CD46 as a Signaling Intermediate in N. gonorrhoeae Infection

摘要 CD46是一种人类特有的免疫调节蛋白，在免疫反应中具有信号和受体特性 细胞。CD46的激活可以导致多种结果，从免疫调节到 炎症，取决于两种异构体的相对水平。几种病毒和细菌作为靶标 CD46在感染过程中，将其用作受体或下调感染细胞中的CD46。淋病奈瑟菌(Ng) 与上皮细胞CD46在多个水平上相互作用。通过IV型毛发直接或间接感染 触发其磷酸化，改变其运输，并导致其分泌。 虽然已经发表了与CD46相关的许多生物学表型，但很少有 知道它们背后的分子机制。我们已经获得了令人信服的证据 致病奈瑟氏菌、淋病奈瑟菌和脑膜炎奈瑟菌通过 早老素/分泌酶(PS)，一种调节许多重要信号蛋白的蛋白酶复合体。 我们的目标是了解CD46的早老素/分泌酶处理如何影响其信号转导 宿主细胞的活动，以及这些活动与感染的关系。为此，我们提出了一个模型 CD46的加工途径，我们建议检验这个模型的预测。我们独一无二 利用我们的尾部特异性单抗和早老素双阴性突变体为这些研究定位 细胞系。我们的研究将有助于阐明奈瑟氏菌生物学的寄主方面。我们的发现也将 增加了CD46功能的知识库，并有望阐明其他病原体/CD46 互动。

Abstract CD46 is a human-specific immunoregulatory protein with signaling and receptor properties in immune cells. Activation of CD46 can lead to a variety of outcomes, ranging from immune regulation to inflammation, depending on the relative levels of the two isoforms. Several viruses and bacteria target CD46 during infection, using it as a receptor or downregulating it in infected cells. N. gonorrhoeae (Ng) interacts with epithelial cell CD46 at multiple levels. Infection via the Type IV pilus directly or indirectly triggers its phosphorylation, alters its trafficking, and causes its secretion. Although is published on the numerous biological phenotypes associated with CD46, little is known about the molecular mechanisms underlying them. We have obtained compelling evidence that the pathogenic Neisseria, N. gonorrhoeae and N. meningitidis, stimulate CD46 processing by Presenilin/¿-Secretase (PS), a protease complex that regulates many important signaling proteins. Our goal is to understand how Presenilin/¿-Secretase processing of CD46 affects its signaling activities of host cells, and how these activities relate to infection. We propose a model for this CD46 processing pathway and we propose to test the predictions from this model. We are uniquely positioned for these studies with our tail-specific mAbs and the Presenilin double negative mutant cell line. Our studies will shed light on the host aspect of Neisseria biology. Our findings will also add to the knowledge base of CD46 function, and hopefully shed light on other pathogens/CD46 interactions.