{"doi":"10.17615/h22d-zx50","title":"DNAJB12 and Hsp70 triage arrested intermediates of N1303K-CFTR for endoplasmic reticulum-associated autophagy","abstract":"The transmembrane Hsp40 DNAJB12 and cytosolic Hsp70 cooperate on the endoplasmic reticulum's (ER) cytoplasmic face to facilitate the triage of nascent polytopic membrane proteins for folding versus degradation. N1303K is a common mutation that causes misfolding of the ion channel CFTR, but unlike F508del-CFTR, biogenic and functional defects in N1303K-CFTR are resistant to correction by folding modulators. N1303K is reported to arrest CFTR folding at a late stage after partial assembly of its N-terminal domains. N1303K-CFTR intermediates are clients of JB12-Hsp70 complexes, maintained in a detergent- soluble state, and have a relatively long 3-h half-life. ER-associated degradation (ERAD)- resistant pools of N1303K-CFTR are concentrated in ER tubules that associate with autophagy initiation sites containing WIPI1, FlP200, and LC3. Destabilization of N1303K-CFTR or depletion of JB12 prevents entry of N1303K-CFTR into the membranes of ER-connected phagophores and traffic to autolysosomes. In contrast, the stabilization of intermediates with the modulator VX-809 promotes the association of N1303K-CFTR with autophagy initiation machinery. N1303K-CFTR is excluded from the ER-exit sites, and its passage from the ER to autolysosomes does not require ER-phagy receptors. DNAJB12 operates in biosynthetically active ER microdomains to triage membrane protein intermediates in a conformation-specific manner for secretion versus degradation via ERAD or selective-ER-associated autophagy.","journal":"UNC Libraries","year":2024,"id":499673,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":585506,"name":"Andrew S. Kennedy","orcid":"0000-0002-9866-7190","position":1,"is_corresponding":false},{"id":1348568,"name":"Suzanne Houck","orcid":null,"position":2,"is_corresponding":false},{"id":402970,"name":"Nancy L. Quinney","orcid":"0000-0003-3437-9621","position":3,"is_corresponding":false},{"id":578777,"name":"Hong Yu Ren","orcid":"0000-0002-8402-0468","position":4,"is_corresponding":false},{"id":72632,"name":"Scott H. Randell","orcid":"0000-0001-5351-2841","position":5,"is_corresponding":false},{"id":1004329,"name":"Liang He","orcid":"0000-0003-1523-067X","position":6,"is_corresponding":false},{"id":528944,"name":"Andrei A. Aleksandrov","orcid":"0000-0002-8671-2732","position":7,"is_corresponding":false},{"id":1348569,"name":"Alexandra Cyr-Scully","orcid":null,"position":8,"is_corresponding":false},{"id":425648,"name":"Douglas Cyr","orcid":"0000-0002-4928-3414","position":9,"is_corresponding":false},{"id":402971,"name":"Martina Gentzsch","orcid":"0000-0002-9435-0321","position":10,"is_corresponding":false},{"id":402969,"name":"Deborah M. Cholon","orcid":"0000-0002-9396-0005","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:09:53.188165Z","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":[]}