{"doi":"10.1038/srep24217","title":"Novel mechanism of enhancing IRE1α-XBP1 signalling via the PERK-ATF4 pathway","abstract":"<jats:title>Abstract</jats:title><jats:p>Mammalian inositol-requiring enzyme 1α (IRE1α) is the most conserved of all endoplasmic reticulum (ER) stress sensors, which includes activating transcription factor (ATF) 6 and double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK). IRE1α has been known to splice <jats:italic>X-box binding protein 1 (XBP1)</jats:italic> mRNA, which is induced by ATF6 under ER stress. This spliced <jats:italic>XBP1</jats:italic> mRNA is translated into the active transcription factor that promotes the expression of specific genes to alleviate ER stress. Herein, we report that in addition to the induction of XBP1 expression by ATF6, IRE1α expression is induced by ATF4, which is downstream of PERK, under ER stress. Increased IRE1α expression results in a higher splicing ratio of <jats:italic>XBP1</jats:italic> mRNA. This effect was not transient and affected not only the intensity but also the duration of the activated state of this pathway. These multiple regulatory mechanisms may modulate the response to various levels or types of ER stress.</jats:p>","journal":"Scientific Reports","year":2016,"id":47227,"datarank":4.522870215885218,"base_score":4.897839799950911,"endowment":4.897839799950911,"self_citation_contribution":0.7346759699926367,"citation_network_contribution":3.7881942458925817,"self_endowment_contribution":0.7346759699926367,"citer_contribution":3.7881942458925817,"corpus_percentile":null,"corpus_rank":null,"citation_count":133,"citer_count":133,"citers_with_citation_signal":116,"citers_with_endowment":116,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":217872,"name":"Yasutaka Imai","orcid":null,"position":1,"is_corresponding":false},{"id":181298,"name":"Michiko Saito","orcid":"0000-0002-6678-2135","position":2,"is_corresponding":false},{"id":181299,"name":"Kenji Kohno","orcid":"0000-0002-3503-6551","position":3,"is_corresponding":false},{"id":217871,"name":"Akio Tsuru","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Novel mechanism of enhancing IRE1α-XBP1 signalling via the PERK-ATF4 pathway","abstract":"<jats:title>Abstract</jats:title><jats:p>Mammalian inositol-requiring enzyme 1α (IRE1α) is the most conserved of all endoplasmic reticulum (ER) stress sensors, which includes activating transcription factor (ATF) 6 and double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK). IRE1α has been known to splice <jats:italic>X-box binding protein 1 (XBP1)</jats:italic> mRNA, which is induced by ATF6 under ER stress. This spliced <jats:italic>XBP1</jats:italic> mRNA is translated into the active transcription factor that promotes the expression of specific genes to alleviate ER stress. Herein, we report that in addition to the induction of XBP1 expression by ATF6, IRE1α expression is induced by ATF4, which is downstream of PERK, under ER stress. Increased IRE1α expression results in a higher splicing ratio of <jats:italic>XBP1</jats:italic> mRNA. This effect was not transient and affected not only the intensity but also the duration of the activated state of this pathway. These multiple regulatory mechanisms may modulate the response to various levels or types of ER stress.</jats:p>","is_dataset_classified":null,"base_score":4.897839799950911,"endowment":4.897839799950911,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"27052593","pmcid":"PMC4823713","openalex_id":"https://openalex.org/W2334966793","authors":[],"funders":[],"total_grants":0,"fwci":8.577,"citation_percentile":0.98230817,"influential_citations":7,"citation_trend":[{"year":2016,"count":1},{"year":2017,"count":8},{"year":2018,"count":17},{"year":2019,"count":20},{"year":2020,"count":17},{"year":2021,"count":11},{"year":2022,"count":12},{"year":2023,"count":12},{"year":2024,"count":13},{"year":2025,"count":15},{"year":2026,"count":7}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.nature.com/articles/srep24217.pdf","host_type":"journal"},{"url":"https://www.nature.com/articles/srep24217.pdf","host_type":"GOLD"},{"url":"https://www.nature.com/articles/srep24217.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/srep24217","host_type":"publisher"},{"url":"https://doi.org/10.1038/srep24217","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/27052593","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4823713","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC4823713","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC4823713?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Endoplasmic Reticulum Stress and Disease","RNA regulation and disease","Autophagy in Disease and Therapy","Medicine","Biology","Activating Transcription Factor 4","Animals","Blotting, Western","Cells, Cultured","Endoplasmic Reticulum Stress","Endoribonucleases","Gene Expression Regulation","HeLa Cells","Hep G2 Cells","Humans","Mice, Inbred C57BL","Mice, Knockout","Protein Serine-Threonine Kinases","RNA Splicing","Rabbits","Reverse Transcriptase Polymerase Chain Reaction","Signal Transduction","Tunicamycin","X-Box Binding Protein 1","eIF-2 Kinase"],"mesh_terms":["X-Box Binding Protein 1","Animals","Cells, Cultured","Endoribonucleases","Gene Expression Regulation","HeLa Cells","Humans","Mice, Inbred C57BL","Rabbits","RNA Splicing","Tunicamycin","Blotting, Western","Signal Transduction","Protein Serine-Threonine Kinases","Mice, Knockout","eIF-2 Kinase","Reverse Transcriptase Polymerase Chain Reaction","Activating Transcription Factor 4","Hep G2 Cells","Endoplasmic Reticulum Stress","Hela Cells"],"keywords":["XBP1","ATF6","Unfolded protein response","ATF4","Endoplasmic reticulum","Protein kinase R","Activating transcription factor","EIF-2 kinase","Cell biology","Transcription factor","Messenger RNA","RNA splicing","Biology","Protein kinase A","Kinase","Chemistry","RNA","Gene","Mitogen-activated protein kinase kinase","Biochemistry","Cyclin-dependent kinase 2"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"gen"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-18T14:14:20.360015Z","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,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}