Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL, USA.
Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, USA.
J Cell Biol. 2024 Dec 2;223(12). doi: 10.1083/jcb.202401082. Epub 2024 Sep 20.
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.
细胞通过动态调节应激反应途径来维持内稳态。应激途径通过负反馈回路短暂诱导反应调控因子，但对于任何途径，单个基因提供反馈的程度尚未得到全面测量。在这里，我们破坏了酿酒酵母热休克反应（HSR）中每个基因的诱导，并在热休克后量化了细胞生长和 HSR 动力学。该筛选揭示了一个核心反馈回路，该回路控制着伴侣蛋白 Hsp70 的表达，该回路由控制 Hsp70 亚细胞定位的辅助反馈回路增强。数学建模和活细胞成像表明，多个 HSR 靶标通过从细胞质凝聚物中释放来协同促进 Hsp70 的核定位。在乙醇应激后，一组不同的因子也同样集中在 Hsp70 上，这表明 HSR 调控因子的非冗余子集在不同条件下赋予反馈。灵活的时空反馈回路可能广泛组织应激反应调控因子并扩大它们的适应能力。
