Targeting plant toxins to the urokinase and α 2-macroglobulin receptors

Abstract

We have conjugated the ribosome-inactivating protein (RIP) saporin to human urokinase-type plasminogen activator (uPA), and tested the uPA-saporin conjugate for cytotoxicity to uPA receptor-expressing cells. Unlike unconjugated uPA, saporin-conjugated uPA did not require any interaction with plasminogen activator inhibitors to be internalized. We have shown that saporin, as well as other RIPs, binds to the α 2-macroglobulin receptor (α 2MR), a cell surface glycoprotein that endocytoses uPA-inhibitor complexes. Thus, the uPA receptor might present uPA-saporin to α 2MR for internalization of the conjugate, a mechanism similar to that of uPA complexed to specific PA inhibitors. The binding of RIPs to α 2MR contrasts with previously proposed non-specific mechanisms for RIP entry into cells. The implications of the interactions between RIPs and α 2MR are discussed, with an emphasis on the role of α 2MR in mediating RIP immunogenicity and immune suppression.