CD46 as a Signaling Intermediate in N. Gonorrhoeae Infection

描述(申请人提供)：CD46是一种人类特有的膜蛋白，具有多种信号和受体特性。尽管这种蛋白质具有多功能的性质，但人们对其生物学表型背后的分子机制知之甚少。有几种病毒和细菌以CD46为靶标，将其用作受体或在感染细胞中下调其表达。致病性奈瑟氏菌(淋球菌和脑膜炎奈瑟氏菌)与上皮细胞CD46在多个水平上相互作用。通过IV型菌毛感染触发了它的磷酸化，改变了它的运输，并导致它的分泌。我们提出的证据表明，奈瑟氏菌感染还通过内源性蛋白酶复合体早老素/3-分泌酶(PS/3-S)刺激其蛋白分解过程，这一事件与细菌入侵有关。我们提出了一个CD46的PS/3-S加工模型，并对该模型所产生的预测进行了检验。我们的总体目标是提供一个强大的分子框架，以了解CD46的众多调控活动，包括它在感染中的作用。 与公共健康相关：CD46是一种人类特有的蛋白质，调节免疫系统的许多功能。CD46有四种丰富的亚型。这些异构体的相对水平有助于确定由CD46控制的生物学结果。CD46也是许多病毒和细菌的靶标-人类疱疹病毒6型、腺病毒、A组链球菌、脑膜炎奈瑟菌和淋球菌。我们的目标是了解奈瑟氏菌是如何通过早老素/3-分泌酶来调节CD46活性的。从这些研究中获得的知识有望指导制定控制微生物感染和干预涉及CD46的非传染性疾病的战略。

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.