{"doi":"10.1083/jcb.202308003","title":"HERC3 facilitates ERAD of select membrane proteins by recognizing membrane-spanning domains","abstract":"Aberrant proteins located in the endoplasmic reticulum (ER) undergo rapid ubiquitination by multiple ubiquitin (Ub) E3 ligases and are retrotranslocated to the cytosol as part of the ER-associated degradation (ERAD). Despite several ERAD branches involving different Ub E3 ligases, the molecular machinery responsible for these ERAD branches in mammalian cells remains not fully understood. Through a series of multiplex knockdown/knockout experiments with real-time kinetic measurements, we demonstrate that HERC3 operates independently of the ER-embedded ubiquitin ligases RNF5 and RNF185 (RNF5/185) to mediate the retrotranslocation and ERAD of misfolded CFTR. While RNF5/185 participates in the ERAD process of both misfolded ABCB1 and CFTR, HERC3 uniquely promotes CFTR ERAD. In vitro assay revealed that HERC3 directly interacts with the exposed membrane-spanning domains (MSDs) of CFTR but not with the MSDs embedded in liposomes. Therefore, HERC3 could play a role in the quality control of MSDs in the cytoplasm and might be crucial for the ERAD pathway of select membrane proteins.","journal":"The Journal of Cell Biology","year":2024,"id":435241,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"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":1235777,"name":"Yuko Ohnishi","orcid":"0009-0007-8058-9642","position":1,"is_corresponding":false},{"id":1242403,"name":"Chikako Nakashima","orcid":"0009-0002-7181-4354","position":2,"is_corresponding":false},{"id":1242404,"name":"Aika Fujii","orcid":"0009-0005-5599-4932","position":3,"is_corresponding":false},{"id":1242405,"name":"Mana Terakawa","orcid":"0009-0000-9280-1179","position":4,"is_corresponding":false},{"id":1242406,"name":"Ikuto Hamano","orcid":"0009-0003-1483-5666","position":5,"is_corresponding":false},{"id":1242407,"name":"Uta Nakayamada","orcid":"0009-0006-4984-8485","position":6,"is_corresponding":false},{"id":1242408,"name":"Saori Katoh","orcid":"0009-0007-9967-488X","position":7,"is_corresponding":false},{"id":1242409,"name":"N Hirata","orcid":"0009-0001-7213-0555","position":8,"is_corresponding":false},{"id":1242410,"name":"H Tateishi","orcid":"0009-0005-1787-8092","position":9,"is_corresponding":false},{"id":1242411,"name":"Ryosuke Fukuda","orcid":"0009-0002-2352-4774","position":10,"is_corresponding":false},{"id":1242412,"name":"Hirotaka Takahashi","orcid":"0000-0002-1278-416X","position":11,"is_corresponding":false},{"id":597496,"name":"Gergely L. Lukács","orcid":"0000-0003-0900-0675","position":12,"is_corresponding":false},{"id":597499,"name":"Tsukasa Okiyoneda","orcid":"0000-0002-5175-2224","position":13,"is_corresponding":false},{"id":1242402,"name":"Yuka Kamada","orcid":"0009-0006-6746-9112","position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":null,"created_at":"2026-07-19T02:00:03.406367Z","pmid":"38722278","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":[]}