Effect of monensin on intracellular transport and receptor-mediated endocytosis of lysosomal enzymes.
In cultured human fibroblasts we observed that monensin, a Na+/H+-exchanging ionophore, (i) inhibits mannose 6-phosphate-sensitive endocytosis of a lysosomal enzyme, (ii) enhances secretion of the precursor of cathepsin D, while inhibiting secretion of the precursors of beta-hexosaminidase, (iii) induces secretion of mature beta-hexosaminidase and mature cathepsin D, and (iv) inhibits carbohydrate processing in and proteolytic maturation of the precursors remaining within the cells; this last effect appears to be secondary to an inhibition of the transport of the precursors. If the treated cells are transferred to a monensin-free medium, about half of the accumulated precursors are secreted, and the intracellular enzyme is converted into the mature form. Monensin blocks formation of complex oligosaccharides in lysosomal enzymes. In the presence of monensin, total phosphorylation of glycoproteins is partially inhibited, whereas the secreted glycoproteins are enriched in the phosphorylated species. The suggested inhibition by monensin of the transport within the Golgi apparatus [Tartakoff (1980) Int. Rev. Exp. Pathol. 22, 227-250] may be the cause of some of the effects observed in the present study (iv). Other effects (i, ii) are rather explained by interference by monensin with the acidification in the lysosomal and prelysosomal compartments, which appears to be necessary for the transport of endocytosed and of newly synthesized lysosomal enzymes.
D001692:Biological Transport / Q000187:drug effects; D050260:Carbohydrate Metabolism; D002402:Cathepsin D; D002403:Cathepsins / Q000378:metabolism*; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D004705:Endocytosis / Q000187:drug effects*; D005347:Fibroblasts / Q000201:enzymology; D005663:Furans / Q000494:pharmacology*; D006596:Hexosaminidases / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology*; D008360:Mannosephosphates / Q000494:pharmacology; D008985:Monensin / Q000494:pharmacology*; D001619:beta-N-Acetylhexosaminidases
D005663:Furans; D008360:Mannosephosphates; C027693:mannose-6-phosphate; D008985:Monensin; D006596:Hexosaminidases; D001619:beta-N-Acetylhexosaminidases; D002403:Cathepsins; D002402:Cathepsin D