It has been recently proposed that lectins such as galectins, C-type lectins and siglecs in innate immunity bind to foreign pathogens by density-dependent recognition of surface glycans (Dam and Brewer 2010). In many cases, foreign pathogens including viruses and bacteria possess glycan epitopes such as Man and LacNAc residues that are also found on host cells (Vasta 2009). Host lectins appear to bind to the pathogens due to their high density and number of glycan epitopes relative to those on host cells (Dam and Brewer 2010). Unique “weak” glycan epitopes on foreign pathogens appear to be strong epitopes when presented in high-density presentations such as polysaccharides and lipopolysaccharides (Dam and Brewer 2010). Thus, the concept of lectins as pattern recognition receptors in innate immunity (Medzhitov and Janeway 2000; Vasta 2009) has been replaced with lectins as density-dependent glycan binding receptors. However, in order for host lectins to bind to density-dependent expression of glycans on foreign pathogens, the glycan density of host cells must be established and controlled. Evidence that metazoans do regulate their surface glycan density comes from a new study on the effects of mutations in the pathway for the formation of a specific branch chain in Nlinked glycoproteins in mouse cells that results in apparent global compensation of glycan epitope number (density) in the remaining branch chains of the mutant’s N-linked carbohydrates (Takamatsu et al. 2010). N-acetylglucosaminyltransferase-IV (GnT-IV) exists as two isoenzymes, a and b, that initiate the synthesis of the GlcNAcβ1-4 branch on the core Manα1-3 arm of N-glycans. One effect of the GlcNAcβ1-4 branch chain is to increase the glycan epitope density per N-linked carbohydrate chain. Takamatsu et al. (2010) engineered and characterized GnT-IVb-deficient mice and double-IVa/IVbdeficient mice. Wild-type mice have GnT-IVa expression restricted to gastrointestinal tissue, while GnT-IVb is broadly expressed among organs. GnT-IVb-deficient mice show aberrant GnT-IVa expression corresponding to the GnT-IVb distribution pattern, and hence, the GnT-IVb-deficient mice show mild phenotypic alterations in hematopoietic cells and hemostasis. Importantly, GnT-IVa/IVb double-deficient mice have completely abolished GnT-IV activity, and thus there is a complete disappearance of the GlcNAcβ1-4 branch on the Manα1-3 arm of the N-linked glycans that was confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MS) and gas chromatography-MS analyses. The absence of the GlcNAcβ1-4 branch, however, was shown by MS analyses as additional glycan epitope extensions on the remaining branches in the tissues of the N-linked glycans of the GnT-IVa/IVb double-deficient mice. For example, the Le epitope is found in greater number in the N-linked glycans from mouse kidney cells, and biosynthetic compensation is observed in biand triantennary N-glycans of the double mutant relative to the tetra-antennary N-glycans of the wild-type cells (Figure 1) (Takamatsu et al. 2010). Similar biosynthetic compensation was observed for other glycan epitopes such as polylactosamine in the pancreas. Analysis shows that these additional glycan epitopes in the GnT-IVa/IVb double-deficient mice are due to elevated expression of glycosyltransferases that are normally involved in their biosynthesis. Remarkably, the phenotype of the GnT-IVa/IVb double-deficient mice was similar to that of the GnT-IVa single-deficient mice, which is relatively mild compared to the wild-type mice. The ability of the GnT-IVa/IVb double-deficient mice to effectively restore glycan epitope density in the remaining N-linked glycans of the different organs of the mice suggests that maintenance of this density is critical to the homeostatic function of the cells and organs of the mouse. The authors describe these findings as the first example of induced glycomic compensation of glycosyltranserase activities of cells from different organs of the mice (Takamatsu et al. 2010). They also suggest that maintenance of the overall expression of glycan ligands for endogenous lectins in the double-mutant mice appears to prevent cellular dysfunctions, but no mechanism was suggested for these effects. We suggest that a possible mechanism for regulating cell surface glycan density in both the wild-type and GnT-IVa/
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Mar 1, 2011
Elena Matei + 3
Open Access
