Annexin A5 increases the cell surface expression and the chloride channel function of the DeltaF508-cystic fibrosis transmembrane regulator.
Cystic fibrosis (CF) is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In CF, the most common mutant DeltaF508-CFTR is misfolded, is retained in the ER and is rapidly degraded. If conditions could allow DeltaF508-CFTR to reach and to stabilize in the plasma membrane, it could partially correct the CF defect. We have previously shown that annexin V (anxA5) binds to both the normal CFTR and the DeltaF508-CFTR in a Ca(2+)-dependent manner and that it regulates the chloride channel function of Wt-CFTR through its membrane integration. Our aim was to extend this finding to the DeltaF508-CFTR. Because some studies show that thapsigargin (Tg) increases the DeltaF508-CFTR apical expression and induces an increased [Ca(2+)](i) and because anxA5 relocates and binds to the plasma membrane in the presence of Ca(2+), we hypothesized that the Tg effect upon DeltaF508-CFTR function could involve anxA5. Our results show that raised anxA5 expression induces an augmented function of DeltaF508-CFTR due to its increased membrane localization. Furthermore, we show that the Tg effect involves anxA5. Therefore, we suggest that anxA5 is a potential therapeutic target in CF.
Le Drévo
Marie-Anne
MA
Inserm, U613, Brest, F-29200, France.
Benz
Nathalie
N
Kerbiriou
Mathieu
M
Giroux-Metges
Marie-Agnès
MA
Pennec
Jean-Pierre
JP
Trouvé
Pascal
P
Férec
Claude
C
D017304:Annexin A5 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D009154:Mutation; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection
D017304:Annexin A5; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019284:Thapsigargin; D000242:Cyclic AMP; D002118:Calcium