Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat.
In the disease cystic fibrosis (CF), the most common mutation delF508 results in endoplasmic reticulum retention of misfolded CF gene proteins (CFTR). We show that the alpha-1,2-glucosidase inhibitor miglustat (N-butyldeoxynojirimycin, NB-DNJ) prevents delF508-CFTR/calnexin interaction and restores cAMP-activated chloride current in epithelial CF cells. Moreover, miglustat rescues a mature and functional delF508-CFTR in the intestinal crypts of ileal mucosa from delF508 mice. Since miglustat is an orally active orphan drug (Zavesca) prescribed for the treatment of Gaucher disease, our findings provide the basis for future clinical evaluation of miglustat in CF patients.
Norez
Caroline
C
Institut de Physiologie et Biologie Cellulaires, CNRS UMR 6187, Université de Poitiers, 40 avenue du recteur Pineau, Poitiers 86022, France. cnorez@ext.univ-poitiers.fr
Noel
Sabrina
S
Wilke
Martina
M
Bijvelds
Marcel
M
Jorna
Huub
H
Melin
Patricia
P
DeJonge
Hugo
H
Becq
Frederic
F
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D037281:Calnexin / Q000378:metabolism; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology; D051379:Mice; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
D065089:Glycoside Hydrolase Inhibitors; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D037281:Calnexin; D017485:1-Deoxynojirimycin; C059896:miglustat