Mechanosensor-mediated Hsp70 phosphorylation orchestrates the landscape of the heat shock response

Cells must respond rapidly to heat stress by activating multiple signaling pathways that preserve proteostasis. In budding yeast, this includes induction of Hsf1 and Msn2/4-mediated transcription, cell integrity signaling, stress-triggered phase separation of proteins, and inhibition of translation. How these pathways are so rapidly activated and coordinated remains unclear. We show that the mechanosensor Mid2 senses heat-induced membrane stretch and leads to rapid phosphorylation of the cytosolic Hsp70 Ssa1 at a well-conserved threonine (T492). Phosphorylation of T492 leads to epichaperome rearrangement promoting fine-tuning of multiple cellular processes including translational pausing, HSF activity, MAPK signaling and stress granule resolution. Taken together, these results provide a comprehensive, unified theory of the global yeast heat shock response mediated by the Hsp70 chaperone code.