title: Endosomal proteolysis precedes ricin A-chain toxicity in macrophages.
abstract: Ricin A-chain is delivered into macrophages via receptor-mediated endocytosis. We have found that following uptake via the mannose receptor, ricin A-chain is rapidly cleaved by endosomal proteases. Inhibition of endosomal proteases such as cathepsin D and B leads to the accumulation of toxin inside the cell. Inhibition of cathepsin D reduces ricin A-chain cytotoxicity, while blocking cathepsin B enhances cytotoxicity. Similar results were obtained using fibroblasts transfected with the mannose receptor. Our data strongly suggest that the activation or membrane translocation of ricin A-chain is dependent upon the action of specific proteases.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: M L
authors.initials: ML
authors.lastname: Fiani
authors.forename: J S
authors.initials: JS
authors.lastname: Blum
authors.forename: P D
authors.initials: PD
authors.lastname: Stahl
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells; D002401:Cathepsin B / Q000378:metabolism*; D002402:Cathepsin D / Q000378:metabolism*; D002478:Cells, Cultured; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D011480:Protease Inhibitors / Q000494:pharmacology; D012276:Ricin / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D007976:Leupeptins; D011480:Protease Inhibitors; C063261:acetylleucyl-leucyl-norleucinal; D012276:Ricin; D002401:Cathepsin B; D002402:Cathepsin D