Heparan sulfates (HS) are formed by the repetition of a disaccharide unit containing uronic acid and glucosamine residues. The fine structure of HS is rendered more complicated by the positioning of sulfate groups within the polymer. This structural diversity is controlled by the biosynthetic enzymes N-deacetylases/N-sulfotransferases (NDSTs), 2-O-, 3-O-, 6-O-sulfotransferases (HS2ST, HS3STs, HS6STs 1-3) and 6-O-endosulfatases (Sulfs), which modify the nascent polymer precursor [GlcUA-GlcNAc]n. Although the main features of HS biosynthesis have been outlined, several aspects, e.g. subcellular organization of the enzymes, mechanism of regulation of HS fine structure and properties of the individual isoenzymes involved, remain unclear.
Over the past few years, we explored the role of HS proteoglycans in the binding and activities of soluble mediators of inflammation and innate immunity. As example, we demonstrated that the responses induced by cyclophilin B are dependent on the interactions with a specialized HS motif, for which the structural features are determined by the high expression of NDST2 and 3-OST3 in T cells and monocytes/macrophages. A large panel of other inflammatory factors, e.g. chemokines and interleukin-4 have been reported to interact with HS. Therefore, it may be hypothesized that cell-type specific activity of these HS-binding factors is likely to be regulated by the coordinated expression and activities of certain HS sulfotransferases.
For the next 5-years period, our main objectives are (i) to elucidate the regulation of expression of HS sulfotransferases in inflammatory and immune cells and (ii) to explore the mechanisms by which these HS modifying enzymes work together in making HS motifs with binding and activating properties for inflammatory factors.
Research topics : Regulation of expression and activity of HS sulfotransferases - Cell-specific synthesis of HS motifs with binding and activating properties for inflammatory factors - Delineation and modelling of the interactions between HS and inflammatory factors - Synthesis of HS mimetics.
Key words : Heparan sulfate, sulfotransferase, inflammation, cancer immunity, cell signalling