Sialylation of Serum Glycoproteins : The role of ST6Gal I sialyltransferase

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Authors
Migliore, Marina
Issue Date
2008
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Thesis
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en_US
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Abstract
The sialyltransferase ST6Gal-l, mediating the synthesis of the a2,6-sialyl linkage to Gal(pl,4)GlcNAc, is expressed ubiquitously in mammals but with particular abundance in the liver. During the acute phase response - the liver's response to insult or injury, there is deposition into circulation of heavily sialylated proteins including haptoglobin, and a 1-acid glycoprotein, to name a few. The acute phase response is also accompanied by hepatic up-regulation of ST6Gal-l expression, but the functional relevance of hepatic ST6Gal-l remains poorly understood. Previously, we generated a mutant mouse, SiatlAPl, by specifically inactivating the liver specific promoter, known as the PI region, of the ST6Gal-l gene. We showed that the SiatlAPl mouse had homeostatic disruption to the myeloid compartment, resulting in an elevated capacity in the bone marrow to replenish the granulocyte compartment. This myelopoietic disruption was presumed to be driven by an extra medullary mechanism, likely involving altered sialylation of hepatically synthesized serum glycoproteins, many of which have known immuno-modulatory properties. An initial examination, however, demonstrated an essential/unchanged degree of overall sialylation between wild-type and SiatlAPl animals. Moreover, serum glycoproteins in animals with globally inactivated ST6Gal-l remain fully sialylated. In the current work, we used high-resolution 2D gel electrophoresis and lectin affinity for an in-depth analysis of serum glycoproteins to reveal significant qualitative and quantitative changes in the sialylation of serum glycoproteins between wild-type and SiatlAPl mice. These changes were further magnified after subcutaneous exposure of the animals to the irritant, turpentine. Thus, not only the extent, but also types of sialyl linkages on serum glycoproteins are important. The deficient a2,6-sialylated hepatically produced serum glycoproteins may very well function distally, resulting in physiologically relevant alterations to acute inflammation and to maintenance of inflammatory cell numbers.
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35 p.
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Kalamazoo College
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