STARD3/STARD3NL and VAP make a novel molecular tether between late endosomes and the ER

Abstract

Inter-organelle membrane contacts sites (MCSs) are specific subcellular regions favoring the exchange of metabolites and information. Here, we investigated the potential role of the late-endosomal membrane-anchored proteins STARD3 (StAR related lipid transfer domain-3) and STARD3NL (STARD3 N-terminal like) in the formation of MCSs involving late-endosomes (LE). We demonstrate that both STARD3 and STARD3NL create MCSs between LE and the endoplasmic reticulum (ER). STARD3 and STARD3NL use a conserved two phenylalanines in an acidic tract (FFAT)-motif to interact with ER-anchored VAP proteins. Together, they form an LE-ER tethering complex allowing heterologous membrane apposition. Of interest, this LE-ER tethering complex affects organelles dynamics by altering the formation of endosomal tubules. In situ proximity ligation assay between STARD3, STARD3NL and VAP proteins marked endogenous LE-ER MCS. Thus, we report here novel molecular actors of inter-organellar interaction.