Management of the endoplasmic reticulum stress by activation of the heat shock response in yeast
Management of the endoplasmic reticulum stress by activation of the heat shock response in yeast
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DOI：
10.1111/1567-1364.12125
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发表时间：
2014-05-01
影响因子：
3.2
通讯作者：
Petranovic, Dina
中科院分区：
文献类型：
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作者：
Hou, Jin;Tang, Hongting;Petranovic, Dina
在酿酒酵母中，内质网（ER）中错误折叠蛋白的积累引起ER应激并激活未折叠蛋白反应（UPR），这是由Hac 1 p介导的。热休克反应（Heat shock response，HSR）是由Hsf 1 p介导的，主要调节细胞内的各种过程，保护细胞免受应激。在这里，我们发现，组成性激活的HSR可以增加ER应激抗性在野生型和UPR缺陷细胞。HSR的激活降低了WT中的UPR激活（如减少的HAC 1 mRNA剪接所示）。我们分析了全基因组的转录反应，以提出管理UPR和HSR之间的相互作用的调控机制，并通过体内和体外实验跟踪假设。有趣的是，我们发现通过HSR调节ER应激反应是（1）仅部分依赖于Kar 2 p（ER应激诱导的ER驻留伴侣）的过表达;（2）不涉及通过蛋白酶体活性增加蛋白质周转;（3）与氧化应激反应有关。从转录数据，我们还建议，HSR增强内质网应激抗性主要是通过促进蛋白质的折叠和分泌。我们还发现，HSR协调多种应激反应途径，包括抑制整体转录和翻译。
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.