Cholesterol Handling in Lysosomes and Beyond

Cholesterol is delivered to lysosomes by receptor-mediated delivery of low density lipoproteins (LDLs) from the extracellular space. In lysosomes, cholesterol esters are hydrolyzed and subject to binding to specialized proteins such as NPC2. The transport of cholesterol to the limiting membrane of the lysosome requires that the dense layer of carbohydrates has to be overcome by hydrophobic tunnel systems found in NPC1 as well as in LIMP-2/SCARB2. At the cytosolic side of the limiting membrane of the lysosome, protein interactions between lysosomal membrane proteins and organelle membrane proteins mediate membrane contact sites and transfer of cholesterol. The lysosomal cholesterol efflux is sensed and translated to the regulation of cell proliferation and autophagy. Lysosomes are of major importance for the regulation of cellular cholesterol homeostasis. Food-derived cholesterol and cholesterol esters contained within lipoproteins are delivered to lysosomes by endocytosis. From the lysosomal lumen, cholesterol is transported to the inner surface of the lysosomal membrane through the glycocalyx; this shuttling requires Niemann–Pick C (NPC) 1 and NPC2 proteins. The lysosomal membrane proteins lysosomal-associated membrane protein (LAMP)-2 and lysosomal integral membrane protein (LIMP)-2/SCARB2 also bind cholesterol. LAMP-2 may serve as a cholesterol reservoir, whereas LIMP-2, like NPC1, is able to transport cholesterol through a transglycocalyx tunnel. Contact sites and fusion events between lysosomes and other organelles mediate the distribution of cholesterol. Lysosomal cholesterol content is sensed thereby regulating mammalian target of rapamycin complex (mTORC)-dependent signaling. This review summarizes our understanding of the major steps in cholesterol handling from the moment it enters the lysosome until it leaves this compartment. Lysosomes are of major importance for the regulation of cellular cholesterol homeostasis. Food-derived cholesterol and cholesterol esters contained within lipoproteins are delivered to lysosomes by endocytosis. From the lysosomal lumen, cholesterol is transported to the inner surface of the lysosomal membrane through the glycocalyx; this shuttling requires Niemann–Pick C (NPC) 1 and NPC2 proteins. The lysosomal membrane proteins lysosomal-associated membrane protein (LAMP)-2 and lysosomal integral membrane protein (LIMP)-2/SCARB2 also bind cholesterol. LAMP-2 may serve as a cholesterol reservoir, whereas LIMP-2, like NPC1, is able to transport cholesterol through a transglycocalyx tunnel. Contact sites and fusion events between lysosomes and other organelles mediate the distribution of cholesterol. Lysosomal cholesterol content is sensed thereby regulating mammalian target of rapamycin complex (mTORC)-dependent signaling. This review summarizes our understanding of the major steps in cholesterol handling from the moment it enters the lysosome until it leaves this compartment. a membrane domain rich in glycoproteins and glycolipids. At the cell surface it contributes to cell–cell recognition, whereas at the inner surface of lysosomes this dense layer of carbohydrates is thought to be protective against lysosomal hydrolase attack. involved in carrying lipids (fatty acids, triglycerides, and esterified and unesterified cholesterol) to cells. Through apoprotein B-100 they can be taken up by cells by LDLR through receptor-mediated endocytosis. a class of around 200 proteins residing in the limiting membrane of the lysosome. At the luminal side they can contribute to the formation of a dense glycan layer. At the cytosolic side they can be involved in cell signaling, fusion events, membrane contact formation, and motility of lysosomes. They can act as a scaffold or transporter of proteins. is a central cellular pathway where the cell’s own material is enwrapped by autophagosomes. Autophagosomes fuse with lysosomes wherein the cellular contents are degraded by acid hydrolases. a huge protein complex involved in nutrient sensing. It acts as a kinase and can be activated at the cytosolic surface of the lysosomal membrane. mTORC controls protein synthesis and autophagic degradation. large bacterial efflux transporters involved in the detoxification and export of virulence factors. They have a large substrate spectrum ranging from metal ions, drugs, to hydrophobic and amphiphilic compounds.