Unraveling the influence of vesicular trafficking on regulation of heparan sulfate biosynthesis

Abstract

It has been assumed that the biosynthesis of Heparan Sulfate ((HS) occurs through a hierarchical sequence of enzymatic events, involving polymerization, sulfation and epimerization, and the 3-O-sulfotransferase (HS3ST) is the last enzyme in this sequence of events. However, we have recently shown that HS3ST can act at different stages of HS biosynthesis and besides enzyme specificity, other factors could regulate this biosynthetic process. Recently we have shown that vesicular traffic influences HS biosynthesis by interfering with charge selection as well as enzyme localization in Golgi cisterns, showing that the different substitution patterns found in HS are a result of the different distribution of the biosynthetic enzymes in the endoplasmatic reticulum-Golgi pathway. However, despite this evidence, the mechanism of selection of HS modifying enzymes in the vesicles as well as in the different Golgi cisterns remains unclear. Thus, in the present project, we will investigate the influence of vesicular trafficking accessory proteins on HS biosynthesis. The mechanisms responsible for the retention of HS modifying enzymes along the secretory route will also be investigated in order to understand the regulatory role played by vesicular trafficking on HS biosynthesis. The field of glycosaminoglycans has greatly expanded in the past three decades and now encompasses different areas of research. In this project we are proposing a new tactic to the understanding of glycosaminoglycans synthesis and we have assembled a blend of diverse techniques to tackle the problem which are in the frontier of Glycobiology Sciences. Few laboratories worldwide are dedicated to this problem due to the array of techniques that are required, and our group has this type of expertise. (AU)