Mannose receptor-mediated uptake of ricin toxin and ricin A chain by macrophages. Multiple intracellular pathways for a chain translocation.
The role of the high mannose carbohydrate chains in the mechanism of action of ricin toxin was investigated. Ricin is taken up by two routes in macrophages, by binding to cell surface mannose receptors, or by binding of the ricin galactose receptor to cell surface glycoproteins. Removal of carbohydrate from ricin by periodate oxidation led to a large loss in toxicity via both routes of uptake by an effect on the B chain not due to a loss of galactose binding affinity. These data suggest that the carbohydrate chains of ricin B chain may be required for full toxicity. The pathway of uptake of ricin by the macrophage mannose receptor was found to differ in several respects from uptake via the galactose-specific pathway. Analysis of intoxication of macrophages by ricin in the presence of ammonium chloride suggested that mannose receptor bound ligand passes through acidic vesicles prior to translocation, unlike galactose bound ligand. Intoxication by ricin via galactose-specific uptake was potentiated by swainsonine but not by castanospermine, suggesting that ricin may be attacked by an endogenous mannosidase within the cell, and that ricin passes through either a lysosomal or a Golgi compartment prior to translocation.
Simmons
B M
BM
Stahl
P D
PD
Russell
J H
JH
D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D001853:Bone Marrow / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005966:Glucuronidase / Q000378:metabolism; D007700:Kinetics; D007739:L Cells / Q000187:drug effects / Q000378:metabolism; D037181:Lectins, C-Type; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008358:Mannose / Q000378:metabolism*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects; D051381:Rats; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000378:metabolism*; D012276:Ricin / Q000302:isolation & purification / Q000378:metabolism*
D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D000643:Ammonium Chloride; D012276:Ricin; D005966:Glucuronidase; D008358:Mannose