Functional rescue of DeltaF508-CFTR by peptides designed to mimic sorting motifs.
The cystic fibrosis (CF)-causing mutant, deltaF508-CFTR, is misfolded and fails to traffic out of the endoplasmic reticulum (ER) to the cell surface. Introduction of second site mutations that disrupt a diarginine (RXR)-based ER retention motif in the first nucleotide binding domain rescues the trafficking defect of deltaF508-CFTR, supporting a role for these motifs in mediating ER retention of the major mutant. To determine if these RXR motifs mediate retention of the native deltaF508-CFTR protein in situ, we generated peptides that mimic these motifs and should antagonize mistrafficking mediated via their aberrant exposure. Here we show robust rescue of deltaF508-CFTR in cell lines and in respiratory epithelial tissues by transduction of RXR motif-mimetics, showing that abnormal accessibility of this motif is a key determinant of mistrafficking of the major CF-causing mutant.
Kim Chiaw
Patrick
P
Research Institute, Hospital for Sick Children, University of Toronto, ON, Canada.
Huan
Ling-Jun
LJ
Gagnon
Stephane
S
Ly
Diane
D
Sweezey
Neil
N
Rotin
Daniela
D
Deber
Charles M
CM
Bear
Christine E
CE
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000378:metabolism
D050505:Mutant Proteins; D010455:Peptides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator