Practice question

Targeting soluble acid hydrolases to lysosomes hinges on carbohydrate tag mannose-6-phosphate discovered by fractionation. In cis-Golgi, UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase alpha2 beta2 gamma2 recognizes structural patch including lysine residues clustered in tertiary structure on hydrolases like cathepsin B and adds GlcNAc-phosphate to terminal mannose of high-mannose N-glycans. Uncovering in TGN by NAGPA removes GlcNAc exposing M6P monoester capable of binding M6P receptors. M6P receptors divert enzymes from default secretory flow into clathrin-AP1 and GGA vesicles destined to late endosomes where acid releases enzyme. If phosphorylation fails due to loss-of-function mutation in GNPTAB encoding alpha beta subunits, as in mucolipidosis II I-cell disease and milder III pseudo-Hurler, hydrolases lack tag cannot bind receptors therefore traverse default secretory conduit to plasma membrane and secreted with high extracellular activity detectable in serum. Lysosomes deficient in over 50 hydrolases accumulating undigestible glycosaminoglycans and sphingolipids forming inclusion bodies pathognomonic. Glycosylation otherwise normal, ER-Golgi transport persists, but lysosomal delivery selectively lost causing severe multisystem disease.