α 2‐Macroglobulin Receptor Mediates Binding and Cytotoxicity of Plant Ribosome‐Inactivating Proteins

Abstract

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. Copyright © 1995, Wiley Blackwell. All rights reserved