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Papers In Press, published online ahead of print January 16, 2006
Physiology Dept., University of Pennsylvania, Philadelphia, PA 19104-6068
Corresponding Author: shuman{at}mail.med.upenn.edu
Members of the ATP binding cassette (ABC) protein superfamily actively transport a wide range of substrates across cell and intracellular membranes. Mutations in ABCA3, a member of the ABCA subfamily with unknown function, lead to fatal respiratory distress syndrome (RDS) in the newborn. Using cultured human lung cells, we found that recombinant wild type hABCA3 localized to both lysosomes and lamellar bodies, which are the intracellular storage organelles for surfactant. In contrast, hABCA3 with mutations linked to RDS failed to target to lysosomes and remained in the ER as unprocessed forms. Treatment of those cells with the chemical chaperone sodium 4-phenylbutyrate partially could restored trafficking of mutant ABCA3 to lamellar body-like structures. Expression of recombinant ABCA3 in non-lung HEK293 cells induced formation of lamellar body-like vesicles that contained lipids. siRNA knockdown of endogenous hABCA3 in differentiating human fetal lung alveolar type II cells resulted in abnormal lamellar bodies comparable to those observed in vivo with mutant ABCA3. Silencing of ABCA3 expression also reduced vesicular uptake of surfactant lipids phosphatidylcholine, sphingomyelin and cholesterol but not phosphatidylethanolamine. We conclude that ABCA3 is required for lysosomal loading of phosphatidylcholine and conversion of lysosomes to lamellar body-like structures.
J. Biol. Chem, 10.1074/jbc.M507515200
Submitted on July 12, 2005
Accepted on January 13, 2006
Functional and trafficking defects in ABCA3 mutants associated with respiratory distress syndrome
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