title: Deletion of the ubiquitin ligase Nedd4L in lung epithelia causes cystic fibrosis-like disease.
abstract: Cystic fibrosis is caused by impaired ion transport due to mutated cystic fibrosis transmembrane conductance regulator, accompanied by elevated activity of the amiloride-sensitive epithelial Na(+) channel (ENaC). Here we show that knockout of the ubiquitin ligase Nedd4L (Nedd4-2) specifically in lung epithelia (surfactant protein C-expressing type II and Clara cells) causes cystic fibrosis-like lung disease, with airway mucus obstruction, goblet cell hyperplasia, massive inflammation, fibrosis, and death by three weeks of age. These effects of Nedd4L loss are likely caused by enhanced ENaC function, as reflected by increased ENaC protein levels, increased lung dryness at birth, amiloride-sensitive dehydration of lung explants, and elevated ENaC currents in primary alveolar type II cells analyzed by patch clamp recordings. Moreover, the lung defects were rescued with administration of amiloride into the lungs of young knockout pups via nasal instillation. Our results therefore suggest that the ubiquitin ligase Nedd4L can suppress the onset of cystic fibrosis symptoms by inhibiting ENaC in lung epithelia.
authors.affiliation: Departments of Biochemistry and Physiology, The Hospital for Sick Children, Programs in Cell Biology and Neuroscience and Mental Health, and University of Toronto, Toronto, ON, Canada M5G 1X8.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawabe
authors.forename: Chong
authors.initials: C
authors.lastname: Jiang
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
authors.forename: Yun-Yan
authors.initials: YY
authors.lastname: Xiang
authors.forename: Chen
authors.initials: C
authors.lastname: Lu
authors.forename: Michael W
authors.initials: MW
authors.lastname: Salter
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Lu
authors.forename: Daniela
authors.initials: D
authors.lastname: Rotin
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D003550:Cystic Fibrosis / Q000209:etiology* / Q000473:pathology; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels / Q000032:analysis; D004848:Epithelium / Q000201:enzymology*; D017353:Gene Deletion; D008168:Lung / Q000166:cytology*; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D018408:Patch-Clamp Techniques; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; D000584:Amiloride; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases