Abstract
ATP-binding-cassette transporter 1 (ABC1) has been implicated in processes related to membrane-lipid turnover. Here, using in vivo loss-of-function and in vitro gain-of-function models, we show that ABC1 promotes Ca2+-induced exposure of phosphatidylserine at the membrane, as determined by a prothrombinase assay, membrane microvesiculation and measurement of transbilayer redistribution of spin-labelled phospholipids. That ABC1 promotes engulfment of dead cells is shown by the impaired ability of ABC1-deficient macrophages to engulf apoptotic preys and by the acquisition of phagocytic behaviour by ABC1 transfectants. Release of membrane phospholipids and cholesterol to apo-AI, the protein core of the cholesterol-shuttling high-density lipoprotein (HDL) particle, is also ABC1-dependent. We propose that both the efficiency of apoptotic-cell engulfment and the efflux of cellular lipids depend on ABC1-induced perturbation of membrane phosphatidylserine turnover. Transient local exposure of anionic phospholipids in the outer membrane leaflet may be sufficient to alter the general properties of the membrane and thus influence discrete physiological functions.
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Acknowledgements
We thank H. Cremer for the pKO vector, Pfizer for support in the generation of ABC1–/– mice, Y. Yamamoto and C. Henderson for help with the whole-mount TUNEL technique, A. LeBivic and S. Meresse for antibodies against giantin, 6C4, Lamp1 and M6PR, S. Granjeaud for help with software, G. Schmitz and W. Drobnik for introducing O.C. to the techniques of lipid effluxes, and J.F. Brunet, P.Golstein, P. Henson and V. Fadok for discussions. P.D. acknowledges the excellent technical assistance of P. Herve and D. Geldwerth during preliminary lipid-scrambling experiments. C.B.and Y.H. were supported by an ARC fellowship. This work was supported by Institutional grants from INSERM and CNRS, and by specific grants from ARC, LLNC and CNRS.
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Hamon, Y., Broccardo, C., Chambenoit, O. et al. ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine.. Nat Cell Biol 2, 399–406 (2000). https://doi.org/10.1038/35017029
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DOI: https://doi.org/10.1038/35017029
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