{"doi":"10.1038/srep32886","title":"Integrated stress response of vertebrates is regulated by four eIF2α kinases","abstract":"<jats:title>Abstract</jats:title><jats:p>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.</jats:p>","journal":"Scientific Reports","year":2016,"id":22352,"datarank":7.891130387379438,"base_score":5.6131281063880705,"endowment":5.6131281063880705,"self_citation_contribution":0.8419692159582107,"citation_network_contribution":7.049161171421227,"self_endowment_contribution":0.8419692159582107,"citer_contribution":7.049161171421227,"corpus_percentile":null,"corpus_rank":null,"citation_count":273,"citer_count":200,"citers_with_citation_signal":200,"citers_with_endowment":200,"datacite_reuse_total":2,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":140793,"name":"Masato Miyake","orcid":null,"position":1,"is_corresponding":false},{"id":140794,"name":"Kazue Tsugawa","orcid":null,"position":2,"is_corresponding":false},{"id":140795,"name":"Miho Oyadomari","orcid":null,"position":3,"is_corresponding":false},{"id":122816,"name":"Seiichi Oyadomari","orcid":null,"position":4,"is_corresponding":false},{"id":140792,"name":"Shusuke Taniuchi","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":5.6131281063880705,"endowment":5.6131281063880705,"datacite_reuse_total":2,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"27633668","pmcid":"PMC5025754","openalex_id":"https://openalex.org/W2518855060","authors":[],"funders":[],"total_grants":0,"fwci":13.0521,"citation_percentile":0.99273452,"influential_citations":14,"citation_trend":[{"year":2016,"count":1},{"year":2017,"count":11},{"year":2018,"count":25},{"year":2019,"count":32},{"year":2020,"count":47},{"year":2021,"count":42},{"year":2022,"count":28},{"year":2023,"count":29},{"year":2024,"count":28},{"year":2025,"count":19},{"year":2026,"count":11}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1038/srep32886","host_type":"journal"},{"url":"https://doi.org/10.1038/srep32886","host_type":"GOLD"},{"url":"https://doi.org/10.1038/srep32886","host_type":"publisher"},{"url":"https://www.nature.com/articles/srep32886.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/srep32886","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/27633668","host_type":"repository"},{"url":"https://tokushima-u.repo.nii.ac.jp/records/2005522","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5025754","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC5025754","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC5025754?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Endoplasmic Reticulum Stress and Disease","CRISPR and Genetic Engineering","RNA regulation and disease","Biology","Medicine","Animals","CRISPR-Cas Systems","Caenorhabditis elegans","Cell Line","Drosophila melanogaster","Endoplasmic Reticulum","Fibroblasts","Gene Editing","Mice","Phosphorylation","Phylogeny","Protein Serine-Threonine Kinases","eIF-2 Kinase"],"mesh_terms":["Gene Editing","Animals","Cell Line","Drosophila melanogaster","Endoplasmic Reticulum","Fibroblasts","Phosphorylation","Phylogeny","Caenorhabditis elegans","Protein Serine-Threonine Kinases","eIF-2 Kinase","Mice","CRISPR-Cas Systems"],"keywords":["Integrated stress response","Protein kinase R","EIF-2 kinase","Kinase","eIF2","Biology","Cell biology","Endoplasmic reticulum","Phosphorylation","Protein kinase A","ASK1","Biochemistry","Translation (biology)","Cyclin-dependent kinase 2","Gene","Messenger RNA"],"sdg_mappings":[],"linked_datasets":[{"doi":"10.6084/m9.figshare.12023913.v1","title":"Additional file 1 of Stress-mediated convergence of splicing landscapes in male and female rock doves","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.12023913","title":"Additional file 1 of Stress-mediated convergence of splicing landscapes in male and female rock doves","publisher":"figshare","resource_type":"JournalArticle"}],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"gen"},{"name":"uniprot"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-06T19:58:52.584179Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}