β-estradiol rescues Δ-F508CFTR functional expression in human cystic fibrosis airway CFBE41o^- cells through the up-regulation of NHERF1

Fanelli, T., Cardone, R. A., Favia, M., Guerra, L., Zaccolo, M., Monterisi, S., De Santis, T., Riccardi, S. M., Reshkin, S. J. and Casavola, V. (2008) β-estradiol rescues Δ-F508CFTR functional expression in human cystic fibrosis airway CFBE41o^- cells through the up-regulation of NHERF1. Biology of the Cell, 100(7), pp. 399-412. (doi: 10.1042/BC20070095)

Abstract

Background information Cystic fibrosis (CF) is a disease caused by mutations within the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common mutation, ΔF508, results in a protein that is defective in folding and trafficking to the cell surface but is functional if properly localized in the plasma membrane. We have recently demonstrated that over-expression of the PDZ protein NHERF1 in (Na⁺/H⁺-exchanger regulatory factor 1) CF airway cells induced both a redistribution of ΔF508CFTR from the cytoplasm to the apical membrane and the PKA-dependent activation of ΔF508CFTR-dependent chloride secretion. In view of the potential importance of the targeted up-regulation of NHERF1 in a therapeutic context and since it has been demonstrated that estrogen treatment increases endogenous NHERF1 expression, we tested the hypothesis that the estrogen treatment can increase NHERF1 expression in a human bronchiolar epithelial CF cell line, CFBE41o^-, with a subsequent rescue of apical ΔF508CFTR chloride transport activity. Results: We found that CFBE41o^- cells do express estrogen receptors in the nuclear fraction and that β-estradiol treatment was able to significantly rescue the ΔF508CFTR-dependent chloride secretion in CFBE41o^- cell monolayers, demonstrating that the ΔF508CFTR translocated to the apical membrane can function as a cAMP-responsive channel. Importantly, knock-down of NHERF1 expression by transfection with siRNA for NHERF1 inhibited the β-estradiol-dependent increase of ΔF508CFTR protein expression levels and completely prevented the β-estradiol-dependent rescue of ΔF508CFTR transport activity. Conclusions. These results demonstrate that β-estradiol-dependent up-regulation of NHERF1 significantly increases ΔF508CFTR functional expression in CFBE41o- cells.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Zaccolo, Professor Manuela
• Authors: Fanelli, T., Cardone, R. A., Favia, M., Guerra, L., Zaccolo, M., Monterisi, S., De Santis, T., Riccardi, S. M., Reshkin, S. J., and Casavola, V.
• Subjects: Q Science > QH Natural history > QH301 Biology
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Biology of the Cell
• ISSN: 0248-4900