Lysosomal lipid catabolite export typically requires lipid transport proteins located in the lysosomal limiting membrane such as CLN3 for glycerophosphodiesters (GPD), SPNS1 for lysophospholipids (LPL), SCARB2 and NPC1 for cholesterol (Chol), sphingosine (Sph) and possibly other lipid species. Fatty acid export proteins are so far unknown. Cholesterol is handed over to NPC1 by the luminal protein NPC2. Lysosomal structural protein LAMP1 can drive cholesterol export by yet-to-be defined mechanisms. After traversing the lysosomal limiting membrane lipids are believed to be transfered to other organelles such as the endoplasmic reticulum (ER) or mitochondria (Mito) by lipid transfer proteins, such as cholesterol and sphingosin transferring STARD3 and cholesterol transferring Gramd1b, ORP5, and ORP1L. Calcium efflux mediated by TRPML1 leads to TFEB activation and lysosome fusion with the plasma membrane which discharges lipid catabolites into the extracellular space. Created with Biorender.
