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Functional implications of the influence of ABCA1 on lipid microenvironment at the plasma membrane: a biophysical study

Ana Zarubica^*,1, Anna Pia Plazzo^,1, Martin Stöckl, Tomasz Trombik^*, Yannick Hamon^*, Peter Müller, Thomas Pomorski, Andreas Herrmann and Giovanna Chimini^*,2

^* Centre d’Immunologie de Marseille Luminy, Institut National de la Santè et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de la Méditerranée, Parc Scientifique de Luminy, Marseille, France; and

Institut für Biologie/Biophysik, Humboldt-Universität zu Berlin, Berlin, Germany

²Correspondence: Centre d’Immunologie de Marseille Luminy, Parc Scientifique de Luminy case 906, 13288 Marseille, Cedex 09 France. E-mail: chimini{at}ciml.univ-mrs.fr

The ABCA1 transporter orchestrates cellular lipid homeostasis by promoting the release of cholesterol to plasmatic acceptors. The molecular mechanism is, however, unknown. We report here on the biophysical analysis in living HeLa cells of the ABCA1 lipid microenvironment at the plasma membrane. The modifications of membrane attributes induced by ABCA1 were assessed at both the outer and inner leaflet by monitoring either the lifetime of membrane inserted fluorescent lipid analogues by fluorescence lifetime imaging microscopy (FLIM) or, respectively, the membrane translocation of cationic sensors. Analysis of the partitioning of dedicated probes in plasma membrane blebs vesiculated from these cells allowed visualization of ABCA1 partitioning into the liquid disordered-like phase and corroborated the idea that ABCA1 destabilizes the lipid arrangement at the membrane. Specificity was demonstrated by comparison with cells expressing an inactive transporter. The physiological relevance of these modifications was finally demonstrated by the reduced membrane mobility and function of transferrin receptors under the influence of an active ABCA1. Collectively, these data assess that the control of both transversal and lateral lipid distribution at the membrane is the primary function of ABCA1 and positions the effluxes of cholesterol from cell membranes downstream to the redistribution of the sterol into readily extractable membrane pools.—Zarubica, A., Plazzo, A. P., Stöckl, M., Trombik, T., Hamon, Y., Müller, P., Pomorski, T., Herrmann, A., Chimini, G. Functional implications of the influence of ABCA1 on lipid microenvironment at the plasma membrane: a biophysical study.

Key Words: FLIM • TfR • cholesterol • phosphatidylserine • FRAP