CD46 as a Signaling Intermediate in N. Gonorrhoeae Infection

描述（由申请人提供）：CD 46是一种具有多种信号传导和受体特性的人特异性膜蛋白。尽管这种蛋白质的多功能性，很少有人知道其生物学表型的分子机制。一些病毒和细菌靶向CD 46，将其用作受体或在感染细胞中下调它。致病性奈瑟氏菌（N.淋病奈瑟菌和淋病奈瑟菌。脑膜炎）与上皮细胞CD 46在多个水平上相互作用。通过IV型菌毛的感染触发其磷酸化，改变其运输，并导致其分泌。我们目前的证据表明，奈瑟菌感染也刺激其蛋白水解加工的内源性蛋白酶复合物早老素/3-分泌酶（PS/3-S），一个事件，是与细菌入侵。我们提出了一个PS/3-S处理的CD 46的模型，并建议测试从这个模型产生的预测。我们的总体目标是提供一个强有力的分子框架，以了解CD 46的许多调节活动，包括其在感染中的作用。 公共卫生相关性：CD 46是一种人类特异性蛋白质，调节免疫系统的许多功能。有四种丰富的CD 46亚型。这些亚型的相对水平有助于确定由CD 46控制的生物学结果。CD 46也是许多病毒和细菌的靶标-人疱疹病毒6、腺病毒、A组链球菌、脑膜炎奈瑟菌和淋病奈瑟菌。我们的目标是了解奈瑟菌如何通过早老素/3-分泌酶蛋白酶调节CD 46的活性。从这些研究中获得的知识将有望指导控制微生物感染和干预涉及CD 46的非感染性疾病的策略的发展。

DESCRIPTION (provided by applicant): CD46 is a human-specific membrane protein with numerous signaling and receptor properties. Despite the multifunctional nature of this protein, little is known about the molecular mechanisms underlying its biological phenotypes. Several viruses and bacteria target CD46, using it as a receptor or downregulating it in infected cells. Pathogenic Neisseria (N. gonorrhoeae and N. meningitidis) interact with epithelial cell CD46 at multiple levels. Infection via the Type IV pilus triggers its phosphorylation, alters its trafficking, and causes its secretion. We present evidence that Neisseria infection also stimulates its proteolytic processing by the endogenous protease complex Presenilin/3- Secretase (PS/3-S), an event that is linked to bacterial invasion. We present a model for PS/3-S processing of CD46, and propose to test predictions arising from this model. Our overall goal is to provide a strong molecular framework for understanding the numerous regulatory activities of CD46, including its role in infection. PUBLIC HEALTH RELEVANCE: CD46 is a human specific protein that regulates many functions of the immune system. There are four abundant isoforms of CD46. The relative levels of these isoforms helps to determine biological outcomes controlled by CD46. CD46 is also the target for many viruses and bacteria - human herpes virus 6, adenovirus, Group A Streptococci, Neisseria meningitidis and Neisseria gonorrhoeae. Our goal is to understand how Neisseria regulates the activity of CD46 through the Presenilin/3-Secretase protease. Knowledge gained from these studies will hopefully guide the development of strategies to control microbial infections and intervene in non-infectious diseases that involve CD46.