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In healthy cells, GlcNAc-1-phosphotransferase in the cis-Golgi adds the M6P tag to lysosomal hydrolases, and the uncovering enzyme later exposes the M6P residue in the trans-Golgi, allowing these enzymes to bind M6P receptors and be routed through endosomes to lysosomes. In ML II/III cells, defective GlcNAc-1-phosphotransferase cannot properly add M6P tags, so hydrolases fail to bind M6P receptors and are instead secreted outside the cell, leading to intracellular accumulation of undegraded substrates within lysosomes.