FOR 2509: The concert of dolichol-based glycosylation: from molecules to disease models

糖单位与蛋白质的共价连接是一种复杂的翻译后修饰，存在于生命的所有领域。N-糖基化、C-甘露糖基化和O-甘露糖基化是普遍的且高度保守的糖基化途径，它们都是脊椎动物发育所必需的。这三种途径起始于内质网，基于脂质多萜醇，并竞争甘露糖供体底物和受体蛋白，在许多情况下，受体蛋白接受一种以上类型的聚糖。沿着这三种糖基化途径，今天我们知道超过30种基因中的内质网相关缺陷导致毁灭性的多系统疾病表现（先天性糖基化障碍（CDG-I）），强调了这些过程的重要性。到目前为止，所提到的三种糖基化途径已经彼此独立地进行了研究。然而，为了理解糖基化障碍的复杂性，必须破译基于多萜醇的N-糖基化、C-和O-甘露糖基化途径的细节，以及它们相互连接的精确条件。为了在分子、细胞和生物体水平上解决这些问题，我们不仅汇集了N-糖基化、C-和O-甘露糖基化方面的专家，还汇集了结构和脂质生物化学、蛋白质组学、糖蛋白质组学、糖组学和脂质组学以及发育生物学方面的专家。因此，在合作研究股的框架内，我们可以利用不同领域的最新方法发展。我们的愿景是更深入地了解基于Dolichol的糖基化，以促进诊断工具和新治疗方法的开发。

The covalent attachment of sugar units to proteins is a complex posttranslational modification found in all domains of life. N-glycosylation, C-mannosylation and O-mannosylation are prevalent and highly conserved glycosylation pathways, all essential for vertebrate development. The three pathways start in the endoplasmic reticulum, are based on the lipid dolichol and compete for both mannosyl donor substrates and acceptor proteins, which in many cases receive more than one type of glycan. Along these three glycosylation routes, today we know of endoplasmic reticulum associated defects in over 30 genes that cause devastating multisystemic disease manifestations (congenital disorders of glycosylation (CDG-I)), underlining the importance of these processes. So far, the three mentioned glycosylation pathways have been studied independently from each other. However, to understand the complexity of glycosylation disorders, it is imperative to decipher the details of the dolichol-based N-glycosylation, C- and O-mannosylation pathways, as well as the precise conditions for their interconnections. To address these questions on the molecular, cellular and organismal level, we have not only brought together experts in N-glycosylation, C- and O-mannosylation, but also in structural and lipid biochemistry, in proteomics, glycoproteomics, glycomics and lipidomics, as well as in developmental biology. In the frame of the collaborative Research Unit, we can thus make use of the newest methodological developments in the different fields. Our vision is to gain a deeper understanding of dolichol-based glycosylation to facilitate the development of diagnostic tools and new therapeutic approaches.