Integrated stress response of vertebrates is regulated by four eIF2? kinases.

ABSTRACT: The integrated stress response (ISR) is a cytoprotective pathway initiated upon phosphorylation of the eukaryotic translation initiation factor 2 (eIF2?) residue designated serine-51, which is critical for translational control in response to various stress conditions. Four eIF2? 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 eIF2? is phosphorylated under various stress conditions, the existence of an additional eIF2? kinase has been suggested. To validate the existence of the unidentified eIF2? kinase, we constructed an eIF2? kinase quadruple knockout cells (4KO cells) in which the four known eIF2? kinase genes were deleted using the CRISPR/Cas9-mediated genome editing. Phosphorylation of eIF2? was completely abolished in the 4KO cells by various stress stimulations. Our data suggests that the four known eIF2? kinases are sufficient for ISR and that there are no additional eIF2? kinases in vertebrates.

SUBMITTER: Taniuchi S 

PROVIDER: S-EPMC5025754 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature