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Cystic fibrosis transmembrane conductance regulator (CFTR) functionality is dependent on coatomer protein I (COPI)


Cystic fibrosis transmembrane conductance regulator (CFTR) functionality is dependent on coatomer protein I (COPI)



Biology of the Cell 99(8): 433-444



ISSN/ISBN: 0248-4900

PMID: 17388782

DOI: 10.1042/bc20060114

Cystic fibrosis results from mutations in the ABC transporter CFTR (cystic fibrosis transmembrane conductance regulator), which functions as a cAMP-regulated anion channel. The most prevalent mutation in CFTR, the Phe(508) deletion, results in the generation of a trafficking and functionally deficient channel. The cellular machineries involved in modulating CFTR trafficking and function have not been fully characterized. In the present study, we identified a role for the COPI (coatomer protein I) cellular trafficking machinery in the development of the CFTR polypeptide into a functional chloride channel. To examine the role of COPI in CFTR biosynthesis, we employed the cell line ldlF, which harbours a temperature-sensitive mutation in epsilon-COP, a COPI subunit, to inhibit COPI function and then determined whether the CFTR polypeptide produced from the transfected gene developed into a cAMP-regulated chloride channel. When COPI was inactivated in the ldlF cells by an elevated temperature pulse (39 degrees C), the CFTR polypeptide was detected on the cell surface by immunofluorescence microscopy and cell-surface biotinylation. Therefore, CFTR proceeded upstream in the secretory pathway in the absence of COPI function, a result demonstrated previously by others. In contrast, electrophysiological measurements indicated an absence of cAMP-stimulated chloride efflux, suggesting that channel function was impaired. In comparison, expression of CFTR at the same elevated temperature (39 degrees C) in an epsilon-COP-rescued cell line [ldlF(ldlF)], which has an introduced wild-type epsilon-COP gene in addition to the mutant epsilon-COP gene, showed restoration of cAMP-stimulated channel activity, confirming the requirement of COPI for channel function. These results therefore suggest that generation of the folded-functional conformation of CFTR requires COPI.

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Accession: 015427607

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