Regulatory Mechanisms of Glycoprotein Sialylation

Case Western Reserve University, Cleveland OH

Investigators

Linked publications & trials

Abstract

Summary A major gap in the “bench to bedside” paradigm is the ability to harness the glycome for the development of novel therapeutics. Although decades of research in glycobiology have established glycomic changes associated with disease, almost nothing is known about how those changes arise, the functions they play in disease initiation or progression, or how the glycome is regulated at the compositional level. Based on our recent discoveries, we propose a transformative new model for glycomic compositional regulation of secreted glycoproteins that provides a clear path for the development of the first generation of glycan- modulating therapies for a wide range of diseases. The model is based on the notion that the glycans on glycoproteins can be remodeled after release from the originating cell, and if correct, our findings will rewrite the glycobiology dogma that glycomic changes are dependent upon the slow process of protein turnover and de novo synthesis to one where change is highly dynamic, rapid, and specific to the immunologic environment. The proposal centers on the molecular action, regulation, and necessary microenvironment for the sialyl transferase ST6Gal1 to add α2,6-linked sialic acids onto IgG glycans. Our proposal focuses upon the B cell-secreted antibody IgG because alterations in sialylation alters Fc domain conformation and FcγR binding such that anti-inflammatory signaling is enhanced. We have discovered that the vascular endothelium and the FcRn-mediated recycling pathway is the dominant system through which IgG is sialylated, leading to two proposed specific aims. In Aim 1, we will define the biochemical and cellular mechanisms of FcRn-dependent IgG sialylation in the endothelium. In Aim 2, we will interrogate the regulatory features underlying changes in IgG sialylation during inflammatory responses. The overall goal is to develop a comprehensive understanding of the mechanisms underlying the regulation of IgG sialylation which will provide a lasting and profound impact on the field and human health. It is known that the suppressive activity of exogenous intravenous Ig therapy is enhanced by IgG sialylation. Through an understanding and targeting of the fundamental regulatory tenets of this novel pathway, we could finally unlock the potential to modulate the sialylation of endogenous IgG within patients with inflammatory disease.