title: RNF185 is a novel E3 ligase of endoplasmic reticulum-associated degradation (ERAD) that targets cystic fibrosis transmembrane conductance regulator (CFTR).
abstract: In the endoplasmic reticulum (ER), misfolded or improperly assembled proteins are exported to the cytoplasm and degraded by the ubiquitin-proteasome pathway through a process called ER-associated degradation (ERAD). ER-associated E3 ligases, which coordinate substrate recognition, export, and proteasome targeting, are key components of ERAD. Cystic fibrosis transmembrane conductance regulator (CFTR) is one ERAD substrate targeted to co-translational degradation by the E3 ligase RNF5/RMA1. RNF185 is a RING domain-containing polypeptide homologous to RNF5. We show that RNF185 controls the stability of CFTR and of the CFTRΔF508 mutant in a RING- and proteasome-dependent manner but does not control that of other classical ERAD model substrates. Reciprocally, its silencing stabilizes CFTR proteins. Turnover analyses indicate that, as RNF5, RNF185 targets CFTR to co-translational degradation. Importantly, however, simultaneous depletion of RNF5 and RNF185 profoundly blocks CFTRΔF508 degradation not only during translation but also after synthesis is complete. Our data thus identify RNF185 and RNF5 as a novel E3 ligase module that is central to the control of CFTR degradation.
authors.affiliation: From the Laboratoire Stress Oxydant et Cancers, Service de Biologie Intégrative et Génétique Moléculaire (SBiGeM), Institut de Biologie et de Technologies de Saclay (IBiTec-S), Commissariat à l'Energie Atomique-Saclay, 91191 Gif-sur-Yvette, Cedex, France.
authors.forename: Elma
authors.initials: E
authors.lastname: El Khouri
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Le Pavec
authors.forename: Michel B
authors.initials: MB
authors.lastname: Toledano
authors.forename: Agnès
authors.initials: A
authors.lastname: Delaunay-Moisan
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology; D055550:Protein Stability; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C505032:CFTR protein, human; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C569560:RNF185 protein, human; C111501:RNF5 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
keywords: CFTR; ER Quality Control; ER-associated Degradation; Protein Degradation; Ubiquitin Ligase; Ubiquitination
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