Golgi Lysosomal enzymes

Figure 14.10 Overview of cellular entry of (non-viral) gene delivery systems, with subsequent plasmid relocation to the nucleus. The delivery systems (e.g. lipoplexes and polyplexes) initially enter the cell via endocytosis (the invagination of a small section of plasma membrane to form small membrane-bound vesicles termed endosomes). Endosomes subsequently fuse with golgi-derived vesicles, forming lysosomes. Golgi-derived hydrolytic lysosomal enzymes then degrade the lysosomal contents. A proportion of the plasmid DNA must escape lysosomal destruction via entry into the cytoplasm. Some plasmids subsequently enter the nucleus. Refer to text for further details...

Lysosomal enzymes are glycosylated and modified in a characteristic way. Most importantly, when they arrive in the Golgi apparatus, specific mannose residues in their oligosaccharide chains are phosphorylated. This phosphorylation is the critical event that removes them Corn the secretion pathway and directs them to lysosomes. Genetic defects affecting this phosphorylation produce I-ceU disease in which lysosomal enzymes are released into the ejctracellular space, and inclusion bodies accumulate in the cell, compromising its function. 

Lysosomal enzymes phosphorylation of mannose by phosphotransferase in Golgi I-cell disease... 

Some hereditary diseases are characterized by lack of two or more lysosomal enzymes. In I-ceII disease (mucolipidosis II), which resembles the Hurler syndrome, at least ten enzymes are absent or are present at much reduced levels.350,361 The biochemical defect is the absence from the Golgi cisternae of the N-acetylglucosaminyl phosphotransferase that transfers P-GlcNAc units from UDP-GlcNAc onto mannose residues (Eq. 20-22) of glycoproteins marked for use in lysosomes. 

Oligomannosyl carbohydrates on soluble enzymes destined to become lysosomal enzymes carry one or two phosphate residues at the 6 position of mannose (Man-6-P). These phosphorylated mannose residues are recognized by a glycoprotein called the Man-6-P receptor, which binds and transports the prelysosomal enzymes to prelysosomal vesicles (see fig. 16.13). This binding ensures that the prelyso-somal enzyme enters a vesicle destined to fuse to and thereby deliver its contents to the lysosome. In an acidic, prelysosomal compartment the binding between the Man-6-P receptor and the lysosomal enzyme is disrupted so that the receptor can be recycled to the Golgi apparatus. 

Madison, K.C., Sando, G.N., Howard, E.J., True, C.A., Gilbert, D., Swartzendruber, D.C., and Wertz, P.W., Lamellar granule biogenesis a role for ceramide glucosyltransferase, lysosomal enzyme transport, and the golgi, J. Invest. Dermatol. Symp. Proc., 3, 80, 1998. 

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