Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, United States.
Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, United States.
Elife. 2023 May 9;12:e79444. doi: 10.7554/eLife.79444.
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.
热休克反应（HSR）控制分子伴侣的表达以维持蛋白质的内稳态。此前，我们提出了 HSR 的反馈回路模型，其中热变性蛋白隔离伴侣 HSP70 以激活 HSR，随后 HSP70 的诱导失活 HSR（Krakowiak 等人，2018；Zheng 等人，2016）。然而，最近的工作表明，新合成的蛋白质（NSPs）-而不是未折叠的成熟蛋白质-和 Hsp70 共伴侣 Sis1 参与了 HSR 的调节，但它们对 HSR 动力学的贡献尚未确定。在这里，我们生成了一个新的数学模型，该模型将 NSPs 和 Sis1 纳入 HSR 激活机制，并进行遗传去耦和脉冲标记实验，以证明 Sis1 的诱导对于 HSR 的失活是可有可无的。Sis1 由 Hsf1 转录调控，而不是对 HSR 提供负反馈，它通过协调应激颗粒和碳代谢来促进适应性。这些结果支持了一个总体模型，即 NSPs 通过隔离 Sis1 和 Hsp70 来信号转导 HSR，而 HSP70 的诱导-而不是 Sis1-则减弱了反应。
