title: The integrated stress response.
abstract: 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 (eIF2α) by one of four members of the eIF2α 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.
authors.affiliation: Apoptosis Research Centre, National University of Ireland Galway, Galway, Ireland School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Pakos-Zebrucka
authors.affiliation: Apoptosis Research Centre, National University of Ireland Galway, Galway, Ireland School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Koryga
authors.affiliation: Apoptosis Research Centre, National University of Ireland Galway, Galway, Ireland School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Mnich
authors.affiliation: Apoptosis Research Centre, National University of Ireland Galway, Galway, Ireland School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
authors.forename: Mila
authors.initials: M
authors.lastname: Ljujic
authors.affiliation: Apoptosis Research Centre, National University of Ireland Galway, Galway, Ireland School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
authors.forename: Afshin
authors.identifier: 0000-0002-8610-8375
authors.initials: A
authors.lastname: Samali
authors.affiliation: Apoptosis Research Centre, National University of Ireland Galway, Galway, Ireland School of Natural Sciences, National University of Ireland Galway, Galway, Ireland adrienne.gorman@nuigalway.ie.
authors.forename: Adrienne M
authors.identifier: 0000-0002-6068-0058
authors.initials: AM
authors.lastname: Gorman
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis; D054884:Host-Pathogen Interactions; D006801:Humans; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors
keywords: activating transcription factor 4; eIF2α kinase; eukaryotic translation initiation factor 2 alpha; integrated stress response