Regulation of Blood Glycoproteins by Lectin Receptors in Health and Disease

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SUMMARY The composition of the blood proteome provides indications of normal health and the presence of disease. Over 90% of non-albumin proteins in the blood of mammals are N-glycoproteins bearing N-glycan structures produced in the Golgi apparatus prior to nascent glycoprotein secretion. We have previously discovered an intrinsic mechanism controlling the half-lives and thereby abundance and function of circulating blood glycoproteins. This mechanism is linked to the progressive glycosidic remodeling of nascent blood glycoproteins by circulating exo-glycosidases thereby resulting in the exposure of cryptic endocytic lectin receptor ligands. Endocytic lectin receptors are highly conserved among mammals and are expressed on the surface of various vascular and organ cell types where they recognize and bind their ligands from among circulating blood components and glycoproteins. We have found that this intrinsic mechanism of blood glycoprotein remodeling and clearance by lectin receptors is targeted by pathogens and the resulting changes in blood glycoprotein abundance are linked to disease onset. Lectin receptor ligands include glycosidic linkages of galactose, N-acetylglucosamine, fucose, or mannose; however, glycoproteins bearing physiological lectin receptor ligands remain mostly unknown and thus the functions of lectin receptors are also mysterious. This laboratory has developed an approach to identify physiological blood glycoprotein ligands of individual lectin receptors by chromatography and mass spectrometry protocols. A subset of mammalian lectin receptors bind to glycosidic linkages bearing exposed mannose, herein termed mannosylated blood glycoproteins. This laboratory discovered in past related studies that the accumulation of mannosylated glycoproteins due to defects in N-glycan synthesis causes chronic inflammation, autoimmunity, and degenerative disease. Normally however, the recognition and clearance of mannosylated blood glycoproteins involves the expression and function of mannose binding lectins including Mrc1. This proposal addresses the hypothesis that Mrc1 controls the levels of mannosylated blood glycoproteins in normal physiology and protects against the onset of disease. Our supporting data demonstrate that Mrc1 has a blood ligand repertoire including key regulators of the vasculature. Absence of Mrc1 results in the accumulation of mannosylated Renin and Angiotensin Converting Enzyme with elevated blood pressure. In addition, accumulating mannosylated Myeloperoxidase in the blood is associated with vascular inflammation, blood-brain barrier breakdown, tissue damage, and autism-like features. The roles of Mrc1 ligands will be addressed with inhibitors. In the blood of humans, we have further discovered a link between individuals with low levels of mannosidase activity and high levels of mannosylated blood proteins. This proposal in summary will investigate how the accumulation of mannosylated blood glycoprotein ligands in Mrc1 deficiency cause disease and establish whether humans bearing high levels of mannosylated blood glycoproteins similarly contain elevated markers of inflammation and vascular defects.