Topology of glycosphingolipid degradation.

Glycosphingolipids (GSLs) form cell-type-specific patterns on the surface of eukaryotic cells. Degradation of plasma-membrane-derived GSLs in the lysosomes after internalization through the endocytic pathway is achieved through the concerted actions of hydrolysing enzymes and sphingolipid activator proteins. The latter are proteins necessary for the degradation of GSLs possessing short oligosaccharide chains. Some activator proteins bind to GSLs and form water-soluble complexes, which lift out of the membrane and give the water-soluble hydrolysing enzymes access to the regions of the GSL that would otherwise be obscured by the membrane. The inherited deficiency of both lysosomal hydrolases and sphingolipid activator proteins gives rise to sphingolipid storage diseases. An analysis of these diseases suggests a new model for the topology of endocytosis and lysosomal digestion, which is discussed in this article.