Mannose 6-Phosphate Receptors and Lysosomal Enzyme Targeting

Abstract

The targeting of lysosomal enzymes from their site of synthesis in the rough endoplasmic reticulum (RER) to their final destination in lysosomes is a multi-step process requiring a series of interactions between cellular components and protein and carbohydrate recognition signals present on the lysosomal enzymes (1-6). These proteins share a common pathway with secretory proteins and membrane proteins during the early stages of their biosynthesis. All three classes of proteins contain a hydrophobic signal sequence that allows for their synthesis on membrane-bound polysomes in the RER and translocation into t.he lumen of this organelle. During this process the lysosomal enzymes as well as many secretory and membrane proteins are co-translationally glycosylated at selected asparagine residues. Following cleavage of the signal sequence and initial proc-essing of asparagine-linked oligosaccharides, the proteins move by vesicular transport from the RER to the Golgi apparatus where they undergo a variety of post-translational modifications and are segre- gated from one another for targeting to their final destinations (7). A key step in the sorting process is the generation of phospho- mannosyl residues on the lysosomal enzymes. The phosphorylating enzyme recognizes a protein determinant shared by lysosomal en- zymes, thereby selectively marking this class of proteins for subse-quent segregation. The phosphomannosyl residues serve as high affinity ligands for binding to mannose 6-phosphate receptors (MPRs)