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  • Title: Receptor-mediated transport of acid hydrolases to lysosomes.
    Author: Sly WS.
    Journal: Curr Top Cell Regul; 1985; 26():27-38. PubMed ID: 3000696.
    Abstract:
    Lysosomal enzymes are the products of 40-50 unlinked genes in the nucleus. Like membrane and secretory proteins, they are synthesized on membrane-bound ribosomes in the rough endoplasmic reticulum. They receive high-mannose oligosaccharide chains from lipid-linked intermediates on asparagine residues. They must be sorted from other proteins present in the lumen of the endoplasmic reticulum and delivered to the lysosomes. The best understood mechanism for this sorting and delivery involves the Man 6-P recognition system. The newly synthesized acid hydrolases acquire Man 6-P residues by a two-step reaction. First, GlcNAc 1-P is transferred to the C-6 position of the mannose residues which are present on the asparagine-linked high-mannose oligosaccharides. Then, N-acetylglucosamine residues are removed by the N-acetylglucosaminyl phosphoglycosidase to generate the Man 6-P monoester, which is capable of binding the Man 6-P receptor. Phosphorylated enzymes can then bind to Man 6-P receptors which collect into vesicles and bud off for delivery of enzymes to lysosomes. The region of the Golgi apparatus where the receptors containing newly synthesized enzymes bud off is not yet clear. Enzymes which fail to bind receptors are secreted. Some cell types express on their cell surfaces receptors which are capable of recapturing phosphorylated enzyme by receptor-mediated endocytosis. This secretion - recapture pathway provides an alternate route to lysosomes. Following delivery of enzyme to lysosomes, the enzymes undergo post-lysosomal processing by acid phosphotases, which remove the phosphomonoester groups, and acid proteases which reduce their size and trim off excess polypeptides. Although the evidence is very persuasive that enzymes can reach lysosomes by pathways that do not depend on the Man 6-P receptor, the mechanisms of Man 6-P receptor-independent segregation of acid hydrolases to lysosomes are totally unclear. In addition to this question, there are two other significant questions that remain to be answered. One of these is the precise intracellular route of newly synthesized enzyme. Where does the enzyme first bind receptor, and where does receptor actually bud off the Golgi apparatus to effect sorting? The second major question is really the central question of the mechanism of sorting of acid hydrolases. Although we know now that the sorting is effected through an enzyme which phosphorylates acid hydrolases, the question remains: How does the processing phosphotransferase distinguish acid hydrolases from other glycoproteins in the endoplasmic reticulum?(ABSTRACT TRUNCATED AT 400 WORDS)
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