title: c-Cbl reduces stability of rescued ∆F508-CFTR in human airway epithelial cells: Implications for cystic fibrosis treatment.
abstract: CFTR is a PKA activated Cl(-) channel expressed in the apical membrane of fluid transporting epithelia. We previously demonstrated that c-Cbl decreases CFTR stability in the plasma membrane by facilitating its endocytosis and lysosomal degradation in human airway epithelium. The most common mutation associated with cystic fibrosis, deletion of Phe508 (∆F508), leads to a temperature sensitive biosynthetic processing defect in the CFTR protein. Mature ∆F508-CFTR that has been rescued by low temperature or chemical chaperones is partially functional as a Cl(-) channel but has decreased plasma membrane stability due to altered post-maturational trafficking. Our present data demonstrate that c-Cbl controls the post-maturational trafficking of rescued ∆F508-CFTR. Partial depletion of c-Cbl increased stability of the plasma membrane associated mature ∆F508-CFTR and the ∆F508-CFTR mediated Cl(-) secretion. These data indicate that correcting the post-maturational trafficking of ∆F508-CFTR may represent a therapeutic approach complementary to the biosynthetic rescue. Because c-Cbl functions as an adaptor and scaffolding protein during CFTR endocytosis, we propose that interfering with the c-Cbl mediated endocytic recruitment of ∆F508-CFTR may increase stability of ∆508-CFTR in the plasma membrane after its biosynthetic rescue.
authors.affiliation: Department of Nephrology; Children's Hospital of Pittsburgh; Pittsburgh, PA USA.
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Cihil
authors.forename: Andrew
authors.initials: A
authors.lastname: Zimnik
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Swiatecka-Urban
keywords: endocytic adaptor; human airway epithelial cells; post-maturational trafficking; ubiquitin ligase