The integrated stress response

In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis. The core event in this pathway is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2¿) by one of four members of the eIF2¿ kinase family, which leads to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, that together promote cellular recovery. The gene expression program activated by the ISR optimizes the cellular response to stress and is dependent on the cellular context, as well as on the nature and intensity of the stress stimuli. Although the ISR is primarily a pro-survival, homeostatic program, exposure to severe stress can drive signaling toward cell death. Here, we review current understanding of the ISR signaling and how it regulates cell fate under diverse types of stress.This work was funded in part by the Health Research Board (Grant Number HRA/2009/59; HRA‐POR‐2014‐643), Belgian Science Policy Office Interuniversity Attraction Poles program (IAP 7/32), and Breast Cancer Campaign grant (2010NovPR13) to A.S. A Science Foundation Ireland (SFI) grant cofunded under the European Regional Development Fund under Grant Number 13/RC/2073. I.K. was funded by an Irish Research Council Scholarship (GOIPG/2014/508) and by the Thomas Crawford Hayes Fund. K.M. is funded by an Irish Research Council Fellowship (GOIPD/2014/53).peer-reviewed2017-03-1