Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
BMB Rep. 2017 Nov;50(11):539-545. doi: 10.5483/bmbrep.2017.50.11.157.
The Integrated Stress Response (ISR) refers to a signaling pathway initiated by stress-activated eIF2α kinases. Once activated, the pathway causes attenuation of global mRNA translation while also paradoxically inducing stress response gene expression. A detailed analysis of this pathway has helped us better understand how stressed cells coordinate gene expression at translational and transcriptional levels. The translational attenuation associated with this pathway has been largely attributed to the phosphorylation of the translational initiation factor eIF2α. However, independent studies are now pointing to a second translational regulation step involving a downstream ISR target, 4E-BP, in the inhibition of eIF4E and specifically cap-dependent translation. The activation of 4E-BP is consistent with previous reports implicating the roles of 4E-BP resistant, Internal Ribosome Entry Site (IRES) dependent translation in ISR active cells. In this review, we provide an overview of the translation inhibition mechanisms engaged by the ISR and how they impact the translation of stress response genes. [BMB Reports 2017; 50(11): 539-545].
整合应激反应(ISR)是指由应激激活的 eIF2α 激酶引发的信号通路。一旦被激活,该通路会导致全局 mRNA 翻译衰减,同时又反常地诱导应激反应基因表达。对该通路的详细分析帮助我们更好地理解了应激细胞如何在翻译和转录水平上协调基因表达。与该通路相关的翻译衰减在很大程度上归因于翻译起始因子 eIF2α 的磷酸化。然而,独立的研究现在指出,涉及下游 ISR 靶标 4E-BP 的第二个翻译调控步骤,在抑制 eIF4E 并特异性地抑制帽依赖性翻译中发挥作用。4E-BP 的激活与先前的报告一致,表明在 ISR 活跃的细胞中,4E-BP 抗性、内部核糖体进入位点(IRES)依赖的翻译发挥作用。在这篇综述中,我们概述了 ISR 参与的翻译抑制机制,以及它们如何影响应激反应基因的翻译。[BMB 报告 2017;50(11):539-545]。