Heat Shock Response Mechanisms in Cellular Stress

The heat shock response represents a conserved cellular programme activated by elevated temperatures and other proteotoxic stresses. Central to this programme is the induction of heat shock proteins (HSPs), molecular chaperones that maintain protein folding and prevent aggregation. Activation begins with the sensing of unfolded or newly synthesised proteins by a family of heat shock transcription factors, of which Heat Shock Factor 1 (HSF1) is the predominant regulator in mammalian cells. Under basal conditions, HSF1 is held in an inactive state through association with Hsp70 chaperones; upon stress, dissociation of this complex permits HSF1 trimerisation, nuclear translocation and binding to heat shock elements within target gene promoters. Subsequent transcriptional upregulation of HSPs restores proteostasis, and feedback mechanisms, including renewed Hsp70 binding and post-translational modifications of HSF1, attenuate the response once damage is mitigated. Beyond classical thermal stress, the heat shock response interfaces with chemical, metabolic and genotoxic stimuli, underscoring its relevance to ageing, neurodegeneration and cancer. Recent work has revealed additional layers of regulation, such as co-chaperone dynamics and non-heat shock transcriptional networks governed by HSF1, highlighting the global significance of this system and its potential for therapeutic intervention.

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Heat Shock Response Mechanisms in Cellular Stress publication trend

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Technical terms

Heat Shock Response (HSR): A conserved cellular programme that senses proteotoxic stress and induces heat shock proteins to restore protein homeostasis.

Heat Shock Factor 1 (HSF1): The principal transcription factor that orchestrates the expression of heat shock proteins under stress conditions.

Heat Shock Proteins (HSPs): A family of stress-induced molecular chaperones that assist protein folding, prevent aggregation and aid in the recovery of damaged proteins.

Molecular Chaperone: A protein that facilitates the proper folding or refolding of client proteins and prevents misfolding and aggregation.

Proteotoxic Stress: Cellular stress resulting from the accumulation of misfolded, aggregated or damaged proteins.

Sis1: A co-chaperone of Hsp70 that contributes to the regulation and signal integration of the heat shock response.

References

1. Targeting HSF1 for cancer treatment: mechanisms and inhibitor development. Theranostics (2023).
2. Targeting the heat shock response induced by modulated electro-hyperthermia (mEHT) in cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer (2024).
3. Transcriptional regulation of Sis1 promotes fitness but not feedback in the heat shock response. eLife (2023).
4. HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential Treatment for Refractory Ovarian Cancer and Other Malignancies. Journal of Medicinal Chemistry (2023).
5. Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation. eLife (2016).
6. Hsf1 and Hsp70 constitute a two-component feedback loop that regulates the yeast heat shock response. eLife (2018).