Structural diversity of mucins : Significance in infection and immunity

这一提议的具体目的是证明或反驳一种假说，粘蛋白是具有高度O-糖基化的上皮表面糖蛋白，作为对抗原生动物、细菌和病毒等寄生虫的特定防御分子。得到以下结论：(1)上皮粘蛋白的糖基化谱高度多样化。(2)粘蛋白的特异性糖基化受多个UDP-GalNAc-多肽N-乙酰半乳糖胺转移酶(PpGalNAc Ts)的协同作用高度调节。(3)Th2细胞因子IL-4显著增强几个ppGalNAc的表达(ppGalNAc T1、4和7)，导致粘蛋白2的糖基化谱改变。(4)这种改变后，分泌的粘蛋白改变了与凝集素的反应活性，(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-多肽复合体。它们被用来确定凝集素对粘蛋白基序的特异性。(6)病原体上的粘蛋白基序的变化也被证明在感染过程中起着重要的调节作用。(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.