CD46 as a Signaling Intermediate in N. Gonorrhoeae Infection

描述（由申请人提供）：CD46是一种人类特异性膜蛋白，具有许多信号和受体特性。尽管这种蛋白具有多种功能，但人们对其生物学表型的分子机制知之甚少。一些病毒和细菌以CD46为靶点，利用它作为受体，或者在感染细胞中下调它的水平。致病性奈瑟菌（淋病奈瑟菌和脑膜炎奈瑟菌）在多个水平上与上皮细胞CD46相互作用。通过IV型菌毛感染会触发其磷酸化，改变其运输，并导致其分泌。我们提供的证据表明，奈瑟菌感染也会刺激内源性蛋白酶复合物早老素/3-分泌酶（PS/3- s）的蛋白水解过程，这一事件与细菌入侵有关。我们提出了一个PS/3-S加工CD46的模型，并提出了测试该模型所产生的预测。我们的总体目标是提供一个强大的分子框架来理解CD46的众多调控活动，包括其在感染中的作用。

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.