{"doi":"10.1101/134726","title":"The unfolded protein response switches from pro-survival to pro-apoptotic to cap the extent of endoplasmic reticulum expansion","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>\n                  Insufficient folding capacity of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis. Yet, how the UPR achieves and evaluates ER homeostatic readjustment is poorly understood. In a HeLa cell model we show that, upon a severe proteostatic insult that eclipses the ER chaperone BiP, the UPR transitions from acute full-gear activation to chronic submaximal activation, when BiP is in excess again. As such, the UPR-driven ER expansion is pro-survival, primarily via the UPR transducer ATF6α. Simultaneous abrogation of ER-associated degradation (ERAD) leads to chronic full-gear UPR activation and further ER expansion, but the UPR transducers IRE1α and PERK turn pro-apoptotic. Pro-survival\n                  <jats:italic>XBP1</jats:italic>\n                  mRNA processing by IRE1α is then trumped since unspliced\n                  <jats:italic>XBP1</jats:italic>\n                  mRNA is depleted and IRE1α’s endonuclease activity is unleashed against other RNAs. Thus, the IRE1α/\n                  <jats:italic>XBP1</jats:italic>\n                  relay serves as a capacitor of ER expansion that heralds cell death if the expansion is deemed excessive.\n                </jats:p>","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":null,"id":25969,"datarank":0.15833866955746234,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.054366592473470525,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.054366592473470525,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"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":145843,"name":"Andrea Orsi","orcid":"0000-0003-2839-1640","position":1,"is_corresponding":false},{"id":145842,"name":"Anush Bakunts","orcid":"0000-0001-8793-1999","position":2,"is_corresponding":false},{"id":145844,"name":"Federica Lari","orcid":"0000-0003-2789-7877","position":3,"is_corresponding":false},{"id":145845,"name":"Laura Tadè","orcid":null,"position":4,"is_corresponding":false},{"id":151440,"name":"Angela Cattaneo","orcid":null,"position":5,"is_corresponding":false},{"id":142647,"name":"Roberto Sitia","orcid":"0000-0001-7086-4152","position":6,"is_corresponding":false},{"id":145849,"name":"Andrea Raimondi","orcid":"0000-0002-4563-386X","position":7,"is_corresponding":false},{"id":151441,"name":"Angela Bachi","orcid":null,"position":8,"is_corresponding":false},{"id":145851,"name":"Eelco van Anken","orcid":"0000-0001-9529-2701","position":9,"is_corresponding":false},{"id":145841,"name":"Milena Vitale","orcid":"0000-0001-7007-402X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"18998881","pmcid":null,"openalex_id":"https://openalex.org/W2610373932","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2017,"count":1}],"oa_status":"green","license":"cc-by","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2017/05/05/134726.full.pdf","host_type":"repository"},{"url":"https://doi.org/10.1101/134726","host_type":"GREEN"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2017/05/05/134726.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/134726","host_type":"publisher"}],"fields_of_study":["Endoplasmic Reticulum Stress and Disease","Autophagy in Disease and Therapy","RNA regulation and disease","Biology","Chemistry","Medicine"],"mesh_terms":[],"keywords":["Unfolded protein response","XBP1","Endoplasmic reticulum","ATF6","Cell biology","Autophagy","Endoplasmic-reticulum-associated protein degradation","Downregulation and upregulation","Apoptosis","Chemistry","RNA splicing","Biology","RNA","Biochemistry"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-08T10:02:23.385876Z","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":[]}