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

• DOI: 10.15252/embj.201695917
• Publication Date: 2017-04-05T00:18:48Z
• Authors: Léa P Wilhelm; Corinne Wendling; Benoît Védie; Toshihide Kobayashi; Marie‐Pierre Chenard; Catherine Tomasetto; Guillaume Drin; Fabien Alpy
• Keywords: membrane contact site; 0303 health sciences; Cell Membrane; Vesicular Transport Proteins; cholesterol; Membrane Proteins; Biological Transport; lipid transfer protein; [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]; Articles; Endosomes; Endoplasmic Reticulum; endoplasmic reticulum; 03 medical and health sciences; Cholesterol; Humans; Carrier Proteins; endosome; HeLa Cells; Protein Binding

AbstractStAR‐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.