspect of the heat shock protein response. HSPs and co-chaperones that are assembled into multichaperone complexes regulate HSF1 activity at different levels. HSP90-containing multichaperone complexes appear to be the most relevant repressors of HSF1 activity. Because HSP90-containing multichaperone complexes interact not only specifically with client proteins including HSF1 but also generically with nonnative proteins, the concentration of nonnative proteins influences assembly on HSF1 of HSP90-containing complexes that repress activation, and may play a role in inactivation, of the transcription factor. Proteins that are unable to achieve stable tertiary structures and remain chaperone substrates are targeted for proteasomal degradation through polyubiquitination by co-chaperone CHIP. CHIP can activate HSF1 to regulate the protein quality control system that balances protection and degradation of chaperone substrates.
Voellmy
Richard
R
HSF Pharmaceuticals SA, Avenue des Cerisiers 39B, 1009 Pully, Switzerland. rvoellmy@hsfpharma.com
Boellmann
Frank
F
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response / Q000502:physiology*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D014157:Transcription Factors