Figure 3.

Proposed topology of endocytosis and lysosomal lipid and membrane digestion (Gallala et al., 2011). “A section of the plasma membrane is internalized by way of coated pits or caveolae. These membrane patches include GSLs (red) and receptors such as epidermal growth factor receptor (EGFR; blue). These vesicles fuse with the early endosomes, which mature to late endosomes. Endosomal perimeter membranes form invaginations, controlled by ESCRT proteins (Wollert and Hurley, 2010), which bud off, forming intra-endosomal vesicles. Lipid sorting occurs at this stage. The pH of the lumen is ∼5. At this pH, ASM is active and degrades sphingomyelin of the intra-endosomal vesicles to ceramide, whereas the perimeter membrane is protected against the action of ASM by the glycocalyx facing the lumen. This decrease in sphingomyelin, coupled with the increase in ceramide, facilitates the binding of cholesterol to NPC2 and its transport to the perimeter membrane of the late endosome where it is transferred to NPC1 (Kwon et al., 2009). This protein mediates the export of cholesterol through the glycocalyx, eventually reaching cholesterol binding proteins in the cytosol. Ultimately, late endosomes fuse with lysosomes. The GSLs are harbored in intralysosomal vesicles that face the lumen of the lysosome, and are degraded by hydrolases with the assistance of SAPs. The products of this degradation are exported to the cytosol or loaded on CD1b immunoreceptors and exported to the plasma membrane for antigen presentation. Gradients of pH in the lysosol, and intra-endolysosomal vesicle content of cholesterol (Chol), BMP, sphingomyelin (SM, hypothetical), and ceramide (Cer, hypothetical) are shown” (modified from Kolter and Sandhoff, 2010).