Transient intracellular acidification regulates the core transcriptional heat shock response.

Catherine G Triandafillou,D Allan Drummond,Aaron R Dinner,Christopher D Katanski

doi:10.7554/elife.54880

Abstract

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.

Highlights

To survive and thrive, organisms must rapidly respond when their environments turn harsh.Cells across the tree of life possess the capacity to adaptively respond to primordial stresses—heat, starvation, hypoxia, exposure to noxious compounds—in a conserved program involving the production of so-called heat shock proteins, many of which act as molecular chaperones (Lindquist, 1986)
We find that acidification universally promotes the heat shock response, and that when canonical triggers for the response—the newly synthesized polypeptides—are suppressed, acidification is required for cells to respond to heat shock
What is the physiological significance of the broadly conserved, transient intracellular acidification triggered by stress in eukaryotes? By decoupling changes in intracellular pH from heat shock in budding yeast, we have discovered that the canonical transcriptional stress response mediated by heat shock factor 1 (Hsf1) depends on cellular acidification

Summary

Introduction

Cells across the tree of life possess the capacity to adaptively respond to primordial stresses—heat, starvation, hypoxia, exposure to noxious compounds—in a conserved program involving the production of so-called heat shock proteins, many of which act as molecular chaperones (Lindquist, 1986). Transcription of heat shock proteins surges at the onset of stress, reaching as much as a thousand fold during thermal stress, with more modest induction accompanying nutrient withdrawal and diverse other stresses (Lindquist, 1986; Zid and O’Shea, 2014; Morano et al, 2012; Gidalevitz et al, 2011). In turn, assist with protein folding, as well as preventing and dispersing stress-induced molecular aggregates (Vabulas et al, 2010; Richter et al, 2010; Cherkasov et al, 2013; Walters et al., 2015; Kroschwald et al, 2015)

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