HSF1 phase transition mediates stress adaptation and cell fate decisions

Under proteotoxic stress, some cells survive whereas others die. Mechanisms governing this heterogeneity in cell fate are unknown. We report that condensation and phase transition of heat-shock factor 1 (HSF1), a transcriptional regulator of chaperones(1,2), is integral to cell fate decisions underlying survival or death. During stress, HSF1 drives chaperone expression but also accumulates separately in nuclear stress bodies (foci)(3–6). Foci formation has been regarded as a marker of cells actively upregulating chaperones(3,6–10). Using multiplexed tissue imaging, we observed HSF1 foci in human tumors. Paradoxically, their presence inversely correlated with chaperone expression. By live-cell microscopy and single-cell analysis, we found that foci dissolution rather than formation promoted HSF1 activity and cell survival. During prolonged stress, the biophysical properties of HSF1 foci changed; small, fluid condensates enlarged into indissoluble gel-like arrangements with immobilized HSF1. Chaperone gene induction was reduced in such cells, which were prone to apoptosis. Quantitative analysis suggests that survival under stress results from competition between concurrent yet opposing mechanisms. Foci may serve as sensors that tune cytoprotective responses, balancing rapid transient responses and irreversible outcomes.