Abstract
LAMP1 and LAMP2 proteins 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 show here that human LAMP1 and LAMP2 bind cholesterol in a manner that buries the cholesterol 3β-hydroxyl group; they also bind tightly to NPC1 and NPC2 proteins that export cholesterol from lysosomes. 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.
Highlights
Eukaryotic lysosomes are acidic, membrane-bound organelles that contain proteases, lipases and nucleases and degrade cellular components to regenerate catabolic precursors for cellular use (Xu and Ren, 2015; Schwake et al, 2013; Saftig and Klumperman, 2009)
The limiting membrane of lysosomes is lined with so-called lysosomal membrane glycoproteins (LAMPs) that are comprised of a short cytoplasmic domain, a single transmembrane span, and a highly, N- and O-glycosylated lumenal domain (Wilke et al, 2012; Kundra and Kornfeld, 1999; Granger et al, 1990)
LAMPs are required for fusion of lysosomes with phagosomes (Huynh et al, 2007) and LAMP2 has been proposed to serve as a receptor for chaperone-mediated autophagy (Cuervo and Dice, 1996, 2000; Bandyopadhyay et al, 2008)
Summary
Eukaryotic lysosomes are acidic, membrane-bound organelles that contain proteases, lipases and nucleases and degrade cellular components to regenerate catabolic precursors for cellular use (Xu and Ren, 2015; Schwake et al, 2013; Saftig and Klumperman, 2009). The limiting membrane of lysosomes is lined with so-called lysosomal membrane glycoproteins (LAMPs) that are comprised of a short cytoplasmic domain, a single transmembrane span, and a highly, N- and O-glycosylated lumenal domain (Wilke et al, 2012; Kundra and Kornfeld, 1999; Granger et al, 1990) Because of their abundance and glycan content, LAMPs have been proposed to serve as a protective barrier to block hydrolase access to the limiting phospholipid bilayer. Li and Pfeffer showed that cells contain 5- to 10-times more LAMP proteins than they do NPC1-cholesterol exporters. This suggests that LAMP proteins have additional roles that need to be characterized and studied to see how important cholesterol binding is for these processes too. We show here that LAMP proteins bind cholesterol directly and this capacity contributes to their role in cholesterol export from lysosomes
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