Glycosyltransferases. Structure, localization, and control of cell type-specific glycosylation.

The oligosaccharide chains (glycans) attached to cell surface and extracellular proteins and lipids are known to mediate many important biological roles. However, for many glycans, there are still no evident functions that are of obvious benefit to the organism that synthesizes them. There is also no clear explanation for the extreme complexity and diversity of glycans that can be found on a given glycoconjugate or cell type. Based on the limited information available about the scope and distribution of this diversity among taxonomic groups, it is difficult to see clear trends or patterns consistent with different evolutionary lineages. It appears that closely related species may not necessarily share close similarities in their glycan diversity, and that more derived species may have simpler as well as more complex structures. Intraspecies diversity can also be quite extensive, often without obvious functional relevance. We suggest one general explanation for these observations, that glycan diversification in complex multicellular organisms is driven by evolutionary selection pressures of both endogenous and exogenous origin. We argue that exogenous selection pressures mediated by viral and microbial pathogens and parasites that recognize glycans have played a more prominent role, favoring intra- and interspecies diversity. This also makes it difficult to appreciate and elucidate the specific endogenous roles of the glycans within the organism that synthesizes them.

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Evolutionary considerations in relating oligosaccharide diversity to biological function.

In this review, we organize the recent data concerning the effects of bioprocess factors on the oligosaccharide structure of human therapeutic glycoproteins, with particular emphasis on the influence of the host cell. We also discuss the effect of oligosaccharide structure on glycoprotein properties, including antigenicity, immunogenicity and plasma clearance rate.

The oligosaccharides of glycoproteins: bioprocess factors affecting oligosaccharide structure and their effect on glycoprotein properties.

The ST6Gal sialyltransferase controls production of the Siaα2-6Galβ1-4GlcNAc (Sia6LacNAc) trisaccharide, which is the ligand for the lectin CD22. Binding of CD22 to Sia6LacNAc is implicated in regulating lymphocyte adhesion and activation. We have investigated mice that lack ST6Gal and report that they are viable, yet exhibit hallmarks of severe immunosuppression unlike CD22-deficient mice. Notably, Sia6LacNAc-deficient mice display reduced serum IgM levels, impaired B cell proliferation in response to IgM and CD40 crosslinking, and attenuated antibody production to T-independent and T-dependent antigens. Deficiency of ST6Gal was further found to alter phosphotyrosine accumulation during signal transduction from the B lymphocyte antigen receptor. These studies reveal that the ST6Gal sialyltransferase and corresponding production of the Sia6LacNAc oligosaccharide are essential in promoting B lymphocyte activation and immune function.

https://www.pnas.org/content/pnas/95/8/4504.full.pdf

Immune regulation by the ST6Gal sialyltransferase

Cultured mammalian cells are being used to produce proteins for therapeutic and diagnostic use because of their ability to perform complex post-translational modifications, including glycosylation. The oligosaccharide moieties can play an important role in defining several biological properties of glycoproteins, including clearance rate, immunogenicity, and biological specific activity. There is a growing interest in defining the factors that influence glycosylation, including the cell culture environment. In this review we organize the published data from in vitro cell culture and tissue culture studies that demonstrate direct effects of the culture environment on N-linked glycosylation.

T. P. O'hanlon

Papers

Regulation of beta-galactoside alpha 2,6-sialyltransferase gene expression by dexamethasone.

Tissue-specific expression of beta-galactoside alpha-2,6-sialyltransferase. Transcript heterogeneity predicts a divergent polypeptide.