α-macroglobulin receptor mediates binding and cytotoxicity of plant ribosome-inactivating proteins

It has been proposed that unconjugated type I ribosome-inactivating proteins (RIP) enter cells through passive mechanisms such as fluid-phase pinocytosis. However, some observations, such as the difference in sensitivity to type I RIP among different cell types, and the organ-specific toxicity of type I RIP, indicate a specific mechanism for the entry of these proteins into target cells. The α₂-macroglobulin receptor (α₂MR) is responsible for the binding and endocytosis of several ligands, including α₂-macroglobulin-proteinase complexes, plasminogen-activator-inhibitor complexes, apoE-enriched β-very low density lipoproteins, and lipoprotein lipase. Here we demonstrate that saporin, a potent type I RIP, binds specifically to purified α₂MR and the binding is prevented by some α₂MR ligands. Moreover, the occupancy of specific ligand-binding sites on cell surface α₂MR decreases the cytotoxicity of saporin. The A chain of ricin, a type II RIP, also interacts with α₂MR. This, and the fact that saporin and ricin A chain both interact: also with α₂-macroglobulin, indicates a general mechanism of complex interactions between RIP and cellular membranes that is mediated by α₂-macroglobulin and the α₂MR system.