The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly.
The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly.
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DOI：
10.7554/elife.05033
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发表时间：
2015-02-26
期刊：
影响因子：
7.7
通讯作者：
Walter P
中科院分区：
文献类型：
--
作者：
Sidrauski C;McGeachy AM;Ingolia NT;Walter P
之前，我们确定ISRIB是综合应激反应（ISR）的有效抑制剂，并表明ISRIB使细胞抵抗eIF2α磷酸化的影响，并增强啮齿动物的长期记忆。在这里，我们通过全基因组的体内核糖体分析表明，ISR激活后诱导了一个有限的mRNA子集的翻译。ISRIB基本上逆转了由eIF2α磷酸化引起的翻译效应，并且在未应激细胞中未诱导翻译或mRNA水平的重大变化。ISRIB可阻断eIF2α磷酸化诱导的应激颗粒（SG）的形成。令人惊讶的是，ISRIB添加到具有预先形成的SG的应激细胞中诱导其快速分解，将mRNA释放到活跃的翻译池中。mRNA翻译的恢复和SG动力学的调节可能是以eIF2α磷酸化、SG形成和认知丧失为特征的神经退行性疾病的有效治疗。DOI：http://dx.doi.org/10.7554/eLife.05033.001网站
Previously, we identified ISRIB as a potent inhibitor of the integrated stress response (ISR) and showed that ISRIB makes cells resistant to the effects of eIF2α phosphorylation and enhances long-term memory in rodents. Here, we show by genome-wide in vivo ribosome profiling that translation of a restricted subset of mRNAs is induced upon ISR activation. ISRIB substantially reversed the translational effects elicited by phosphorylation of eIF2α and induced no major changes in translation or mRNA levels in unstressed cells. eIF2α phosphorylation-induced stress granule (SG) formation was blocked by ISRIB. Strikingly, ISRIB addition to stressed cells with pre-formed SGs induced their rapid disassembly, liberating mRNAs into the actively translating pool. Restoration of mRNA translation and modulation of SG dynamics may be an effective treatment of neurodegenerative diseases characterized by eIF2α phosphorylation, SG formation, and cognitive loss. DOI: http://dx.doi.org/10.7554/eLife.05033.001