The multiple facets of Rab proteins modulating the cellular distribution of cholesterol from the late endosomal compartment.

Cholesterol is an essential lipid that ensures the functional integrity of mammalian cells. Most cells acquire cholesterol via endocytosis of low-density lipoproteins (LDL). Upon reaching late endosomes/lysosomes (LE/Lys), incoming ligands, including LDL-derived cholesterol, are distributed to other organelles. Niemann-Pick Type C1/2 (NPC1/2) proteins, members of the steroidogenic acute regulatory-related lipid transfer domain (StARD) and oxysterol-binding protein (OSBP) families facilitate the cellular distribution of cholesterol. NPC disease, a rare neurodegenerative disorder characterized by LE/Lys-cholesterol accumulation due to loss-of-function NPC1/2 mutations, underscores the physiological importance of LE/Lys-cholesterol distribution. Several Rab-GTPase family members, which play fundamental roles in directional membrane and lipid transport, including Rab7, 8 and 9, are critical for the delivery of cholesterol from LE/Lys to other organelles along vesicular and non-vesicular pathways. The insights gained from these regulatory circuits provide a foundation for the development of therapeutic strategies that could effectively address the cellular pathogenesis triggered by NPC1 deficiency and other lysosomal storage disorders.