{"doi":"10.1101/573428","title":"Size-Dependent Secretory Protein Reflux into the Cytosol in Association with Acute Endoplasmic Reticulum Stress","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>Once secretory proteins have been targeted to the endoplasmic reticulum (ER), the proteins typically remain partitioned from the cytosol. If the secretory proteins misfold, they can be unfolded and retrotranslocated into the cytosol for destruction by the proteasome by ER-associated protein Degradation (ERAD). Here, we report that correctly folded and targeted luminal ER fluorescent protein reporters accumulate in the cytosol during acute misfolded secretory protein stress in yeast. Photoactivation fluorescence microscopy experiments reveal that luminal reporters already localized to the ER relocalize to the cytosol, even in the absence of essential ERAD machinery. We named this process “ER reflux.” Reflux appears to be regulated in a size-dependent manner for reporters. Interestingly, prior heat shock stress also prevents ER stress-induced reflux. Together, our findings establish a new ER stress-regulated pathway for relocalization of small luminal secretory proteins into the cytosol, distinct from the ERAD and pre-emptive quality control pathways.</jats:p>","journal":null,"year":null,"id":626694,"datarank":0.31191623125197543,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.0,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"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":163948,"name":"Erik L. Snapp","orcid":"0000-0001-9482-2272","position":1,"is_corresponding":false},{"id":821739,"name":"Patrick Lajoie","orcid":"0000-0002-1614-176X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Size-Dependent Secretory Protein Reflux into the Cytosol in Association with Acute Endoplasmic Reticulum Stress","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>Once secretory proteins have been targeted to the endoplasmic reticulum (ER), the proteins typically remain partitioned from the cytosol. If the secretory proteins misfold, they can be unfolded and retrotranslocated into the cytosol for destruction by the proteasome by ER-associated protein Degradation (ERAD). Here, we report that correctly folded and targeted luminal ER fluorescent protein reporters accumulate in the cytosol during acute misfolded secretory protein stress in yeast. Photoactivation fluorescence microscopy experiments reveal that luminal reporters already localized to the ER relocalize to the cytosol, even in the absence of essential ERAD machinery. We named this process “ER reflux.” Reflux appears to be regulated in a size-dependent manner for reporters. Interestingly, prior heat shock stress also prevents ER stress-induced reflux. Together, our findings establish a new ER stress-regulated pathway for relocalization of small luminal secretory proteins into the cytosol, distinct from the ERAD and pre-emptive quality control pathways.</jats:p>","is_dataset_classified":null,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19767382","pmcid":null,"openalex_id":"https://openalex.org/W2921660181","authors":[],"funders":[{"funder_name":"Natural Sciences and Engineering Research Council of Canada","grant_id":"unidentified","title":"unidentified"},{"funder_name":"National Institutes of Health","grant_id":"5F32GM010599-02","title":"STRUCTURE AND MECHANISM OF YEAST AMP DEAMINASE"}],"total_grants":2,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2019,"count":1},{"year":2020,"count":2},{"year":2021,"count":1},{"year":2023,"count":1},{"year":2024,"count":1}],"oa_status":"green","license":"CC BY","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2019/03/12/573428.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2019/03/12/573428.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/573428","host_type":"publisher"},{"url":"https://doi.org/10.1101/573428","host_type":"repository"},{"url":"https://doi.org/10.1111/tra.12729","host_type":""},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/tra.12729","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/32246734","host_type":""},{"url":"http://dx.doi.org/10.1111/tra.12729","host_type":""},{"url":"https://dx.doi.org/10.1101/573428","host_type":""},{"url":"https://dx.doi.org/10.1111/tra.12729","host_type":""},{"url":"http://dx.doi.org/10.1101/573428","host_type":""}],"fields_of_study":["Endoplasmic Reticulum Stress and Disease","Genetic Neurodegenerative Diseases","Cellular transport and secretion","0301 basic medicine","03 medical and health sciences"],"mesh_terms":[],"keywords":["Endoplasmic-reticulum-associated protein degradation","Endoplasmic reticulum","Cytosol","Unfolded protein response","Cell biology","Secretory pathway","Secretory protein","Proteasome","Biology","Proteostasis","Chemistry","Biochemistry","Secretion","Golgi apparatus","Enzyme","Protein Folding","Original Articles","Endoplasmic Reticulum-Associated Degradation","Endoplasmic Reticulum Stress"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-04T14:52:30.484790Z","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":[]}