Monensin inhibits recycling of macrophage mannose-glycoprotein receptors and ligand delivery to lysosomes

T. Wileman, R. L. Boshans, P. Schlesinger, P. Stahl

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1. Binding studies with cells that had been permeabilized with saponin indicate that alveolar macrophages have an intracellular pool of mannose-specific binding sites which is about 4-fold greater than the cell surface pool. 2. Monensin, a carboxylic ionophore which mediates proton movement across membranes, has no effect on binding of ligand to macrophages but blocks receptor-mediated uptake of 125I-labelled β-glucuronidase. 3. Inhibition of uptake was concentration- and time-dependent. 4. Internalization of receptor-bound ligand, and warming to 37°C was unaffected by monensin. Moreover, internalization of ligand in the presence of monensin resulted in an intracellular accumulation of receptor-ligand complexes. 5. The monensin effect was not dependent on the presence of ligand, since incubation of macrophages with monensin at 37°C without ligand resulted in a substantial decrease in cell-surface binding activity. However, total binding activity, measured in the presence of saponin, as much less affected by monensin treatment. Removal of monensin followed by a brief incubation at pH 6.0 and 37°C, restored both cell-surface binding and uptake activity. 6. Fractionation experiments indicate that ligands enter a low-density (endosomal) fraction within the first few minutes of uptake, and within 20 min transfer to the lysosomal fraction has occurred. Monensin blocks the transfer from endosomal to lysosomal fraction. 7. Lysomomal pH, as measured by the fluorescein-dextran method, was increased by monensin in the same concentration range that blocked ligand uptake. 8. The results indicate that monensin blockade of receptor-mediated endocytosis of mannose-terminated ligands by macrophages is due to entrapment of receptor-ligand complexes and probably receptors in the pre-lysosomal compartment. The inhibition is linked with an increase in the pH of acid intracellular vesicles.

Original languageEnglish
Pages (from-to)665-675
Number of pages11
JournalBiochemical Journal
Issue number3
StatePublished - 1984


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