Is CFTR-delF508 Really Absent from the Apical Membrane of the Airway Epithelium?
Open Access
- 3 August 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (8), e23226
- https://doi.org/10.1371/journal.pone.0023226
Abstract
Understanding where mutant CFTR is localised in airway epithelia is essential in guiding the best therapeutic approach to correct the dysfunction of the CFTR protein. The widely held paradigm is that CF patients harbouring the commonest mutation, CFTR-delF508, trap CFTR within the endoplasmic reticulum and target it for degradation. However there are conflicting reports concerning expression and localisation of CFTR-delF508 in lung tissue. To attempt to resolve this fundamental issue we developed a novel approach to measure CFTR-delF508 in the lower airways of patients who have undergone lung transplantation for advanced CF. By sampling CF and non-CF epithelium simultaneously from the same individual, confounding factors of different airway microenvironments which may have influenced previous observations can be overcome. Epithelia sampled by bronchial brushing above (CF) and below (non-CF) the bronchial anastomosis were stained for CFTR and the localisation and level of expression assessed (n = 12). There was no significant difference in the proportion of tall columnar cells showing CFTR immunostaining as a discrete band at the apical membrane in cells harbouring the CFTR-delF508 mutation compared to non-CF cells (p = 0.21, n = 12). However, the amount of CFTR expressed at the apical surface was reduced by ∼50% in CF cells compared to non-CF cells (p = 0.04, n = 5). Our novel observation challenges the prevailing paradigm that CFTR is essentially absent from the apical membrane of respiratory cells harbouring the CFTR-delF508 mutation. Moreover, it raises the possibility that the new generation of CFTR potentiators may offer a realistic therapeutic option for CF patients.Keywords
This publication has 35 references indexed in Scilit:
- Cystic fibrosisThe Lancet, 2009
- Low temperature induces the delivery of mature and immature CFTR to the plasma membraneBiochemical and Biophysical Research Communications, 2008
- CFTR localization in native airway cells and cell lines expressing wild-type or F508del-CFTR by a panel of different antibodies.Journal of Histochemistry & Cytochemistry, 2004
- Applicability of Different Antibodies for Immunohistochemical Localization of CFTR in Sweat Glands from Healthy Controls and from Patients with Cystic FibrosisJournal of Histochemistry & Cytochemistry, 2000
- Cystic Fibrosis F508del Patients Have Apically Localized CFTR in a Reduced Number of Airway CellsLaboratory Investigation, 2000
- ΔF508 CFTR protein expression in tissues from patients with cystic fibrosisJCI Insight, 1999
- Evidence for Periciliary Liquid Layer Depletion, Not Abnormal Ion Composition, in the Pathogenesis of Cystic Fibrosis Airways DiseaseCell, 1998
- Cystic fibrosisThe Lancet, 1998
- Differential Localization of the Cystic Fibrosis Transmembrane Conductance Regulator in Normal and Cystic Fibrosis Airway EpitheliumAmerican Journal of Respiratory Cell and Molecular Biology, 1992
- Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitiveNature, 1992