Proteins comprise well-ordered structural domains and intrinsically disordered regions that explore broad conformational ensembles, a pervasive feature of the human proteome that underlies key aspects of cellular physiology. In the crowded intracellular environment, stress can shift protein conformational equilibria toward aggregation-prone states, exposing hydrophobic regions that can drive aberrant protein-protein interactions, promoting aggregation. To maintain proteome integrity, cells depend on an integrated protein‑quality‑control network in which molecular chaperones, their co‑factors and dedicated degradation systems act in concert. Within this network, small heat shock proteins serve as an ATP-independent first line of defense that stabilizes non-native proteins and limits irreversible aggregation. Recent work shows that small heat shock proteins can also safeguard the liquid‑like dynamics of biomolecular condensates formed by liquid-liquid phase separation. These membraneless compartments organize cellular biochemistry but are susceptible to stress- and disease-induced arrest or aggregation. Rather than undergoing phase separation autonomously, small heat shock proteins can be recruited into pre-existing condensates such as stress granules, nuclear speckles, p62 bodies, and condensates formed by disease-associated proteins, where they help preserve condensate fluidity. Together, these findings position small heat shock proteins as modulators of condensate dynamics that link protein quality control to mesoscale cellular organization, with important implications for cell biology, aging, and human disease.
Crotti et al. (Fri,) studied this question.