Endosomal cholesterol trafficking: protein factors at a glance

The delivery of low-density lipoprotein-derived cholesterol (LDL-C) from endosomal compartments to the plasma membrane and the endoplasmic reticulum (ER) is an important yet poorly understood cellular process. Niemann-Pick C1 (NPC1), a multi-pass integral membrane protein on the limiting membranes of late endosomes (LE)/lysosomes (Ly), is known to insert lumenal LDL-C to the limiting membrane of LE/Ly. Recent progress has identified novel cytoplasmic proteins that regulate the exit of LDL-C from LE/Ly, such as ORP5, a member of the oxysterol-binding protein-related protein (ORPs) family, and Hrs/VPS27, a well-established regulator of the endosomal sorting complex required for transport pathway. Whereas ORP5/ORPs may serve as cytosolic cholesterol carriers and deliver cholesterol in a non-vesicular manner, how Hrs/VPS27 regulate endosomal cholesterol sorting remains enigmatic. We discuss the functional relationship between NPC1, Hrs, and ORP5, and formulate possible schemes on how LDL-C may be moved from endosomal compartments to other cellular organelles.