Transcriptional regulation of Sis1 promotes fitness but not feedback in the heat shock response
- University of Chicago, United States
- University of Delaware, United States
Abstract
The heat shock response (HSR) controls expression of molecular chaperones to maintain protein homeostasis. Previously, we proposed a feedback loop model of the HSR in which heat-denatured proteins sequester the chaperone Hsp70 to activate the HSR, and subsequent induction of Hsp70 deactivates the HSR (Krakowiak et al., 2018; Zheng et al., 2016). However, recent work has implicated newly synthesized proteins (NSPs) - rather than unfolded mature proteins - and the Hsp70 co-chaperone Sis1 in HSR regulation, yet their contributions to HSR dynamics have not been determined. Here we generate a new mathematical model that incorporates NSPs and Sis1 into the HSR activation mechanism, and we perform genetic decoupling and pulse-labeling experiments to demonstrate that Sis1 induction is dispensable for HSR deactivation. Rather than providing negative feedback to the HSR, transcriptional regulation of Sis1 by Hsf1 promotes fitness by coordinating stress granules and carbon metabolism. These results support an overall model in which NSPs signal the HSR by sequestering Sis1 and Hsp70, while induction of Hsp70 - but not Sis1 - attenuates the response.
Data availability
All data presented in the paper and custom analysis software are deposited in Dryad and Zenodo, respectively, with the following accessions: https://doi.org/doi:10.5061/dryad.b2rbnzsm6https://doi.org/10.5281/zenodo.7860686
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Induction of Sis1 promotes fitness but not feedback in the heat shock responseDryad Digital Repository, doi:10.5061/dryad.b2rbnzsm6.
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Induction of Sis1 promotes fitness but not feedback in the heat shock responsehttps://doi.org/10.5281/zenodo.7860686.
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Measuring the dependence of the yeast heat shock response on intracellular pH and translation during stressNCBI Gene Expression Omnibus, GSE19373GEO GSE152916.
Article and author information
Author details
Funding
National Institutes of Health (GM124446)
- Abhyudai Singh
National Science Foundation (OMA-2121044)
- David Pincus
National Institutes of Health (GM138689)
- David Pincus
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Garde 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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Transcriptional regulation of Sis1 promotes fitness but not feedback in the heat shock response
eLife 12:e79444.
https://doi.org/10.7554/eLife.79444
Further reading
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- Cell Biology
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Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. Here we show that in budding yeast, Hsf1 basally associates with the chaperone Hsp70 and this association is transiently disrupted by heat shock, providing the first evidence that a chaperone repressor directly regulates Hsf1 activity. We develop and experimentally validate a mathematical model of Hsf1 activation by heat shock in which unfolded proteins compete with Hsf1 for binding to Hsp70. Surprisingly, we find that Hsf1 phosphorylation, previously thought to be required for activation, in fact only positively tunes Hsf1 and does so without affecting Hsp70 binding. Our work reveals two uncoupled forms of regulation - an ON/OFF chaperone switch and a tunable phosphorylation gain - that allow Hsf1 to flexibly integrate signals from the proteostasis network and cell signaling pathways.
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