Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis

• Published in: The Journal of biological chemistry 2010-08, Vol.285 (32), p.25009-25017
• Main Authors: Jones, Mark B., Nasirikenari, Mehrab, Feng, Li, Migliore, Marina T., Choi, Kyoung-Soo, Kazim, Latif, Lau, Joseph T.Y.
• Format: Article
• Language: English
• Subjects: Acute Phase Response; Animals; Blood; Female; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Glycobiology and Extracellular Matrices; Glycoproteins - chemistry; Glycosylation; Hematopoietic Stem Cells - cytology; Liver; Liver - metabolism; Male; Mass Spectrometry - methods; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Bases of Disease; Myelopoiesis; Serum; Sialyltransferase; Sialyltransferases - blood; Sialyltransferases - metabolism; Stem Cells
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.104406

Recent findings have established a role for the ST6Gal-1 sialyltransferase in modulating inflammatory cell production during Th1 and Th2 responses. ST6Gal-1 synthesizes the Sia(α2,6) to Gal(β1,4)GlcNAc linkage on glycoproteins on cell surfaces and in systemic circulation. Engagement of P1, one of six promoter/regulatory regions driving murine ST6Gal-1 gene expression, generates the ST6Gal-1 for myelopoietic regulation. P1 utilization, however, is restricted to the liver and silent in hematopoietic cells. We considered the possibility that myelopoiesis is responsive to the sialylation of liver-derived circulatory glycoproteins, such that reduced α2,6-sialylation results in elevated myelopoiesis. However, 2-dimensional differential in gel electrophoresis (2D-DIGE) analysis disclosed only minimal alterations in the sialylation of sera glycoproteins of ST6Gal-1-deficient mice when compared with wild-type controls, either at baseline or during an acute phase response when the demand for sialylation is greatest. Furthermore, sera from ST6Gal-1-deficient animals did not enhance myelopoietic activity in ex vivo colony formation assays. Whereas there was only minimal consequence to the α2,6-sialylation of circulatory glycoproteins, ablation of the P1 promoter did result in strikingly depressed levels of ST6Gal-1 released into systemic circulation. Therefore, we considered the alternative possibility that myelopoiesis may be regulated not by the hepatic sialyl glycoproteins, but by the ST6Gal-1 that was released directly into circulation. Supporting this, ex vivo colony formation was notably attenuated upon introduction of physiologic levels of ST6Gal-1 into the culture medium. Our data support the idea that circulatory ST6Gal-1, mostly of hepatic origin, limits myelopoiesis by a mechanism independent of hepatic sialylation of serum glycoproteins.