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Cells maintain homeostasis via dynamic regulation of stress response pathways. Stress pathways transiently induce response regulons via negative feedback loops, but the extent to which individual genes provide feedback has not been comprehensively measured for any pathway. Here, we disrupted the induction of each gene in the Saccharomyces cerevisiae heat shock response (HSR) and quantified cell growth and HSR dynamics following heat shock. The screen revealed a core feedback loop governing the expression of the chaperone Hsp70 reinforced by an auxiliary feedback loop controlling Hsp70 subcellular localization. Mathematical modeling and live imaging demonstrated that multiple HSR targets converge to promote Hsp70 nuclear localization via its release from cytosolic condensates. Following ethanol stress, a distinct set of factors similarly converged on Hsp70, suggesting that nonredundant subsets of the HSR regulon confer feedback under different conditions. Flexible spatiotemporal feedback loops may broadly organize stress response regulons and expand their adaptive capacity.
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This content will become publicly available on December 2, 2025
Preserve or destroy: Orphan protein proteostasis and the heat shock response
Most eukaryotic genes encode polypeptides that are either obligate members of hetero-stoichiometric complexes or clients of organelle-targeting pathways. Proteins in these classes can be released from the ribosome as “orphans”—newly synthesized proteins not associated with their stoichiometric binding partner(s) and/or not targeted to their destination organelle. Here we integrate recent findings suggesting that although cells selectively degrade orphan proteins under homeostatic conditions, they can preserve them in chaperone-regulated biomolecular condensates during stress. These orphan protein condensates activate the heat shock response (HSR) and represent subcellular sites where the chaperones induced by the HSR execute their functions. Reversible condensation of orphan proteins may broadly safeguard labile precursors during stress.
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- Award ID(s):
- 2121044
- PAR ID:
- 10591564
- Publisher / Repository:
- PubMedCentral
- Date Published:
- Journal Name:
- Journal of Cell Biology
- Volume:
- 223
- Issue:
- 12
- ISSN:
- 0021-9525
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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