Mannose 6-phosphate tagging of lysosomal hydrolases — Golgi GlcNAc-1-phosphotransferase (GNPTAB) and its retention factor LYSET

Newly synthesised soluble lysosomal acid hydrolases are sorted away from the secretory pathway by a mannose 6-phosphate (M6P) recognition marker on their N-glycans. In the cis-Golgi the GlcNAc-1-phosphotransferase complex (alpha2beta2gamma2; catalytic alpha/beta subunits encoded by GNPTAB, gamma by GNPTG) recognises a conformational protein determinant shared by lysosomal hydrolases and transfers GlcNAc-1-phosphate from UDP-GlcNAc to C6 hydroxyls of mannose residues of their high-mannose N-glycans. The Golgi membrane protein LYSET (TMEM251) binds the GlcNAc-1-phosphotransferase, stabilising it and supporting its site-1 protease activation and Golgi retention, and is required for M6P tagging. In the trans-Golgi network the uncovering enzyme NAGPA removes the covering GlcNAc to expose M6P, and the M6P receptors (cation-dependent M6PR and cation-independent IGF2R) bind the tagged hydrolases and deliver them to endosomes, from which the receptors recycle. Loss of GNPTAB causes mucolipidosis II (I-cell disease) and MLIII alpha/beta, GNPTG loss causes MLIII gamma, and LYSET deficiency causes a mucolipidosis-like disorder, all with hypersecretion of lysosomal enzymes and lysosomal storage.