Characterization of phosphatidylserine-dependent beta2-glycoprotein I macrophage interactions. Implications for apoptotic cell clearance by phagocytes.
The binding and uptake of phosphatidylserine (PS)-expressing cells appears to involve multiple receptor-mediated systems that recognize the lipid either directly or indirectly through intermediate proteins that form a molecular bridge between the cells. Here we show that beta2-glycoprotein I (beta2GPI), a 50-kDa serum glycoprotein, binds PS-containing vesicles and serves as an intermediate for the interaction of these vesicles with macrophages. Chemical modification of lysines and cysteines abolished beta2GPI-dependent PS uptake by inhibiting the binding of PS to beta2GPI and the binding of PS.beta2GPI complex to macrophages, respectively. Recognition was mediated by beta2GPI and not by the lipid because antibodies to beta2GPI inhibited binding of the complex to macrophages. These results indicate that human (THP-1-derived) macrophages bind beta2GPI only after it is bound to its lipid ligand. Competition experiments with monosaccharides that inhibit lectin-dependent interactions, and PS.beta2GPI binding experiments using deglycosylated beta2GPI, suggested that carbohydrate residues were not required for macrophage recognition of the complex. Antibodies to putative macrophage PS receptors (CD36, CD68, and CD14) did not inhibit uptake of the complex. These data suggest that beta2GPI can bind cells that fail to maintain membrane lipid asymmetry and generate a specific bridging moiety that is recognized for clearance by a phagocyte receptor that is distinct from CD36, CD68, and CD14.
Balasubramanian
K
K
Department of Cell Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Schroit
A J
AJ
D017209:Apoptosis; D050260:Carbohydrate Metabolism; D002478:Cells, Cultured; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000378:metabolism*; D010718:Phosphatidylserines / Q000378:metabolism*; D011485:Protein Binding; D014407:Tumor Cells, Cultured; D053482:beta 2-Glycoprotein I
D006023:Glycoproteins; D008024:Ligands; D010718:Phosphatidylserines; D053482:beta 2-Glycoprotein I