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NHE-RF1 protein rescues Delta F508-CFTR function

Bossard, F; Robay, A; Toumaniantz, G; Dahimene, S; Becq, F; Merot, J; Gauthier, C; (2007) NHE-RF1 protein rescues Delta F508-CFTR function. AM J PHYSIOL-LUNG C , 292 (5) L1085 - L1094. 10.1152/ajplung.00445.2005.

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Abstract

In cystic fibrosis ( CF), the Delta F508- CFTR anterograde trafficking from the endoplasmic reticulum to the plasma membrane is inefficient. New strategies for increasing the delivery of Delta F508- CFTR to the apical membranes are thus pathophysiologically relevant targets to study for CF treatment. Recent studies have demonstrated that PDZ-containing proteins play an essential role in determining polarized plasma membrane expression of ionic transporters. In the present study we have hypothesized that the PDZ- containing protein NHE-RF1, which binds to the carboxy terminus of CFTR, rescues Delta F508- CFTR expression in the apical membrane of epithelial cells. The plasmids encoding Delta F508- CFTR and NHE- RF1 were intranuclearly injected in A549 or Madin- Darby canine kidney ( MDCK) cells, and Delta F508- CFTR channel activity was functionally assayed using SPQ fluorescent probe. Cells injected with Delta F508- CFTR alone presented a low chloride channel activity, whereas its coexpression with NHE- RF1 significantly increased both the basal and forskolin- activated chloride conductances. This last effect was lost with Delta F508- CFTR deleted of its 13 last amino acids or by injection of a specific NHE- RF1 antisense oligonucleotide, but not by NHE- RF1 sense oligonucleotide. Immunocytochemical analysis performed in MDCK cells transiently transfected with Delta F508- CFTR further revealed that NHE- RF1 specifically determined the apical plasma membrane expression of Delta F508- CFTR but not that of a trafficking defective mutant potassium channel ( KCNQ1). These data demonstrate that the modulation of the expression level of CFTR protein partners, like NHE- RF1, can rescue Delta F508- CFTR activity.

Type: Article
Title: NHE-RF1 protein rescues Delta F508-CFTR function
DOI: 10.1152/ajplung.00445.2005
Keywords: cystic fibrosis, Delta F508 cystic fibrosis transmembrane conductance, regulator, Na+/H+ exchanger regulatory factor isoform 1, polarized expression, traffic, TRANSMEMBRANE-CONDUCTANCE-REGULATOR, PDZ-INTERACTING DOMAIN, A-INDEPENDENT PATHWAY, CYSTIC-FIBROSIS, EPITHELIAL-CELLS, PLASMA-MEMBRANE, MACROMOLECULAR COMPLEXES, ENDOPLASMIC-RETICULUM, AIRWAY EPITHELIA, APICAL MEMBRANE
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1325260
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