The role of the Mannose 6-Phosphate recognition marker in Lysosomal Function and Dysfunction

To accomplish their degradative function lysosomes must be filled with specific proteins, which after being synthesized in the endoplasmic reticulum (ER) have to be directed to the trans-Golgi network (TGN) for further processing and lysosomal targeting. The explanation of how lysosomal enzymes are accurately recognized and selected over many other proteins in the TGN relies on a small recognition marker, added exclusively to their N-linked oligosaccharides as they pass through the cis-Golgi: the mannose 6-phosphate (M6P) group. Generation of the M6P recognition marker depends on a two-step reaction involving two different enzymes: UDP-N-acetylglucosamine 1-phosphotransferase (GlcNAc-phosphotransferase) and -N-acetylglucosamine-1-phosphodiester -N-acetylglucosaminidase (uncovering enzyme). GlcNAc-phosphotransferase catalyses the transfer of a GlcNAc-1-phosphate residue from UDP-GlcNAc to C6 positions of selected mannoses in high-mannose type oligosaccharides of the hydrolases. Then, the uncovering enzyme removes the terminal GlcNAc, exposing the M6P recognition signal. At the TGN, the recognition signal allows the segregation of lysosomal hydrolases from all other types of proteins through selective binding to the M6P receptors: the cation-independent M6P receptor (CI-MPR) and/or the cation-dependent M6P receptor (CD-MPR). The produced clathrin-coated vesicles bud off from the TGN and fuse with late endosomes (LE). At the low pH of the LE, the hydrolases dissociate from the M6P receptors and the empty receptors are recycled to the Golgi for further rounds of transport. Impairments in this delivery/transport pathway may result in missorting of lysosomal enzymes, with consequent severe pathological condition. Additionally, the expression levels of M6P pathway functional components and of the recognition marker itself may have an influence on the efficacy of some therapeutic approaches. Here we will review the current knowledge on each of the major proteins involved in the M6P-dependent pathway, highlighting their involvement in disease. Special attention will be given to the lysosomal storage disorders associated to GlcNAc-phosphotransferase loss of function: Mucolipidosis type II and III