title: Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling.
abstract: Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) that affect protein structure and channel function. CFTR, localized in the apical membrane within cholesterol and sphingomyelin rich regions, is an ABC transporter that functions as a chloride channel. Here, we report that expression of defective CFTR (DeltaF508CFTR or decreased CFTR) in human lung epithelial cell lines increases sphingolipid synthesis and mass of sphinganine, sphingosine, four long-chain saturated ceramide species, C16 dihydroceramide, C22, C24, C26-ceramide, and sphingomyelin, and decreases mass of C18 and unsaturated C18:1 ceramide species. Decreased expression of CFTR is associated with increased expression of long-chain base subunit 1 of serine-palmitoyl CoA, the rate-limiting enzyme of de novo sphingolipid synthesis and increased sphingolipid synthesis. Overexpression of DeltaF508CFTR in bronchoalveolar cells that do not express CFTR increases sphingolipid synthesis and mass, whereas overexpression of wild-type CFTR, but not of an unrelated ABC transporter, ABCA7, decreases sphingolipid synthesis and mass. The data are consistent with a model in which CFTR functions within a feedback system that affects sphingolipid synthesis and in which increased sphingolipid synthesis could reflect a physiological response to sequestration of sphingolipids or altered membrane structure.
authors.affiliation: Department of Pathology, Columbia University, New York, NY 10032, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hamai
authors.forename: Fannie
authors.initials: F
authors.lastname: Keyserman
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Quittell
authors.forename: Tilla S
authors.initials: TS
authors.lastname: Worgall
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D009154:Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D051102:Serine C-Palmitoyltransferase / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000096:biosynthesis / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: C505032:CFTR protein, human; D002518:Ceramides; D011994:Recombinant Proteins; D013107:Sphingolipids; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C487784:SPTLC1 protein, human; D051102:Serine C-Palmitoyltransferase