NPC1‐mediated cholesterol export from lysosomes

Abstract

Endocytosed, LDL‐derived cholesterol is exported from the interior of lysosomes by a process that requires the action of NPC1 and NPC2 proteins. We have recently shown that LAMP1 and LAMP2 proteins interact with NPC1 and NPC2 and also bind cholesterol (1). LAMPs are highly abundant, ubiquitous, mammalian proteins that line the lysosome limiting membrane, and protect it from lysosomal hydrolase action. LAMP2 deficiency causes Danon's disease, an X‐linked hypertrophic cardiomyopathy. LAMP2 is needed for chaperone‐mediated autophagy, and its expression improves tissue function in models of aging. We have shown that human LAMP2 binds cholesterol in a manner that buries the cholesterol 3β‐hydroxyl group; it also binds tightly to NPC1 and NPC2 (1). Quantitation of cellular LAMP2 and NPC1 protein levels suggest that LAMP proteins represent a significant cholesterol binding site at the lysosome limiting membrane, and may signal cholesterol availability. Functional rescue experiments show that the ability of human LAMP2 to facilitate cholesterol export from lysosomes relies on its ability to bind cholesterol directly (1). Why do LAMP proteins bind cholesterol and what is the significance of their interaction with NPC1 and NPC2 proteins? Our recent determination of the structure of a complex of NPC1 and NPC2 proteins in collaboration with Xiaochun Li and Günter Blobel (2) provides a model for how NPC2 may deliver cholesterol to NPC1. Current work is exploring the subsequent steps involved in exporting that cholesterol across the lysosomal glycocalyx (3) and into the cytoplasm.Support or Funding InformationThis research was funded by the Ara Parseghian Medical Research Foundation and the NIH (DK37332).