Endocytosis is enhanced in Tangier fibroblasts: possible role of ATP-binding cassette protein A1 in endosomal vesicular transport.
A human genetic disorder, Tangier disease, has been linked recently to mutations in ATP-binding cassette protein A1 (ABCA1). In addition to its function in apoprotein A-I-mediated lipid removal, ABCA1 was also shown to be a phosphatidylserine (PS) translocase that facilitates PS exofacial flipping. This PS translocation is crucial for the plasma membrane to produce protrusions enabling the engulfment of apoptotic cells. In this report, we show that ABCA1 also plays a role in endocytosis. Receptor-mediated endocytosis, probed by both transferrin and low density lipoprotein, is up-regulated by more than 50% in homozygous Tangier fibroblasts in comparison with controls. Fluid-phase uptake is increased similarly. We also demonstrate that bulk membrane flow, including lipid endocytosis and exocytosis, is accelerated greatly in Tangier cells. Moreover, endocytosis is similarly enhanced in normal fibroblasts when ABCA1 function is inhibited by glyburide, whereas glyburide has no effect on endocytosis in Tangier cells. In addition, we demonstrate a decreased annexin V binding in Tangier fibroblasts as compared with controls, supporting the notion that PS transmembrane distribution is indeed defective in the presence of ABCA1 mutations. Furthermore, adding a PS analog to the exofacial leaflet of the plasma membrane normalizes endocytosis in Tangier cells. Taken together, these data demonstrate that ABCA1 plays an important role in endocytosis. We speculate that this is related to the PS translocase function of ABCA1. A loss of functional ABCA1, as in the case of Tangier cells, enhances membrane inward bending and facilitates endocytosis.
Zha
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Lipoprotein and Atherosclerosis Group, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada.
Genest
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McPherson
R
R
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017304:Annexin A5 / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D010718:Phosphatidylserines / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D013631:Tangier Disease / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014168:Transferrin / Q000378:metabolism; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D017304:Annexin A5; D007004:Hypoglycemic Agents; D008077:Lipoproteins, LDL; D010718:Phosphatidylserines; D014168:Transferrin; D005905:Glyburide