Induction of HSP70 promotes DeltaF508 CFTR trafficking.
The DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) is a temperature-sensitive trafficking mutant that is detected as an immature 160-kDa form (band B) in gel electrophoresis. The goal of this study was to test the hypothesis that HSP70, a member of the 70-kDa heat shock protein family, promotes DeltaF508 CFTR processing to the mature 180-kDa form (band C). Both pharmacological and genetic techniques were used to induce HSP70. IB3-1 cells were treated with sodium 4-phenylbutyrate (4PBA) to promote maturation of DeltaF508 CFTR to band C. A dose-dependent increase in band C and total cellular HSP70 was observed. Under these conditions, HSP70-CFTR complexes were increased and 70-kDa heat shock cognate protein-CFTR complexes were decreased. Increased DeltaF508 CFTR maturation was also seen after transfection with an HSP70 expression plasmid and exposure to glutamine, an inducer of HSP70. With immunofluorescence techniques, the increased appearance of CFTR band C correlated with CFTR distribution beyond the perinuclear regions. These data suggest that induction of HSP70 promotes DeltaF508 CFTR maturation and trafficking.
Choo-Kang
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LR
Eudowood Division of Pediatric Respiratory Sciences, Department of Pediatrics, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-2533, USA.
Zeitlin
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PL
D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005973:Glutamine / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000494:pharmacology*; D006801:Humans; D008970:Molecular Weight; D009154:Mutation; D010654:Phenylbutyrates / Q000378:metabolism / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014018:Tissue Distribution
C505032:CFTR protein, human; D018840:HSP70 Heat-Shock Proteins; D010654:Phenylbutyrates; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D005973:Glutamine; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C075773:4-phenylbutyric acid