Cystic Fibrosis Transmembrane Conductance Regulator Controls Lung Proteasomal Degradation and Nuclear Factor-κB Activity in Conditions of Oxidative Stress
Copyright policy )Cystic Fibrosis Transmembrane Conductance Regulator Controls Lung Proteasomal Degradation and Nuclear Factor-κB 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.
- Université Libre de Bruxelles Belgium
- Inserm France
- French Institute of Health and Medical Research France
- Sorbonne University France
- Sorbonne Paris Cité France
Proteasome Endopeptidase Complex, I-kappa B Kinase -- metabolism, Caspase 3 -- antagonists & inhibitors -- metabolism, Knockout, Cystic Fibrosis Transmembrane Conductance Regulator, Proteasome Endopeptidase Complex -- physiology, Cell Line, Mice, Epithelial Cells -- metabolism, Lung -- cytology -- metabolism, NF-kappa B -- metabolism, Cystic Fibrosis Transmembrane Conductance Regulator -- genetics -- physiology, Animals, Humans, Lung, Mice, Knockout, Caspase 3, NF-kappa B, Ubiquitination, Epithelial Cells, Sciences bio-médicales et agricoles, Caspase Inhibitors, I-kappa B Kinase, [SDV] Life Sciences [q-bio], Oxidative Stress
Proteasome Endopeptidase Complex, I-kappa B Kinase -- metabolism, Caspase 3 -- antagonists & inhibitors -- metabolism, Knockout, Cystic Fibrosis Transmembrane Conductance Regulator, Proteasome Endopeptidase Complex -- physiology, Cell Line, Mice, Epithelial Cells -- metabolism, Lung -- cytology -- metabolism, NF-kappa B -- metabolism, Cystic Fibrosis Transmembrane Conductance Regulator -- genetics -- physiology, Animals, Humans, Lung, Mice, Knockout, Caspase 3, NF-kappa B, Ubiquitination, Epithelial Cells, Sciences bio-médicales et agricoles, Caspase Inhibitors, I-kappa B Kinase, [SDV] Life Sciences [q-bio], Oxidative Stress
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