Transient intracellular acidification regulates the core transcriptional heat shock response
- University of Chicago, United States
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.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE143292 and GSE152916. Raw and processed flow cytometry data, raw qPCR and translation data to reproducedoi:10.5061/dryad.zgmsbcc6v.
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Transient intracellular acidification regulates the core transcriptional heat shock responseDryad Digital Repository, doi:10.5061/dryad.zgmsbcc6v.
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Transient intracellular acidification regulates the core transcriptional heat shock responseNCBI Gene Expression Omnibus, GSE143292.
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Transient intracellular acidification regulates the core transcriptional heat shock responseNCBI Gene Expression Omnibus, GSE152916.
Article and author information
Author details
Catherine G Triandafillou
David Allan Drummond
Funding
National Institutes of Health (GM126547)
- David Allan Drummond
National Institutes of Health (GM127406)
- David Allan Drummond
Army Research Office (W911NF-14-1-0411)
- David Allan Drummond
National Institutes of Health (GM109455)
- Aaron R Dinner
National Institutes of Health (T32EB009412)
- Christopher D Katanski
National Institutes of Health (T32GM007183)
- Catherine G Triandafillou
National Science Foundation (DGE-1144082)
- Catherine G Triandafillou
National Institutes of Health (GM136381)
- Aaron R Dinner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Triandafillou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Transient intracellular acidification regulates the core transcriptional heat shock response
eLife 9:e54880.
https://doi.org/10.7554/eLife.54880
Further reading
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In healthy cells, cyclin D1 is expressed during the G1 phase of the cell cycle, where it activates CDK4 and CDK6. Its dysregulation is a well-established oncogenic driver in numerous human cancers. The cancer-related function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G-Two and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unrecognized substrate of cyclin D1–CDK4/6 in tumor cells overexpressing cyclin D1 during G1 and subsequent phases. The phosphorylation of GTSE1 mediated by cyclin D1–CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 across all cell cycle phases. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1’s role in cell cycle control and oncogenesis beyond RB phosphorylation.
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