Delayed Ras/PKA signaling augments the unfolded protein response.
Delayed Ras/PKA signaling augments the unfolded protein response.
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延迟的 Ras/PKA 信号传导增强了未折叠的蛋白质反应。
DOI：
10.1073/pnas.1409588111
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发表时间：
2014
影响因子：
11.1
通讯作者：
El-Samad,Hana
中科院分区：
文献类型：
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作者：
Pincus,David;Aranda-Díaz,Andrés;Zuleta,IgnacioA;Walter,Peter;El-Samad,Hana
在环境、发育或遗传压力期间，细胞的折叠能力可能会变得不堪重负，错误折叠的蛋白质可能会在所有细胞隔间积累。真核生物进化出未折叠蛋白反应(UPR)，以对抗内质网(ER)中的蛋白毒性应激。尽管UPR对于恢复内质网中蛋白质折叠的动态平衡至关重要，但很明显，对内质网应激的反应并不局限于UPR。在这里，我们使用工程正交UPR诱导，深层mRNA测序，和动态流式细胞术来全面剖析细胞对内质网应激的反应。我们发现，发芽酵母通过延迟的RAS/PKA信号来增强UPR。这第二波转录动力学是独立于UPR的，对于内质网应激的存在是必要的，部分原因是一般蛋白质合成减少。这种RAS/PKA介导的效应在功能上模仿了其他机制，如由PKR样ERK(PERK)和调节的肌醇要求酶1(IRE1)依赖的mRNA衰退(RIDD)进行翻译控制，这些机制减少了后生动物细胞对ER应激反应进入内质网的蛋白质负荷。
During environmental, developmental, or genetic stress, the cell’s folding capacity can become overwhelmed, and misfolded proteins can accumulate in all cell compartments. Eukaryotes evolved the unfolded protein response (UPR) to counteract proteotoxic stress in the endoplasmic reticulum (ER). Although the UPR is vital to restoring homeostasis to protein folding in the ER, it has become evident that the response to ER stress is not limited to the UPR. Here, we used engineered orthogonal UPR induction, deep mRNA sequencing, and dynamic flow cytometry to dissect the cell’s response to ER stress comprehensively. We show that budding yeast augments the UPR with time-delayed Ras/PKA signaling. This second wave of transcriptional dynamics is independent of the UPR and is necessary for fitness in the presence of ER stress, partially due to a reduction in general protein synthesis. This Ras/PKA-mediated effect functionally mimics other mechanisms, such as translational control by PKR-like ER kinase (PERK) and regulated inositol-requiring enzyme 1 (IRE1)-dependent mRNA decay (RIDD), which reduce the load of proteins entering the ER in response to ER stress in metazoan cells.