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

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.

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

“…We note that although the mechanism by which C99 translocates to ER‐MAM is unknown, recent work has demonstrated the existence of ER‐endosome contacts (Rowland et al , 2014) where lipid and protein exchange may occur (Wilhelm et al , 2017). Thus, it is possible that C99 is delivered to ER via a similar mechanism, where it regulates the interaction between ER and mitochondria.…”

Emerging Roles for the Lysosome in Lipid Metabolism

“…The STAR Related Lipid Transfer Domain-3 (STARD-3) protein, also known as MLN-64, localizes to the LE/LY membrane and is thought to interact with VAPA/B on the ER membranes (Alpy et al, 2013, Tsujishita and Hurley, 2000). Overexpressing STARD-3/MLN-64 is sufficient to enhance the contacts between LE/LY and ER in a VAP-dependent manner, and to enhance cholesterol transfer in the ER-to-lysosome direction (Alpy et al, 2013, Wilhelm et al, 2017). Interestingly, STARD-3/MLN-64 was also shown to transfer cholesterol from LE/LY to mitochondria, providing the precursor for steroid hormones synthesized in the mitochondria (Charman et al, 2010).…”

Myristoylated methionine sulfoxide reductase A is a late endosomal protein

“…Myristoylated msrA is anchored to the late endosome by interaction with STARD3, an interaction initially detected with a protein array of human proteins. STARD3 is anchored in the membrane of late endosomes and functions to transfer lipids between organelles, notably cholesterol from the endoplasmic reticulum into late endosomes (36)(37)(38). The interaction of STARD3 and myristoylated msrA clarifies the role of myristoylation of msrA and broadens the possible in vivo functions of msrA.…”