Title: Arsenic promotes ubiquitinylation and lysosomal degradation of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels in human airway epithelial cells.
Authors: Bomberger, Jennifer M; Coutermarsh, Bonita A; Barnaby, Roxanna L; Stanton, Bruce A
Published In J Biol Chem, (2012 May 18)
Abstract: Arsenic exposure significantly increases respiratory bacterial infections and reduces the ability of the innate immune system to eliminate bacterial infections. Recently, we observed in the gill of killifish, an environmental model organism, that arsenic exposure induced the ubiquitinylation and degradation of cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is essential for the mucociliary clearance of respiratory pathogens in humans. Accordingly, in this study, we tested the hypothesis that low dose arsenic exposure reduces the abundance and function of CFTR in human airway epithelial cells. Arsenic induced a time- and dose-dependent increase in multiubiquitinylated CFTR, which led to its lysosomal degradation, and a decrease in CFTR-mediated chloride secretion. Although arsenic had no effect on the abundance or activity of USP10, a deubiquitinylating enzyme, siRNA-mediated knockdown of c-Cbl, an E3 ubiquitin ligase, abolished the arsenic-stimulated degradation of CFTR. Arsenic enhanced the degradation of CFTR by increasing phosphorylated c-Cbl, which increased its interaction with CFTR, and subsequent ubiquitinylation of CFTR. Because epidemiological studies have shown that arsenic increases the incidence of respiratory infections, this study suggests that one potential mechanism of this effect involves arsenic-induced ubiquitinylation and degradation of CFTR, which decreases chloride secretion and airway surface liquid volume, effects that would be proposed to reduce mucociliary clearance of respiratory pathogens.
PubMed ID: 22467879
MeSH Terms: Arsenic/adverse effects; Arsenic/pharmacology*; Cell Line; Chlorides/metabolism; Cystic Fibrosis Transmembrane Conductance Regulator/genetics; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism*; Dose-Response Relationship, Drug; Epithelial Cells/metabolism*; Gene Knockdown Techniques; Humans; Ion Transport/drug effects; Ion Transport/genetics; Proteolysis/drug effects*; Proto-Oncogene Proteins c-cbl/genetics; Proto-Oncogene Proteins c-cbl/metabolism; Respiratory Mucosa/metabolism*; Respiratory Tract Infections/chemically induced; Respiratory Tract Infections/epidemiology; Respiratory Tract Infections/metabolism; Time Factors; Ubiquitin Thiolesterase/genetics; Ubiquitin Thiolesterase/metabolism; Ubiquitination/drug effects*; Ubiquitination/genetics