title: Correcting the cystic fibrosis disease mutant, A455E CFTR.
abstract: Cystic fibrosis is caused by more than 1000 mutations, the most common being the ΔF508 mutation. These mutations have been divided into five classes [1], with ΔF508 CFTR in class II. Here we have studied the class V mutation A455E. We report that the mature and immature bands of A455E are rapidly degraded primarily by proteasomes; the short protein half-life of this mutant therefore resembles that of ΔF508 CFTR. A455E could be rescued by treatment of the cells with proteasome inhibitors. Furthermore, co-transfection of A455E with the truncation mutant Δ264 CFTR also rescued the mature C band, indicating that A455E can be rescued by transcomplementation. We found that Δ264 CFTR bound to A455E, forming a bimolecular complex. Treatment with the compound correctors C3 and C4 also rescued A455E. These results are significant because they show that although ΔF508 belongs to a different class than A455E, it can be rescued by the same strategies, offering therapeutic promise to patients with Class V mutations.
authors.affiliation: Department of Ophthalmology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America ; Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Cebotaru
authors.affiliation: Department of Ophthalmology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America ; Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Daniele
authors.initials: D
authors.lastname: Rapino
authors.affiliation: Department of Medicine, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Valeriu
authors.initials: V
authors.lastname: Cebotaru
authors.affiliation: Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: William B
authors.initials: WB
authors.lastname: Guggino
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D019556:COS Cells; D002522:Chlorocebus aethiops; D003513:Cycloheximide / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005816:Genetic Complementation Test; D006207:Half-Life; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D009154:Mutation; D010957:Plasmids; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000813:Anilides; D001897:Boronic Acids; C505032:CFTR protein, human; D006877:Hydroxamic Acids; D007976:Leupeptins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D054852:Small Molecule Libraries; C474316:tubacin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000069286:Bortezomib; D003513:Cycloheximide; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde