ROLE OF CMV ENVELOPE GLYCOPROTEINS IN POLARIZED CELLS

CMV 包膜糖蛋白在极化细胞中的作用

• 批准号: 6518745
• 负责人: LENORE PALMA PEREIRA
• 金额: $ 29.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6518745
• 关键词: biological signal transduction; cellular polarity; cytomegalovirus; epithelium; intracellular transport; protein transport; tissue /cell culture; vascular endothelium; virus infection mechanism; virus protein

DESCRIPTION (Adapted from applicant's abstract): Human cytomegalovirus (CMV) infection of polarized cells is central to invasion at the portal of entry and virus dissemination in the host. This applicant's hypothesis is that key CMV envelope glycoproteins, gB and the gH complex, contain sorting signals recognized by cognate partners in the endocytic pathway that are co-opted to direct virion envelopment and egress from a cytosolic compartment. CMV gB, the major component of the virion envelope, is transported to the apical membrane domain where virions egress in polarized human epithelial cells. In transfected cells, gH targets to basolateral membranes. Both glycoproteins traffic in the endocytic pathway. Our unexpected new finding, that gB and the gH complex converge in a perinuclear endocytic compartment with virion matrix proteins, establishes that envelopment occurs in cytosolic vesicles of epithelial cells and suggests that virion egress could be regulated by glycoproteins sorted in common endosomes and/or the apical recycling compartment. A central question is how the sorting signal hierarchy in gB and gH complex modulates virion envelopment and egress routes in the context of two polarized cell types: epithelial and endothelial cells. The specific aims are to: (1) Finish identifying functional sorting signals in CMV gB and gH complex used for trafficking in polarized cells. The hypothesis is that the cytosolic domains of these glycoproteins contain multipartite signals that regulate their trafficking in endocytic pathways. (2) Continue to identify cognate binding partners co-opted by cytosolic sorting signals in CMV gB and gH complex. The goal is to determine which cellular proteins regulate their transport in the endocytic/recycling pathway. (3) Elucidate CMV virion envelopment and egress routes in the context of infected polarized epithelial cells and the signal hierarchy that modulates this pathway. (4) Investigate CMV glycoprotein sorting and virion envelopment and egress pathways in endothelial cells, another polarized cell type that plays a critical role in CMV infection. These experiments will advance knowledge of transport motifs and cellular molecules that modulate virion envelopment and egress routes in polarized epithelial cells and improve understanding of virus release from endothelial cells as a model for transmission from vascular beds in vivo. Conceivably, these findings will be of interest to cell biologists and could have medical relevance to vascular biology and organ transplantation. Possibly, the strategies used by CMV for selective targeting to endocytic subcompartments could be incorporated into novel approaches for introducing antiviral compounds into cytosolic vesicles in polarized cells in order to preclude virion envelopment and egress.

描述（改编自申请人的摘要）：人类巨细胞病毒（CMV） 极化细胞的感染对于进入入侵的入侵至关重要， 宿主中的病毒传播。该申请人的假设是关键CMV 信封糖蛋白，GB和GH综合体包含排序信号 在内吞途径中被同源伴侣认可的 直接从胞质室中的直接病毒包膜和出口。 CMV GB， 病毒座包膜的主要组成部分被运输到顶膜 域中病毒体在极化的人上皮细胞中。在转染中 细胞，GH靶向基底外侧膜。两种糖蛋白在 内吞途径。我们意外的新发现，GB和GH综合体 用病毒体基质蛋白在核周内吞室中收敛， 确定包膜发生在上皮细胞的胞质囊泡中 并表明可以通过分类的糖蛋白来调节病毒体的出口 常见的内体和/或顶端回收室。一个核心问题是 GB和GH复合物中的排序信号层次结构如何调节病毒粒子 在两种极化细胞类型的背景下，包络和出口路线： 上皮和内皮细胞。具体目的是：（1）完成 在CMV GB和GH复合物中识别功能排序信号 在极化细胞中运输。假设是 这些糖蛋白包含调节其的多部分信号 贩运内吞途径。 （2）继续识别同源绑定 CMV GB和GH复合物中的胞质分选信号选择的伴侣。这 目标是确定哪种细胞蛋白调节其在 内吞/回收途径。 （3）阐明CMV病毒座包裹和出口 在感染的偏光上皮细胞和信号的背景下的路线 调节此途径的层次结构。 （4）研究CMV糖蛋白分选 以及内皮细胞中的病毒座包裹和出口途径，另一个 极化细胞类型在CMV感染中起关键作用。这些 实验将提高对传输基序和细胞分子的了解 该调节病毒座包裹和出口路线在极化上皮 细胞并提高对病毒从内皮细胞释放的理解 体内血管床传播的模型。可以想象，这些发现 细胞生物学家将感兴趣，并且可以与 血管生物学和器官移植。可能是，使用的策略 可以将CMV用于选择性靶向内吞子分街的靶向 进入新的方法，用于将抗病毒化合物引入胞质 极化细胞中的囊泡以排除病毒座包膜和出口。