The Lipid Transfer Protein STARD3: an Architect from inside the Cell

Abstract

STARD3 [(StAR)‐related lipid transfer domain protein 3] belongs to the START domain protein family, a group of protein having lipid transfer properties. STARD3 is a sterol binding protein located on the limiting membrane of late endosomes, where it is involved in cholesterol transport. Indeed in mammalian cells, high levels of STARD3 are associated with the presence of enlarged endosomes enriched in cholesterol. Using a correlative electron and light microscopy approach, we showed that STARD3 remodels the subcellular architecture. Remarkably, STARD3 ties endosomes with the endoplasmic reticulum. The molecular mechanism of this attachment was solved and relies on the specific interaction between STARD3 and VAP proteins [VAMP‐Associated Proteins (VAP‐A and VAP‐B)]. Altogether our results show that STARD3 and VAP proteins form a novel molecular machinery creating inter‐organelle membrane contacts sites (MCSs), governing the formation of a specific subcellular territory between endosomes and the endoplasmic reticulum. Using in vitro reconstitution, we are able to address the lipid transfer potential of this novel machinery. How STARD3‐made endoplasmic reticulum‐endosomes MCSs control the dynamics of the endosomal compartment will be presented.