CD46 as a Signaling Intermediate in N. Gonorrhoeae Infection

CD46 作为淋病奈瑟菌感染中的信号传导中间体

• 批准号: 8015469
• 负责人: MAGDALENE Y SO
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015469
• 关键词: Adenoviruses; Affect; Bacteria; Biological; CD46 Antigen; Cells; Cleaved cell; Communicable Diseases; Complex; Cytoplasmic Tail; Development; Epithelial Cells; Event; Goals; Herpesviridae; Human; Immune system; Infection; Knowledge; Link; Matrix Metalloproteinases; Membrane; Membrane Proteins; Modeling; Molecular; Nature; Neisseria; Neisseria gonorrhoeae; Neisseria meningitidis; Outcome; Peptide Hydrolases; Phenotype; Phosphorylation; Pilum; Process; Property; Protein Isoforms; Proteins; Proteolytic Processing; Receptor Signaling; Relative (related person); Role; Signal Transduction; Streptococcus pyogenes; Testing; Virus; microbial; presenilin; public health relevance; receptor; secretase; trafficking

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.

描述（由申请人提供）：CD46是一种具有许多信号传导和受体特性的人特异性膜蛋白。尽管该蛋白质具有多功能性，但对其生物学表型的分子机制知之甚少。几种病毒和细菌靶向CD46，将其用作受体或在感染细胞中下调。致病性奈瑟氏菌（N. Gonorrhoeae和N.脑膜炎）在多个水平上与上皮细胞CD46相互作用。通过IV型菌毛的感染触发其磷酸化，改变其贩运并引起其分泌。我们提供的证据表明，奈瑟氏菌感染还通过内源性蛋白酶复合蛋白复合蛋白/3-泌尿酶（PS/3-S）刺激其蛋白水解加工，这一事件与细菌浸润有关。我们提出了一个用于CD46的PS/3-S处理的模型，并建议测试该模型产生的预测。我们的总体目标是提供一个强大的分子框架，以了解CD46的众多调节活动，包括其在感染中的作用。 公共卫生相关性：CD46是一种人类特异性蛋白质，可调节免疫系统的许多功能。 CD46有四个丰富的同工型。这些同工型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，腺病毒，A组，链球菌，奈瑟氏菌脑膜炎和淋病奈瑟氏菌。我们的目标是了解奈瑟氏菌如何通过Presenilin/3-泌尿蛋白酶蛋白酶调节CD46的活性。从这些研究中获得的知识将有望指导制定控制微生物感染并干预涉及CD46的非感染疾病的策略。