Mammalian sugar-binding receptors: known functions and unexplored roles

Abstract

Mammalian glycan-binding receptors, sometimes known as lectins, interact with glycans, the oligosaccharide portions of endogenous mammalian glycoproteins and glycolipids as well as sugars on the surfaces of microbes. These receptors guide glycoproteins out of and back into cells, facilitate communication between cells through both adhesion and signaling, and allow the innate immune system to respond quickly to viral, fungal, bacterial, and parasitic pathogens. For many of the roughly 100 glycan-binding receptors that are known in humans, there are good descriptions of what types of glycans they bind and how selectivity for these ligands is achieved at the molecular level. In some cases, there is also comprehensive evidence for the roles that the receptors play at the cellular and organismal levels. In addition to highlighting these well-understood paradigms for glycan-binding receptors, this review will suggest where gaps remain in our understanding of the physiological functions that they can serve.

Keywords: glycan-binding proteins; glycoprotein turnover; innate immunity; intracellular trafficking; lectins.

Figure 1

Glycan‐binding receptors in cell adhesion. (A) P‐ and E‐selectins in adhesion between leukocytes and endothelial cells. The sialyl‐Lewis^x tetrasaccharide on endothelial cells at sites of inflammation serves as an attachment point for the C‐type CRD of the selectin, mediating an initial weak adhesion that results in leukocytes rolling along the endothelium. (B) Sugar‐binding activity of laminin in cell‐matrix interaction. A repeating disaccharide unit attached to dystroglycan at the surface of muscle cells is bound by the LG domain of laminin, which in turn links to the extracellular matrix.

Figure 2

Galectin‐mediated autophagy. Lysis of cytoplasmic vesicles can be induced by bacteria that have entered the cell by endocytosis. To prevent the bacteria from colonizing the cytoplasm, glycans on the lysed vacuolar membrane are bound by galectin‐8, which through interaction with the autophagy receptor NDP52 initiates formation of an autophagosome to enclose the bacterium.

Figure 3

Glycan‐binding receptors that selectively remove glycoproteins from blood. (A) Receptors in the liver. The mannose receptor on liver sinusoidal endothelial cells and Kupffer cells binds to glycoproteins that constitutively display glycans that signal rapid clearance from the circulation. Binding and uptake by the asialoglycoprotein receptor on hepatocytes usually requires triggering by removal of terminal sialic acid residues to expose galactose residues. (B) The SRCL on vascular endothelial cells. Binding to the Lewis^x trisaccharide on proteins in secondary granules of neutrophils results in uptake and degradation.

Figure 4

Mechanisms of controlling intracellular signaling by glycan‐binding receptors. (A) Transmembrane glycan‐binding receptors that initiate signaling through ITIMs in the cytoplasmic domain of the receptors. (B) Receptors that initiate signaling through ITAMs in associated adapter polypeptides such as the Fc receptor γ chain or DAP‐12. (C) Formation of a functional ITAM in the cytoplasmic domain of detcin‐1 by dimerization. (D) Galectin modulation of signaling by interaction with glycans on membrane receptors. In the example shown, bivalent galectin‐1 stimulates phosphatase activity of CD45 by clustering of the receptor.