Environmentally relevant levels of arsenic promotes c‐Cbl‐mediated lysosomal degradation of CFTR in polarized human airway epithelial cells

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a cyclic AMP‐regulated Cl channel that maintains airway surface liquid and mucociliary clearance in the airway. Endocytic trafficking of the channel is critical in regulating CFTR apical membrane abundance and function in Cl secretion. Many studies report an increased incidence of respiratory infection in patients with chronic arsenic exposure. We hypothesized that chronic arsenic exposure reduces the expression and function of CFTR in human airway epithelial cells, thus reducing innate immune defense in the lung. We report that low dose arsenic exposure promoted a time and dose‐dependent decrease in CFTR protein expression and function in airway epithelial cells. Arsenic exposure promoted endocytosis of CFTR and induced a time and dose‐dependent increase in the multi‐ubiquitination of CFTR, concurrent with the arsenic‐mediated lysosomal degradation of CFTR. To determine the mechanism by which arsenic down‐regulates CFTR, we targeted two proteins previously published to regulate the ubiquitination status and endocytic trafficking of CFTR, the deubiquitinating enzyme USP10 and the E3 ligase c‐Cbl. While arsenic treatment had no effect on the abundance or activity of USP10, siRNA‐mediated knockdown of c‐Cbl abolished the arsenic‐stimulated degradation of CFTR. This work demonstrates that arsenic promotes the c‐Cbl‐mediated ubiquitination and lysosomal degradation of CFTR and reduction in CFTR‐dependent chloride secretion, suggesting a reduction in mucociliary clearance and innate immune defenses in the lungs of persons with chronic arsenic exposure.