A truncated CFTR protein rescues endogenous ΔF508-CFTR and corrects chloride transport in mice

Estelle Cormet-Boyaka, Jeong S. Hong, Bakhram K. Berdiev, James A. Fortenberry, Jessica Rennolds, J. P. Clancy, Dale J. Benos, Prosper N. Boyaka, Eric J. Sorscher

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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 languageEnglish
Pages (from-to)3743-3751
Number of pages9
JournalFASEB Journal
Volume23
Issue number11
DOIs
Publication statusPublished - 2009

Keywords

  • Cystic fibrosis
  • In vivo rescue
  • Processing
  • Transcomplementation

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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