The chicken oocyte receptor for lipoprotein deposition recognizes α2-Macroglobulin

Abstract

α2-Macroglobulin (α2M), a major plasma component in all vertebrates, is proposed to function as a broad spectrum protease inhibitor. The α2M-proteinase complex (activated α2M; α2M*) is removed rapidly by receptor-mediated endocytosis in the liver. Here we demonstrate by Western blotting that α2M is also present in the yolk of chicken oocytes. Plasma levels of α2M are increased by estrogen, and yolk α2M is partially proteolyzed, consistent with the action of cathepsin D on endocytosed α2M. Two known estrogen-induced ligands of the oocytespecific 95-kDa very low density lipoprotein/vitellogenin receptor (OVR) are also fragmented by yolk cathepsin D (Retzek, H., Steyrer, E., Sanders, E. J., Nimpf, J., and Schneider, W. J. (1992) DNA Cell Biol. 11, 661-672). Since these findings suggested a common uptake mechanism for lipoproteins and α2M by oocytes, we investigated whether OVR, a member of the low density lipoprotein receptor family, functions in the metabolism of α2M. Ligand blotting of oocyte membrane extracts with chicken α2M* revealed that it binds to OVR. Surprisingly, the oocyte receptor also recognizes native α2M, in sharp contrast to the hepatic receptor, which only binds α2M*. Receptor interaction of both forms requires Ca2+; however, competition experiments suggest that α2M and α2M* interact with slightly different, or overlapping, sites on the receptor. Colocalization of α2M and OVR in coated vesicles isolated from growing oocytes, and internalization and degradation of methylamine-activated α2M by COS-7 cells transfected with OVR, strongly suggest that α2M is transported into growing oocytes via OVR. We propose that this multifunctional receptor mediates pathways at the metabolic crossroads of lipoproteins and protease inhibitor complexes.