|Wild-type, but not ΔF508 CFTR, inhibits the proteolysis of ENaC by matriptase.
Mutations in the cystic fibrosis transmembrane conductance regulator that prevent its proper folding and trafficking to the cell membrane are the cause of cystic fibrosis, which is characterized by poorly hydrated airway surfaces and difficulty breathing due to defective chloride secretion. In addition to defective Cl− export, CF airway cells also undergo excessive Na+ absorption, which exacerbates these conditions. However, the molecular link between missing CFTR and increased Na+ absorption has remained elusive; evidence implicates hyperactivity of the epithelial Na+ channel, though some suggest that such findings merely are electrophysiological or expression-related artifacts. In this study, the authors confirm that ENaC and CFTR physically interact and also show that wild-type CFTR protects ENaC from proteolytic cleavage and stimulation of open probability; in contrast, the common CF mutant ΔF508 failed to protect ENaC from proteolytic cleavage and stimulation. The authors followed up these observations in Xenopus oocytes with studies in human-airway epithelia, finding that ENaC associates with the anti-CFTR immune precipitate in healthy cells, whereas in CF cultures, the proportion of full-length ENaC protein was reduced consistently. This study provides solid evidence for a potential mechanism for CFTR-dependent down-regulation of Na+ absorption, which may help resolve the outstanding debate.
The Cystic Fibrosis Transmembrane Conductance Regulator Impedes Proteolytic Stimulation of the Epithelial Na+ Channel
Martina Gentzsch, Hong Dang, Yan Dang, Agustin Garcia-Caballero, Hamsa Suchindran, Richard C. Boucher and M. Jackson Stutts
J. Biol. Chem., published online Aug. 13, 2010
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