Glycosyltransferase Function in Development and Disease

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

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Abstract

Summary Glycosyltransferases generate covalent glycosidic linkages that include post-translational modifications to the vast majority of secreted and cell surface glycoproteins. Mammalian sialyltransferases are a highly conserved family of glycosyltransferases that attach sialic acids at distal and terminal positions during glycan synthesis mostly as a2-3 and a2-6 anomeric linkages. Sialic acid linkages can form ligands of various receptors including the Siglec receptors of immune cells. Siglecs bind sialic acids in cis and trans at cell surfaces thereby controlling the assembly and signaling of immune cell receptor complexes. For example, Siglec binding to cell surface sialic acid linkages induces immunological tolerance with the induction of B lymphocyte anergy and apoptosis, which can block autoantibody induction and inhibit the onset of lupus-like autoimmune disease in mouse models. The pathogenesis of autoimmune disease reflects defects in immunological tolerance but remains poorly understood. Most mammalian cell surfaces are covered with glycoproteins bearing sialylated asparagine-linked (N)-glycans. Unexpectedly, we have observed low levels of sialyltransferase expression and sialic acids among normal mouse and human pancreatic beta cells. This intrinsically low level of sialylation limits the expression of Siglec ligands and may be disadvantageous in the presence of a dysfunctional hyperactive immune system. In Type 1 diabetes (T1D), a defect in immunological tolerance results in the destruction of pancreatic beta cells. Although dysregulation of the immune system is believed to represent the origin of this disease, the reason why pancreatic beta cells are targeted is not known. This research proposal is focused on a unique hypothesis reinforced by significant supporting data that the susceptibility of pancreatic beta cells to immunological attack in autoimmune diabetes reflects low levels of toleragenic sialic acids. To identify the mechanistic features of immunological tolerance to pancreatic beta cells, we have initially studied the Non-Obese Diabetic ShiLT/J (NOD) mouse because of its well-defined disease signs that include spontaneous insulitis progressing to beta cell destruction, insulin deficiency and diabetes, and because of the large body of immunological knowledge that has been acquired using this model of human T1D. We have generated and analyzed transgenic syngeneic NOD mice bearing increased expression of sialic acids on pancreatic beta cell glycoproteins. Remarkably, augmentation of sialic acid linkages protects NOD mice from insulitis and the immunological destruction of pancreatic beta cells. The research proposed herein will compare disease protection afforded by transgenic sialyltransferase expression augmenting a2-3 and a2-6 sialic acid linkages and Siglec ligands in NOD beta cells, and complete transplant studies to gain mechanistic insights of how sialic acids participate in immunological tolerance. Discovering the roles of glycosyltransferases in tissue- specific autoimmunity will enhance the understanding of immunological tolerance mechanisms and is likely to aid in the development of preventative and curative approaches to autoimmune diseases such as T1D.