Lysosomes are cellular stomachs. They degrade macromolecules and release their components as nutrients into the cytosol. Digestion of
sphingolipids and other
membrane lipids occurs at
luminal intraendosomal vesicles and IMs (intraendosomal membranes).
Sphingolipid and membrane digestion needs catabolic
hydrolases with the help of
lipid-
binding proteins [SAPs (
sphingolipid activator proteins)] and anionic
lipids such as BMP [
bis(monoacylglycero)phosphate]. Inherited defects of
hydrolases or SAPs or uptake of cationic amphiphilic drugs cause
lipid accumulation, eventually leading to death, especially in inherited
sphingolipid storage diseases. IMs are formed during endocytosis and their
lipid composition is adjusted for degradation. Their
cholesterol content, which stabilizes membranes, decreases and the level of negatively charged BMP, which stimulates
sphingolipid degradation, increases. At the level of late endosomes,
cholesterol is transported out of the
luminal vesicles preferentially by
cholesterol-
binding proteins, NPC (Niemann-Pick type C)-2 and NPC-1. Their defects lead to an endolysosomal accumulation of
cholesterol and
sphingolipids in
Niemann-Pick type C disease. BMP and
ceramide stimulate NPC-2-mediated
cholesterol transfer, whereas
sphingomyelin inhibits it. Anionic
membrane lipids also activate
sphingomyelin degradation by ASM (
acid sphingomyelinase), facilitating
cholesterol export by NPC-2. ASM is a non-specific
phospholipase C and degrades more than 23
phospholipids. SAPs are membrane-perturbing
proteins which solubilize
lipids, facilitating
glycolipid digestion by presenting them to soluble catabolic
enzymes at acidic pH. High BMP and low
cholesterol levels favour
lipid extraction and membrane disintegration by
saposin A and B. The simultaneous inherited defect of
saposins A-D causes a severe membrane and
sphingolipid storage disease, also disrupting the water permeability barrier of the skin.