STARD3 mediates endoplasmic reticulum‐to‐endosome cholesterol transport at membrane contact sites |
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Authors: | Léa P Wilhelm Corinne Wendling Benoît Védie Toshihide Kobayashi Marie‐Pierre Chenard Catherine Tomasetto Guillaume Drin Fabien Alpy |
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Institution: | 1. Functional Genomics and Cancer Department, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France;2. Institut National de la Santé et de la Recherche Médicale (INSERM), U 964, Illkirch, France;3. Centre National de la Recherche Scientifique (CNRS), UMR 7104, Illkirch, France;4. Université de Strasbourg, Illkirch, France;5. AP‐HP (Assistance Publique – H?pitaux de Paris), H?pital Européen Georges Pompidou, Service de Biochimie, Paris, France;6. Laboratory of Biophotonics and Pharmacology, Centre National de la Recherche Scientifique (CNRS), UMR 7213, Illkirch, France;7. Service d'Anatomie Pathologique Générale, Centre Hospitalier Universitaire de Hautepierre, Strasbourg, France;8. Université C?te d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France |
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Abstract: | StAR‐related lipid transfer domain‐3 (STARD3) is a sterol‐binding protein that creates endoplasmic reticulum (ER)–endosome contact sites. How this protein, at the crossroad between sterol uptake and synthesis pathways, impacts the intracellular distribution of this lipid was ill‐defined. Here, by using in situ cholesterol labeling and quantification, we demonstrated that STARD3 induces cholesterol accumulation in endosomes at the expense of the plasma membrane. STARD3‐mediated cholesterol routing depends both on its lipid transfer activity and its ability to create ER–endosome contacts. Corroborating this, in vitro reconstitution assays indicated that STARD3 and its ER‐anchored partner, Vesicle‐associated membrane protein‐associated protein (VAP), assemble into a machine that allows a highly efficient transport of cholesterol within membrane contacts. Thus, STARD3 is a cholesterol transporter scaffolding ER–endosome contacts and modulating cellular cholesterol repartition by delivering cholesterol to endosomes. |
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Keywords: | cholesterol endoplasmic reticulum endosome lipid transfer protein membrane contact site |
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