Structural diversity of mucins : Significance in infection and immunity

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）的特定防御分子发挥作用。得到以下结论：(1)上皮黏蛋白的糖基化谱高度多样化。(2)黏蛋白的特异性糖基化是由多个udp - galnac -多肽n -乙酰半乳糖氨基转移酶（ppGalNAc Ts）协同作用的高度保真度调节的。(3) Th2细胞因子IL-4可显著增强ppGalNAc t （ppGalNAc T1、4和7）的表达，从而导致粘蛋白2糖基化谱的改变。(4)经过这样的改变，分泌的粘蛋白改变了它与凝集素、碳水化合物结合蛋白的反应性。(5)利用重组ppGalNAc Ts和其他糖基转移酶在体外制备了多种寡糖-多肽复合物。他们进行了测试，以确定凝集素对粘蛋白基序的特异性。(6)病原体黏液蛋白基序的变化，如埃博拉病毒的表面涂层糖蛋白，也被证明在感染过程的调节中发挥重要作用。(7)在这些过程中，巨噬细胞和树突状细胞上的c型/半乳糖型凝集素被证明显著参与。

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.