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Structural diversity of mucins : Significance in infection and immunity

粘蛋白的结构多样性：在感染和免疫中的意义

基本信息

批准号：
12307054
负责人：
IRIMURA Tatsuro
金额：
$ 27.58万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

项目摘要

The specific aim of this proposal was to prove or disprove a hypothesis whether mucins, epithelial surface glycoproteins with a high degree of O-glycosylation, played roles as specific defense molecules against parasites, such as protozoa, bacteria, and viruses. The following conclusions were obtained.(1)Epithelial mucins were highly diverse in their glycosylation profiles.(2)The specific glycosylation of mucins were regulated in a high degree of fidelity by concerted actions of multiple UDP-GalNAc-polypeptide N-acetylgalactosaminyltransferases (ppGalNAc Ts).(3)A Th2 cytokine, IL-4, drastically enhance the expression of a few ppGalNAc Ts (ppGalNAc T1, 4, and 7), which resulted in an alteration of glycosylation profiles of mucin 2.(4)After such alterations, the secreted mucins changed its reactivity with lectins, carbohydrate-binding proteins.(5)Various oligosaccharide-polypeptide complexes were prepared by the use of recombinant ppGalNAc Ts and other glycosyltransferases in vitro. They were tested to determine the specificity of lectins toward mucin motifs.(6)Variations in mucin motifs on pathogens, such as the surface coat glycoproteins of Ebola virus, were also shown to play important roles in the regulation of infective processes.(7)In these processes, C-type/galactose-type lectins on macrophages and dendritic cells were shown to be significantly involved.

该提案的具体目的是证明或反驳一个假设，即粘蛋白（具有高度O-糖基化的上皮表面糖蛋白）是否作为针对寄生虫（如原生动物、细菌和病毒）的特异性防御分子发挥作用。得出以下结论。（1）上皮粘蛋白的糖基化谱高度多样。（2）多个UDP-GalNAc-多肽N-乙酰氨基半乳糖转移酶（ppGalNAc Ts）协同作用，高度精确地调控粘蛋白的特异性糖基化。(3)A Th 2细胞因子IL-4显著增强了几个ppGalNAc Ts（ppGalNAc T1、4和7）的表达，这导致粘蛋白2的糖基化谱的改变。（4）在这种改变之后，分泌的粘蛋白改变了其与糖结合蛋白凝集素的反应性。（5）利用重组ppGalNAc Ts和其他糖基转移酶在体外制备了各种寡糖-多肽复合物。测试它们以确定凝集素对粘蛋白基序的特异性。（6）病原体上粘蛋白基序的变化，例如埃博拉病毒的表面外壳糖蛋白，也被证明在感染过程的调节中发挥重要作用。(7)In巨噬细胞和树突状细胞上的C型/半乳糖型凝集素显示出显著参与这些过程。