title: Integrated stress response of vertebrates is regulated by four eIF2α kinases.
abstract: The integrated stress response (ISR) is a cytoprotective pathway initiated upon phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α) residue designated serine-51, which is critical for translational control in response to various stress conditions. Four eIF2α kinases, namely heme-regulated inhibitor (HRI), protein kinase R (PKR), PKR-like endoplasmic reticulum kinase, (PERK) and general control non-depressible 2 (GCN2), have been identified thus far, and they are known to be activated by heme depletion, viral infection, endoplasmic reticulum stress, and amino acid starvation, respectively. Because eIF2α is phosphorylated under various stress conditions, the existence of an additional eIF2α kinase has been suggested. To validate the existence of the unidentified eIF2α kinase, we constructed an eIF2α kinase quadruple knockout cells (4KO cells) in which the four known eIF2α kinase genes were deleted using the CRISPR/Cas9-mediated genome editing. Phosphorylation of eIF2α was completely abolished in the 4KO cells by various stress stimulations. Our data suggests that the four known eIF2α kinases are sufficient for ISR and that there are no additional eIF2α kinases in vertebrates.
authors.affiliation: Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.|Department of Molecular Research, Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.|Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Taniuchi
authors.affiliation: Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.|Department of Molecular Research, Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.|Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Miyake
authors.affiliation: Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.|Department of Molecular Research, Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Tsugawa
authors.affiliation: Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.|Department of Molecular Research, Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Oyadomari
authors.affiliation: Division of Molecular Biology, Institute for Genome Research, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.|Department of Molecular Research, Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.|Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Oyadomari
mesh_terms: D000818:Animals; D064113:CRISPR-Cas Systems; D017173:Caenorhabditis elegans; D002460:Cell Line; D004331:Drosophila melanogaster; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D000072669:Gene Editing; D051379:Mice; D010766:Phosphorylation; D010802:Phylogeny; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C070634:Eif2ak4 protein, mouse; C531557:eIF2alpha kinase, mouse; C000605978:protein kinase R, mouse