Abstract
Cystic fibrosis (CF) is most frequently associated with deletion of phenylalanine at position 508 (ΔF508) in the CF transmembrane conductance regulator (CFTR) protein. The ΔF508-CFTR mutant protein exhibits a folding defect that affects its processing and impairs chloride-channel function. This study aimed to determine whether CFTR fragments approximately half the size of wild-type CFTR and complementary to the portion of CFTR bearing the mutation can specifically rescue the processing of endogenous ΔF508-CFTR in vivo. cDNA encoding CFTR fragments were delivered to human airway epithelial cells and mice harboring endogenous ΔF508-CFTR. Delivery of small CFTR fragments, which do not act as chloride channels by themselves, rescue ΔF508-CFTR. Therefore, we can speculate that the presence of the CFTR fragment, which does not harbor a mutation, might facilitate intermolecular interactions. The rescue of CFTR was evident by the restoration of chloride transport in human CFBE41o- bronchial epithelial cells expressing ΔF508-CFTR in vitro. More important, nasal administration of an adenovirus expressing a complementary CFTR fragment restored some degree of CFTR activity in the nasal airways of ΔF508 homozygous mice in vivo. These findings identify complementary protein fragments as a viable in vivo approach for correcting disease-causing misfolding of plasma membrane proteins.
Original language | English |
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Pages (from-to) | 3743-3751 |
Number of pages | 9 |
Journal | FASEB Journal |
Volume | 23 |
Issue number | 11 |
DOIs | |
Publication status | Published - 2009 |
Keywords
- Cystic fibrosis
- In vivo rescue
- Processing
- Transcomplementation
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics