C-Type Lectins and Sialyl Lewis X Oligosaccharides

Abstract

Carbohydrates are major components of the outer surface of mammalian cells and these carbohydrates are very often characteristic of cell-types and developmental stages (Feizi, 1985; Hakomori, 1985). One of such cell type-specific carbohydrates is sialyl Lewis X, NeuNAc 2 → 3Gal 1 → 4(Fuc 1 → 3)GlcNAc → R. Sialyl Lewis X and Lewis X, Gal 1 → 4(Fuc 1 → 3)GlcNAc, were originally discovered as differentiation antigens specific to granulocytes and monocytes (Fukuda et al., 1984; Mizogu-chi et al., 1984). These oligosaccharides can be synthesized when 1,3-fucosyltransferase(s) is present (Maly et al., 1996). Erythroid cells, which lack the 1,3-fucosyltrans-ferase, in contrast, express 1,2-fucosyltransferase. Resultant H-type oligosaccharides (O blood type), Fuc 1 → 2Gal 1 → 4GlcNAc 1 → R, are converted to A and B blood group antigens by addition of 1,3-linked N-acetyl-galactosamine or galactose through erythroid cell specific expression of two unique glycosyltransferases (Hakomori, 1985). These results show a typical example of cell type-specific oligosaccharides, of which synthesis is dependent on cell type-specific expression of a unique glycosyltrans-ferase. Specific expression of unique oligosaccharides strongly suggests that these oligosaccharides may serve as cell surface markers. Indeed, rapid and explosive understanding of the roles of sialyl Lewis X and its variants as cell recognition molecules has been taking place recently. In this mini-review, we would like to focus on the roles of this group of carbohydrates and C-type lectins that recognize those carbohydrates (for other aspects on this subject, see Springer, 1994; Butcher and Picker, 1996). In mammals, lymphocytes circulate in the vascular and lymphatic compartments, allowing maximum exposure of lymphocytes to foreign pathogens. Lymphocytes leave the vascular compartment at lymph nodes, traverse the lym-phatic organs, and then return to the vascular system. This directed flow of lymphocytes is dependent on carbohydrate ligands present on specialized endothelial cells, termed high endothelial venules (HEV) 1. It was discovered that lymphocyte binding to HEV is dependent on sialic acid on HEV and can be inhibited by fucosylated sul-fated oligosaccharides (Rosen and Bertozzi, 1996). When the homing receptor on lymphocytes, now called L-selec-tin, was molecularly cloned, its cDNA sequence predicted a carbohydrate-binding domain at its NH 2-terminus. This carbohydrate-binding domain is similar to that of the he-patic lectin, which recognizes asialo plasma glycoproteins (Ashwell and Harford, 1982). Carbohydrate-binding activity of these lectins is dependent on Ca , thus they are collectively called C-type lectin (Drickamer, 1994). Counter-receptors on HEV capture circulating lymphocytes via L-selectin-dependent adhesion, leading to transmigration (Fig. 1). L-selectin was found to be required for this process (Arbones et al., 1994). In parallel to this, two other adhesion molecules playing critical roles in the interaction between leukocyte-endo-thelial cells were identified. One of them, P-selectin, appears on the cell surface of platelets upon stimulation. Similarly, P-selectin, then E-selectin, another adhesive molecule, appears on the cell surface of endothelial cells after stimulation by inflammatory agents. E-and P-selec-tin also contain a carbohydrate-binding domain, which is highly homologous to that of L-selectin, having 60% identity at the amino acid levels among these molecules (Springer, 1994). Once these adhesion molecules were recognized as carbohydrate binding proteins, carbohydrate-ligands for E-and P-selectin were immediately identified as sialyl Lewis X (Lowe et al., 1990, for others, see Springer, 1994), previously shown to be present on neutrophils. During inflammation , leukocytes expressing sialyl Lewis X are recognized by P-or E-selectin and such initial adhesion results in the slowing down of leukocytes, a "rolling effect." This rolling effect leads to vascular extravasation of leukocytes, similar to the process shown in Fig. 1. The above results so far indicate that all selectins recognize sialyl Lewis X as ligands. How then could each interaction achieve a more specific interaction? First, glycoproteins presenting sialyl Lewis X oligosac-charides are specific for each cell-type, providing unique interactions to each cell-type. L-selectin carbohydrate ligands are presented by GlyCAM-1, CD34, MAdCAM-1, and other glycoproteins, all of which contain mucin-type O-linked oligosaccharides. P-selectin carbohydrate ligands