Interplay between Asters/GRAMD1s and phosphatidylserine in intermembrane transport of LDL cholesterol

Significance Cholesterol constitutes 50% of lipids in the plasma membrane (PM) of animal cells. Sensors in the endoplasmic reticulum (ER) maintain this level by adjusting cholesterol uptake, synthesis, and storage. Uptake is mediated by LDL receptors, which deliver cholesterol-carrying LDL to lysosomes from which cholesterol moves to the PM and then to the ER. We report PM-to-ER transport of LDL cholesterol requires cholesterol-binding Aster proteins anchored to the ER and phosphatidylserine embedded in the PM. Asters are known to bind phosphatidylserine, and this accounts for part of the phosphatidylserine requirement. However, the current data suggest an additional requirement for phosphatidylserine independent of Asters. These data advance our knowledge of PM cholesterol homeostasis, a control mechanism essential for cell growth and survival.