Novo Nordisk Foundation Center for Biosustainability, Department of Chemical and Biological Engineering, Chalmers University of Technology, Göteborg, Sweden; State Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong, China.
FEMS Yeast Res. 2014 May;14(3):481-94. doi: 10.1111/1567-1364.12125. Epub 2013 Dec 12.
In yeast Saccharomyces cerevisiae, accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and activates the unfolded protein response (UPR), which is mediated by Hac1p. The heat shock response (HSR) mediated by Hsf1p, mainly regulates cytosolic processes and protects the cell from stresses. Here, we find that a constitutive activation of the HSR could increase ER stress resistance in both wild-type and UPR-deficient cells. Activation of HSR decreased UPR activation in the WT (as shown by the decreased HAC1 mRNA splicing). We analyzed the genome-wide transcriptional response in order to propose regulatory mechanisms that govern the interplay between UPR and HSR and followed up for the hypotheses by experiments in vivo and in vitro. Interestingly, we found that the regulation of ER stress response via HSR is (1) only partially dependent on over-expression of Kar2p (ER resident chaperone induced by ER stress); (2) does not involve the increase in protein turnover via the proteasome activity; (3) is related to the oxidative stress response. From the transcription data, we also propose that HSR enhances ER stress resistance mainly through facilitation of protein folding and secretion. We also find that HSR coordinates multiple stress-response pathways, including the repression of the overall transcription and translation.
在酵母酿酒酵母中，内质网（ER）中错误折叠蛋白的积累会导致 ER 应激，并激活未折叠蛋白反应（UPR），该反应由 Hac1p 介导。由 Hsf1p 介导的热休克反应（HSR）主要调节细胞溶质过程，并保护细胞免受应激。在这里，我们发现 HSR 的组成性激活可以提高野生型和 UPR 缺陷细胞的 ER 应激抗性。HSR 的激活降低了 WT 中的 UPR 激活（如 HAC1 mRNA 剪接减少所示）。我们分析了全基因组转录反应，以提出调节 UPR 和 HSR 相互作用的调控机制，并通过体内和体外实验对假设进行了验证。有趣的是，我们发现通过 HSR 对 ER 应激反应的调节（1）仅部分依赖于 ER 驻留伴侣蛋白 Kar2p（由 ER 应激诱导的内质网伴侣）的过表达；（2）不涉及通过蛋白酶体活性增加蛋白质周转率；（3）与氧化应激反应有关。从转录数据中，我们还提出 HSR 主要通过促进蛋白质折叠和分泌来增强 ER 应激抗性。我们还发现 HSR 协调多个应激反应途径，包括总体转录和翻译的抑制。
