STARD3 mediates endoplasmic reticulum‐to‐endosome cholesterol transport at membrane contact sites

• Léa P Wilhelm ^[5] ; Corinne Wendling ^[5] ; Benoît Védie ^[1] ; Toshihide Kobayashi ^[2] ; Marie‐Pierre Chenard ^[3] ; Catherine Tomasetto ^[5] ; Guillaume Drin ^[4] ; Fabien Alpy ^[5]
  1. [1] Hôpital Européen Georges-Pompidou

     Hôpital Européen Georges-Pompidou

     París, Francia

     
  2. [2] University of Strasbourg

     University of Strasbourg

     Arrondissement de Strasbourg-Ville, Francia

     
  3. [3] Institute of Genetics and Molecular and Cellular Biology

     Institute of Genetics and Molecular and Cellular Biology

     Arrondissement de Strasbourg-Campagne, Francia

     
  4. [4] Université Côte d'Azur

     Université Côte d'Azur

     Arrondissement de Grasse, Francia

     
  5. [5] 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

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 36, Nº. 10, 2017, págs. 1412-1433
• Idioma: inglés
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  • 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.