Cystic fibrosis transmembrane conductance regulator can export hyaluronan.
OBJECTIVE
Hyaluronan, a major water binding component of the extracellular matrix, is synthesised within the cytosol and exported across the plasma membrane by the ABC-transporter MRP5 in fibroblasts. Although its synthesis is vital for embryogenesis, MRP5-deficient mice are without phenotype, suggesting that another transporter had substituted for the MRP5 protein. Thus, we searched for a compensatory exporter in fibroblasts from MRP5 deficient mice and found that cystic fibrosis transmembrane conductance regulator (CFTR) mRNA was upregulated.


METHODS
Hyaluronan export was measured in cell culture. The CFTR transporter was knocked out using si-RNA. Blockers of the ABC-transporter family were used to ascertain the hyaluronan transport capabilities functionally.


RESULTS
CFTR specific siRNA inhibited hyaluronan export. The tetrasaccharide was exported in undegraded form only from normal human epithelial cells and not from human epithelial cells carrying DeltaF508 CFTR. The CFTR inhibitors GlyH-101 and CFTR(172) reduced hyaluronan export from CFTR-expressing mouse fibroblasts and from human breast cancer cell lines. Bronchial secretions from patients with cystic fibrosis that consist mainly of necrotic epithelia contained at least 40-fold higher concentration of hyaluronan than secretions from patients with acute bronchitis.


CONCLUSIONS
CFTR transports hyaluronan across the plasma membrane of epithelial cells and this transport mechanism is defective in cystic fibrosis patients.
Schulz
Tobias
T
Münster University Hospital, Institute of Physiological Chemistry and Pathobiochemistry, Münster, Germany.
Schumacher
Udo
U
Prante
Christian
C
Sextro
Wolfgang
W
Prehm
Peter
P
D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D006820:Hyaluronic Acid; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C492376:Abcc5 protein, mouse