{"doi":"10.1242/jcs.144386","title":"A cytosolic degradation pathway, prERAD, monitors pre-inserted secretory pathway proteins","abstract":"<jats:p>The endoplasmic reticulum (ER) identifies and disposes of misfolded secretory pathway proteins through the actions of ER associated degradation (ERAD) pathways. It is becoming evident that a substantial fraction of the secretome transiently resides in the cytosol before translocating into the ER, both in yeast and in higher eukaryotes. To uncover factors that monitor this transient cytosolic protein pool, we carried out a genetic screen in Saccharomyces cerevisiae. Our findings highlighted a preinsertional degradation mechanism at the cytosolic leaflet of the ER, which we termed prERAD. prERAD relies on the concurrent action of ER localized ubiquitination and deubiquitination machineries, Doa10 and Ubp1. By recognizing C-terminal hydrophobic motifs, prERAD tags for degradation pre-inserted proteins that have remained on the cytosolic leaflet of the ER for too long. Our discoveries delineate a novel cellular safeguard, which ensures that every stage of secretory pathway protein biogenesis is scrutinized and regulated.</jats:p>","journal":"Journal of Cell Science","year":2014,"id":688354,"datarank":0.5709993734655481,"base_score":3.8066624897703196,"endowment":3.8066624897703196,"self_citation_contribution":0.5709993734655481,"citation_network_contribution":0.0,"self_endowment_contribution":0.5709993734655481,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":44,"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":898462,"name":"Naama Aviram","orcid":"0000-0002-0581-958X","position":1,"is_corresponding":false},{"id":1798269,"name":"Silvia Gabriela Chuartzman","orcid":null,"position":2,"is_corresponding":false},{"id":366119,"name":"Maya Schuldiner","orcid":"0000-0001-9947-115X","position":3,"is_corresponding":false},{"id":105005,"name":"Tslil Ast","orcid":"0000-0002-6927-6238","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"A cytosolic degradation pathway, prERAD, monitors pre-inserted secretory pathway proteins","abstract":"<jats:p>The endoplasmic reticulum (ER) identifies and disposes of misfolded secretory pathway proteins through the actions of ER associated degradation (ERAD) pathways. It is becoming evident that a substantial fraction of the secretome transiently resides in the cytosol before translocating into the ER, both in yeast and in higher eukaryotes. To uncover factors that monitor this transient cytosolic protein pool, we carried out a genetic screen in Saccharomyces cerevisiae. Our findings highlighted a preinsertional degradation mechanism at the cytosolic leaflet of the ER, which we termed prERAD. prERAD relies on the concurrent action of ER localized ubiquitination and deubiquitination machineries, Doa10 and Ubp1. By recognizing C-terminal hydrophobic motifs, prERAD tags for degradation pre-inserted proteins that have remained on the cytosolic leaflet of the ER for too long. Our discoveries delineate a novel cellular safeguard, which ensures that every stage of secretory pathway protein biogenesis is scrutinized and regulated.</jats:p>","is_dataset_classified":null,"base_score":3.8066624897703196,"endowment":3.8066624897703196,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"24849653","pmcid":null,"openalex_id":"https://openalex.org/W2145675438","authors":[],"funders":[{"funder_name":"European Commission","grant_id":"260395","title":"Uncovering the Mechanisms of Endoplasmic Reticulum Sub-Domain Creation and Maintenance"}],"total_grants":1,"fwci":1.9699,"citation_percentile":0.85059415,"influential_citations":0,"citation_trend":[{"year":2014,"count":3},{"year":2015,"count":5},{"year":2016,"count":4},{"year":2017,"count":2},{"year":2018,"count":6},{"year":2019,"count":7},{"year":2020,"count":7},{"year":2021,"count":3},{"year":2022,"count":5},{"year":2024,"count":2}],"oa_status":"closed","license":null,"oa_locations":[{"url":"http://journals.biologists.com/jcs/article-pdf/127/14/3017/1936231/jcs-127-14-3017.pdf","host_type":"publisher"},{"url":"http://journals.biologists.com/jcs/article-pdf/doi/10.1242/jcs.144386/2046344/jcs144386.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1242/jcs.144386","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/24849653","host_type":"repository"},{"url":"http://jcs.biologists.org/cgi/content/short/127/14/3017","host_type":"repository"},{"url":"https://jcs.biologists.org/content/joces/127/14/3017.full.pdf","host_type":""},{"url":"https://dx.doi.org/10.1242/jcs.144386","host_type":""},{"url":"http://dx.doi.org/10.1242/jcs.144386","host_type":""}],"fields_of_study":["Endoplasmic Reticulum Stress and Disease","Cellular transport and secretion","Autophagy in Disease and Therapy","0301 basic medicine","0303 health sciences","03 medical and health sciences","Cytosol","Endoplasmic Reticulum","Endoplasmic Reticulum-Associated Degradation","Humans","Saccharomyces cerevisiae","Saccharomyces cerevisiae Proteins","Secretory Pathway"],"mesh_terms":["Cytosol","Endoplasmic Reticulum","Humans","Saccharomyces cerevisiae","Saccharomyces cerevisiae Proteins","Secretory Pathway","Endoplasmic Reticulum-Associated Degradation"],"keywords":["Endoplasmic-reticulum-associated protein degradation","Cytosol","Biology","Endoplasmic reticulum","Cell biology","Saccharomyces cerevisiae","Secretory protein","Biogenesis","Secretory pathway","Ubiquitin","Protein degradation","Yeast","Secretion","Biochemistry","Unfolded protein response","Gene","Golgi apparatus","Quality control","Translocation","GPI-anchored protein","ERAD","Doa10","Srp-independent Substrate","Saccharomyces cerevisiae Proteins","Humans","Endoplasmic Reticulum-Associated Degradation"],"sdg_mappings":[{"sdg_number":2,"sdg_label":"2. Zero hunger"},{"sdg_number":15,"sdg_label":"15. Life on land"},{"sdg_number":0,"sdg_label":"Life in Land"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-19T15:29:46.263950Z","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":[]}