Transient intracellular acidification regulates the core transcriptional heat shock response

Heat shock induces a conserved transcriptional program regulated by heat
shock factor 1 (Hsf1) in eukaryotic cells. Activation of this heat-shock
response is triggered by heat-induced misfolding of newly synthesized
polypeptides, and so has been thought to depend on ongoing protein
synthesis. Here, using the budding yeast Saccharomyces
cerevisiae, we report the discovery that Hsf1 can be robustly
activated when protein synthesis is inhibited, so long as cells undergo
cytosolic acidification. Heat shock has long been known to cause transient
intracellular acidification which, for reasons which have remained
unclear, is associated with increased stress resistance in eukaryotes. We
demonstrate that acidification is required for heat shock response
induction in translationally inhibited cells, and specifically affects
Hsf1 activation. Physiological heat-triggered acidification also increases
population fitness and promotes cell cycle reentry following heat shock.
Our results uncover a previously unknown adaptive dimension of the
well-studied eukaryotic heat shock response.