{"doi":"10.1091/mbc.e23-08-0336","title":"Small-molecule correctors divert CFTR-F508del from ERAD by stabilizing sequential folding states","abstract":"Over 80% of people with cystic fibrosis (CF) carry the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel at the apical plasma membrane (PM) of epithelial cells. F508del impairs CFTR folding causing it to be destroyed by endoplasmic reticulum associated degradation (ERAD). Small-molecule correctors, which act as pharmacological chaperones to divert CFTR-F508del from ERAD, are the primary strategy for treating CF, yet corrector development continues with only a rudimentary understanding of how ERAD targets CFTR-F508del. We conducted genome-wide CRISPR/Cas9 knockout screens to systematically identify the molecular machinery that underlies CFTR-F508del ERAD. Although the ER-resident ubiquitin ligase, RNF5 was the top E3 hit, knocking out RNF5 only modestly reduced CFTR-F508del degradation. Sublibrary screens in an RNF5 knockout background identified RNF185 as a redundant ligase and demonstrated that CFTR-F508del ERAD is robust. Gene-drug interaction experiments illustrated that correctors tezacaftor (VX-661) and elexacaftor (VX-445) stabilize sequential, RNF5-resistant folding states. We propose that binding of correctors to nascent CFTR-F508del alters its folding landscape by stabilizing folding states that are not substrates for RNF5-mediated ubiquitylation.","journal":"Molecular Biology of the Cell","year":2023,"id":352045,"datarank":0.3453877639491069,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.0,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9468,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1097583,"name":"Magda Wąchalska","orcid":"0000-0003-0429-888X","position":1,"is_corresponding":false},{"id":287533,"name":"Kirandeep K. Deol","orcid":"0000-0001-6499-8592","position":2,"is_corresponding":false},{"id":457593,"name":"Anais K. Amaya","orcid":"0000-0002-8396-2226","position":3,"is_corresponding":false},{"id":251111,"name":"Matthew H. Porteus","orcid":"0000-0002-3850-4648","position":4,"is_corresponding":false},{"id":166314,"name":"James A. Olzmann","orcid":"0000-0001-7751-8316","position":5,"is_corresponding":false},{"id":467783,"name":"Ron R. Kopito","orcid":"0000-0001-5027-6935","position":6,"is_corresponding":false},{"id":705414,"name":"Celeste Riepe","orcid":"0000-0001-8672-5392","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:12:50.107998Z","pmid":"38019608","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":[]}