COPII-dependent export of cystic fibrosis transmembrane conductance regulator from the ER uses a di-acidic exit code.
Cystic fibrosis (CF) is a childhood hereditary disease in which the most common mutant form of the CF transmembrane conductance regulator (CFTR) DeltaF508 fails to exit the endoplasmic reticulum (ER). Export of wild-type CFTR from the ER requires the coat complex II (COPII) machinery, as it is sensitive to Sar1 mutants that disrupt normal coat assembly and disassembly. In contrast, COPII is not used to deliver CFTR to ER-associated degradation. We find that exit of wild-type CFTR from the ER is blocked by mutation of a consensus di-acidic ER exit motif present in the first nucleotide binding domain. Mutation of the code disrupts interaction with the COPII coat selection complex Sec23/Sec24. We propose that the di-acidic exit code plays a key role in linking CFTR to the COPII coat machinery and is the primary defect responsible for CF in DeltaF508-expressing patients.
Wang
Xiaodong
X
Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Matteson
Jeanne
J
An
Yu
Y
Moyer
Bryan
B
Yoo
Jin-San
JS
Bannykh
Sergei
S
Wilson
Ian A
IA
Riordan
John R
JR
Balch
William E
WE
D000818:Animals; D022181:COP-Coated Vesicles / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D014162:Transfection; D014616:Vaccinia virus / Q000235:genetics; D033921:Vesicular Transport Proteins
C505032:CFTR protein, human; D008565:Membrane Proteins; D011506:Proteins; C512739:SEC23A protein, human; D033921:Vesicular Transport Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator