Glycoprotein Aging with Increased Mannose Exposure Linked to Cardiovascular Disease through the Macrophage Mannose Receptor (Mrc1)

Abstract

N‐glycosylation is common to the vast majority of secretory proteins that are found at the cell surface or secreted. We have previously discovered that as secreted glycoproteins age in the blood circulation their glycan linkages are progressively hydrolyzed from the terminal position inward in what appears to be primarily a stepwise exo‐glycosidic process starting with neuraminidases and followed by a series of glycosidases that results in the exposure of different potential lectin ligands. We have also published that this mechanism includes cell surface glycoproteins of the intestinal tract. This intrinsic mechanism of glycoprotein aging is common to all plasma glycoproteins and appears to determine the half‐lives of glycoproteins in circulation in the limited cases where it has been studied ‐ specifically two circulating alkaline‐phosphatase enzymes. The presence of lectins that recognize further aged glycoproteins includes the mannose receptors, which would detect mannose ligands exposed following loss of sialic acid, galactose, and N‐acetylglucosamine linkages. Herein we have investigated the identities of glycoproteins modulated by mannose exposure with increasing age, and those are further regulated in their clearance and function by the endogenous macrophage mannose receptor (Mrc1). Mrc1 is found on macrophages and specialized cells in most organs as well as the vasculature and has a broad spectrum of both glycan and protein ligands due to its complex domain‐repeat structure composed of three distinct binding sites. A cysteine rich domain and a fibronectin like domain allow the binding of sulfated glycoproteins and collagens respectively. The lectin domain of Mrc1 can bind and endocytose mannosylated particles ranging from pathogens and allergens to mannosylated glycoproteins. Our studies reveal that the Mrc1 receptor has a lectin function that controls the half‐lives of specific glycoproteins in blood circulation, including those that have a regulatory role in cardiovascular and inflammatory processes.Support or Funding InformationNIH grant HL131474.