Cystic fibrosis transmembrane conductance regulator controls lung proteasomal degradation and nuclear factor-kappaB activity in conditions of oxidative stress.
Cystic fibrosis is a lethal inherited disorder caused by mutations in a single gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, resulting in progressive oxidative lung damage. In this study, we evaluated the role of CFTR in the control of ubiquitin-proteasome activity and nuclear factor (NF)-kappaB/IkappaB-alpha signaling after lung oxidative stress. After a 64-hour exposure to hyperoxia-mediated oxidative stress, CFTR-deficient (cftr(-/-)) mice exhibited significantly elevated lung proteasomal activity compared with wild-type (cftr(+/+)) animals. This was accompanied by reduced lung caspase-3 activity and defective degradation of NF-kappaB inhibitor IkappaB-alpha. In vitro, human CFTR-deficient lung cells exposed to oxidative stress exhibited increased proteasomal activity and decreased NF-kappaB-dependent transcriptional activity compared with CFTR-sufficient lung cells. Inhibition of the CFTR Cl(-) channel by CFTR(inh-172) in the normal bronchial immortalized cell line 16HBE14o- increased proteasomal degradation after exposure to oxidative stress. Caspase-3 inhibition by Z-DQMD in CFTR-sufficient lung cells mimicked the response profile of increased proteasomal degradation and reduced NF-kappaB activity observed in CFTR-deficient lung cells exposed to oxidative stress. Taken together, these results suggest that functional CFTR Cl(-) channel activity is crucial for regulation of lung proteasomal degradation and NF-kappaB activity in conditions of oxidative stress.
Boncoeur
Emilie
E
INSERM, U719, Paris, France.
Roque
Telma
T
Bonvin
Elise
E
Saint-Criq
Vinciane
V
Bonora
Monique
M
Clement
Annick
A
Tabary
Olivier
O
Henrion-Caude
Alexandra
A
Jacquot
Jacky
J
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D054875:Ubiquitination
D061945:Caspase Inhibitors; D016328:NF-kappa B; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D051550:I-kappa B Kinase; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex