Lysosomal enzymes transport

Munier-Lehmann, H., Mauxion, F. and Hoflack, B. Function of the two mannose 6-phosphate receptors in lysosomal enzyme transport. Biochem. Soc. Trans. 24 133-136,1996. 

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. 

Sohar, I., D. Sleat, C. Gong Liu, T. Ludwig, and P. Lobel. 1998. Mouse mutants lacking the cation-independent mannose 6-phosphate/insulin-like growth factor II receptor are impaired in lysosomal enzyme transport comparison of cation-independent and cation-dependent mannose 6-phosphate receptor-deficient mice. Biochem J. 330 fPr 2 903-908. 

Hille-Rehfeld A. 1995. Mannose 6-phosphate receptors in sorting and transport of lysosomal enzymes. Biochim Biophys Acta 1241 177-194. 

A successful tool in the early studies of metabolic pathways was blocking the pathway at some specific point. This could be done by the use of either mutants or inhibitors. Schekman et al have isolated a number of yeast mutants with blocks in their secretion pathway (Schekman, 1982). It is not yet known which proteins these mutations affect, but this is clearly a most promising approach for identifying those components involved in transport. In animal cells there are no cellular mutants with blocks in the intracellular transport of protein from the ER to the cell surface. There are, however, genetic diseases which affect the routing of lysosomal enzymes to the lysosomes (Neufeld et al, 1975 Sly and Fischer, 1982). For viruses it has been possible to isolate temperature-sensitive mutants in which a mutation in the viral glycoprotein arrests... 

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. 

Passini, M. A. et al. (2002). Distribution of a lysosomal enzyme in the adult brain by axonal transport and by cells of the rostral migratory stream. J. Neurosci. 22(15), 6437-6446. 

Fig. 10.1. Lysosomal enzymes are synthesized as precursor proteins that undergo extensive modifications during transport to the lysosome. Newly synthesized lysosomal proteins have an amino-terminal signal sequence that mediates... 

Prenatal diagnosis of I-cell disease has been based on greatly reduced phosphotransferase activity (cf. Biochemical Perspectives section) and abnormal intracellular-extracellular distribution of lysosomal enzymes in cultured amni-otic fluid cells (Table 17-3).As indicated in Table 17-3, amniotic fluid cells secrete large amounts of lysosomal enzymes into the extracellular medium. Decreased levels of lysosomal enzymes in chorionic villi obtained by biopsy have also been observed in I-cell disease however, the characteristic secondary effect (i.e.,increased levels of lysosomal enzymes in the extracellular compartment) is only partially expressed or not expressed at all in chorionic villi, suggesting an alternative mechanism for the transport of lysosomal proteins. Although... 

The I-cell patient has proved invaluable for elucidation of the complex nature of intracellular packaging and sorting of lysosomal enzymes. The physiological importance of this signal-mediated pathway is evident in that fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy secrete rather than target most of their lysosomal enzymes. Thus, the molecular theme of I-cell disease is that of faulty lysosomal targeting, the inability to transport (i.e., sort) lysosomal enzymes from their site of synthesis to the lysosome. 

In healthy individuals lysosomal enzymes are transported from the endoplasmic reticulum to the lysosome via mannose-6-phosphate (M6P) mediated vesicles or other receptor-mediated transporters [5]. The phosphate-labeled enzyme in the case of M6P-mediated transport is released to the lysosome by... 

Imort, M., Zuhlsdorf, M., Feige, U., Hasihk, A., and vonFigura, K., Biosynthesis and transport of lysosomal enzymes in human monocytes and macrophages. Effects of ammonium chloride, zymosan and tunicamycin. Biochem. J. 214(3), 671-678 (1983). 

Urayama A, Grubb JH, Sly WS, Banks WA (2004) Developmentally regulated mannose 6- phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain banier. Proc Natl Acad Sci USA 101 12663. 

In LLC-PKj cells gentamicin induces membrane damage as shown by the loss of specific membrane enzymes (y-glutamyl transpeptidase, alkaline phosphatase and aminopeptidase), a decrease of the lysosomal enzyme N-acetyl-P-D-glucosaminidase, an inhibition of apical Na -dependent glucose transporter and the basolateral Na-K-ATPase pump as well as a decrease in dome formation [141, 142]. Furthermore gentamicin results in a dose dependent decrease in intracellular ATP and cAMP [142]. 

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