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Article Dans Une Revue American Journal of Pathology Année : 2008

Cystic fibrosis transmembrane conductance regulator controls lung proteasomal degradation and nuclear factor-κB activity in conditions of oxidative stress

Résumé

Cystic fibrosis is a lethal inherited disorder caused by mutations in a single gene encoding the cystic fibrosis transmembrane conductance regulator (CFrR) protein, resulting in progressive oxidative lung damage. in this study, we evaluated the role of CFrR in the control of ubiquitin-proteasome activity and nuclear factor (NF)-kappa B/I kappa B-alpha signaling after lung oxidative stress. After a 64-hour exposure to hyperoxia-mediated oxidative stress, MR-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-kappa B inhibitor I kappa B-alpha. In vitro, human MR-deficient lung cells exposed to oxidative stress exhibited increased proteasomal activity and decreased NF-kappa B-dependent transcriptional activity compared with CFTR-sufficient lung cells. Inhibition of the CFIR Cl- channel by CFTRinh-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-kappa B 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-kappa B activity in conditions of oxidative stress.

Dates et versions

hal-02410539 , version 1 (13-12-2019)

Identifiants

Citer

Emilie Boncoeur, Telma Roque, Elise Bonvin, Vinciane Saint-Criq, Monique Bonora, et al.. Cystic fibrosis transmembrane conductance regulator controls lung proteasomal degradation and nuclear factor-κB activity in conditions of oxidative stress. American Journal of Pathology, 2008, 172 (5), pp.1184-1194. ⟨10.2353/ajpath.2008.070310⟩. ⟨hal-02410539⟩
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