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: 6266309
• 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/6266309
• 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（改编自申请人摘要）：人巨细胞病毒（CMV） 极化细胞的感染是在入口处侵入的中心， 病毒在宿主体内传播。本申请人的假设是，关键CMV 包膜糖蛋白gB和gH复合物含有分选信号 被内吞途径中的同源伙伴识别， 直接从胞质区室释放病毒粒子。CMV gB， 病毒体包膜的主要成分，被运输到顶膜 在极化的人类上皮细胞中，病毒体在其中排出。转染 细胞，gH靶向基底外侧膜。这两种糖蛋白都在 内吞途径我们意外的新发现，gB和gH复合体 与病毒体基质蛋白会聚在核周内吞区室中， 证实了凋亡发生在上皮细胞的胞质小泡中， 并表明病毒体的排出可能受到糖蛋白的调节， 共同的内体和/或顶端再循环室。一个核心问题是 gB和gH复合体中的分选信号层次如何调节病毒体 在两种极化小区类型的上下文中的迁移和外出路线： 上皮细胞和内皮细胞。具体目标是：（1）完成 鉴定CMV gB和gH复合物中的功能性分选信号， 极化细胞的运输这一假说是， 这些糖蛋白含有调节它们的 内吞途径的运输。(2)继续识别同源结合 在CMV gB和gH复合物中，通过胞质分选信号选择配偶体。的 目的是确定哪些细胞蛋白质调节它们在细胞中的转运。 内吞/再循环途径。(3)阐明CMV病毒粒子的迁移和逃逸 在感染的极化上皮细胞的情况下， 调节这一途径的层次结构。(4)研究CMV糖蛋白分选 以及内皮细胞中的病毒粒子增殖和排出途径，另一个 极化细胞类型，在CMV感染中起关键作用。这些 实验将推进运输基序和细胞分子的知识 调节极化上皮细胞中病毒粒子的增殖和外出途径 细胞，并提高对病毒从内皮细胞释放的理解， 体内血管床传播模型。可以想象，这些发现 将引起细胞生物学家的兴趣，并可能与医学相关， 血管生物学和器官移植。很可能， 可以掺入用于选择性靶向内吞亚区室的CMV 用于将抗病毒化合物引入细胞溶质中的新方法 极化细胞中的囊泡，以阻止病毒粒子的扩散和排出。