title: A truncated CFTR protein rescues endogenous DeltaF508-CFTR and corrects chloride transport in mice.
abstract: Cystic fibrosis (CF) is most frequently associated with deletion of phenylalanine at position 508 (DeltaF508) in the CF transmembrane conductance regulator (CFTR) protein. The DeltaF508-CFTR mutant protein exhibits a folding defect that affects its processing and impairs chloride-channel function. This study aimed to determine whether CFTR fragments approximately half the size of wild-type CFTR and complementary to the portion of CFTR bearing the mutation can specifically rescue the processing of endogenous DeltaF508-CFTR in vivo. cDNA encoding CFTR fragments were delivered to human airway epithelial cells and mice harboring endogenous DeltaF508-CFTR. Delivery of small CFTR fragments, which do not act as chloride channels by themselves, rescue DeltaF508-CFTR. Therefore, we can speculate that the presence of the CFTR fragment, which does not harbor a mutation, might facilitate intermolecular interactions. The rescue of CFTR was evident by the restoration of chloride transport in human CFBE41o- bronchial epithelial cells expressing DeltaF508-CFTR in vitro. More important, nasal administration of an adenovirus expressing a complementary CFTR fragment restored some degree of CFTR activity in the nasal airways of DeltaF508 homozygous mice in vivo. These findings identify complementary protein fragments as a viable in vivo approach for correcting disease-causing misfolding of plasma membrane proteins.
authors.affiliation: Division of Pulmonary Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH 43201, USA. estelle.boyaka@osumc.edu
authors.forename: Estelle
authors.initials: E
authors.lastname: Cormet-Boyaka
authors.forename: Jeong S
authors.initials: JS
authors.lastname: Hong
authors.forename: Bakhram K
authors.initials: BK
authors.lastname: Berdiev
authors.forename: James A
authors.initials: JA
authors.lastname: Fortenberry
authors.forename: Jessica
authors.initials: J
authors.lastname: Rennolds
authors.forename: J P
authors.initials: JP
authors.lastname: Clancy
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Benos
authors.forename: Prosper N
authors.initials: PN
authors.lastname: Boyaka
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sorscher
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D017136:Ion Transport / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology*
chemical_list: D002712:Chlorides; D010446:Peptide Fragments; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator