Molecular Chaperone Functions of Heat Shock Proteins

Heat shock proteins (HSPs) form a versatile family of molecular chaperones that safeguard cellular proteins from misfolding and aggregation. Central to proteostasis, they assist nascent polypeptides in folding to their native states, refold stress-denatured proteins and target irreversibly damaged species for degradation. HSPs range from the ATP-independent small heat shock proteins (sHsps), which sequester unfolded proteins in reversible oligomeric assemblies, to ATP-dependent families such as Hsp70 and Hsp90, which employ regulated binding–release cycles. By forming dynamic networks with cochaperones and the proteasome or autophagy machinery, HSPs maintain protein quality control under basal conditions and in response to stress. Beyond their classical intracellular roles, HSPs can localise to distinct compartments—including mitochondria, endoplasmic reticulum and extracellular space—where they perform specialised chaperone functions. Dysregulation of HSP activity underlies a range of human diseases, from neurodegeneration to cancer, making HSP modulation an attractive therapeutic strategy. Recent advances have illuminated both the structural basis of HSP–substrate recognition and the non–cell-autonomous modes of action that extend their protective influence across tissues.

Research from Nature Portfolio

Recent studies have revealed an unexpected role for small heat shock proteins within the mitochondrial intermembrane space. Under normal conditions, cytosolic sHsps translocate into this compartment where they recognise and bind misfolded proteins, preventing aggregation that would otherwise impair mitochondrial respiration and organelle integrity. Loss of these sHsps in the intermembrane space leads to mitochondrial swelling and reduced energy production, highlighting a compartment-specific chaperone system essential for cellular homeostasis. In parallel, foundational work has demonstrated that distinct sHsp paralogues coaggregate with misfolding substrates in a near-native state, forming storage complexes that are later disassembled by ATP-dependent chaperones. This two-tiered mechanism—initial sequestration by sHsps followed by refolding via Hsp70–Hsp100 systems—illustrates how cells balance immediate protection against aggregation with efficient substrate recovery after stress.

Molecular Chaperone Functions of Heat Shock Proteins publication trend

The graph below shows the total number of articles in molecular chaperone functions of heat shock proteins across all publications each year (not limited to Nature Index journals).

Technical terms

Molecular chaperone: A protein that assists other proteins to fold, refold or be degraded without being part of the final structure.

Proteostasis: The cellular network of processes that maintain protein synthesis, folding, trafficking and clearance in balanced states.

Oligomerisation: The assembly of protein subunits into multi-unit complexes, often regulating chaperone activity.

Chaperone-assisted selective autophagy (CASA): A selective degradation pathway in which chaperones target damaged or misfolded proteins for lysosomal removal.

Mitochondrial intermembrane space: The compartment between the inner and outer mitochondrial membranes where specific chaperones maintain local proteostasis.

References

1. Human Small Heat Shock Protein B8 Inhibits Protein Aggregation without Affecting the Native Folding Process. Journal of the American Chemical Society (2023).
2. Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space. Nature Cell Biology (2023).
3. Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding. Nature Communications (2016).
4. Reactive astrocytes secrete the chaperone HSPB1 to mediate neuroprotection. Science Advances (2024).
5. HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies. Autophagy (2023).