Regulatory Mechanisms of Glycoprotein Sialylation

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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 actually regulated. Based on provocative new data, we propose a transformative new model for glycomic compositional regulation of soluble 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 of glycoproteins can be remodeled after release from the originating cell, and if correct, our findings will refute the glycobiology dogma in which glycomic changes are dependent upon the slow process of protein turnover and de novo synthesis to one that is highly dynamic, rapid, and specific to the immunologic environment. The proposal centers on the molecular action, regulation and necessary microenvironment for ST6Gal1 to add α2,6-linked sialic acids onto glycans with available terminal galactose residues. Our proposal also focuses upon the B cell-secreted glycoprotein/antibody IgG. This is a critical pathway to understand because ST6Gal1 is the sole enzyme that determines whether anti-inflammatory α2,6-sialyl-IgG or pro-inflammatory asialyl-IgG is produced at any given time, thereby making it a key immunomodulatory factor. In Aim 1, we will dissect the enzymatic action of ST6Gal1 from cells other than B cells during IgG production. In Aim 2, we will extend our studies to the microenvironment necessary to support ST6Gal1 activity in modifying IgG sialylation. Even if our model for glycoprotein glycan remodeling is limited to sialylation, such a pathway could influence immune pathways such as leukocyte trafficking, the distinction between self and non-self by siglecs, synthesis of the ABO blood groups, transplantation, IgG functionality and many others. Our findings could redefine the nature of the glycome as one under dynamic regulation that could be therapeutically harnessed via the creation of an entirely new class of glycosylation-altering drugs for the treatment of diseases ranging from inflammatory disorders and autoimmunity to cancer.