CMV Control of Host Membrane Trafficking

CMV 对宿主膜运输的控制

• 批准号: 10350615
• 负责人: Felicia D Goodrum
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350615
• 关键词: Address; Affect; Aging; Biogenesis; Biology; Cell Fractionation; Cells; Cellular Membrane; Cellular biology; Complex; Cytomegalovirus; Cytomegalovirus Infections; DNA Viruses; Disease; Endothelial Cells; Environment; Exhibits; Exocytosis; Failure; Family; Genes; Goals; Herpesviridae; Human; Immunosuppression; Infection; Inflammation; Integration Host Factors; Intracellular Membranes; Mediating; Membrane; Morphology; Multivesicular Body; Mutation; Organelles; Pathway interactions; Phenotype; Positioning Attribute; Process; Proteins; Proteomics; RNA Interference; RNA Viruses; Recruitment Activity; Regulation; Role; Signal Transduction; Site; Transplantation; Vesicle; Viral; Viral Proteins; Virion; Virus; Virus Diseases; Virus Replication; Work; congenital infection; design; extracellular; high resolution imaging; insight; intercellular communication; knock-down; member; recombinant virus; success; trafficking; virus host interaction

PROJECT SUMMARY / ABSTRACT Viruses commandeer host membrane trafficking to promote viral replication. While this is a critical control point for virus infection, how viruses hijack host proteins and pathways to promote infection is incompletely understood. Viral-mediated alterations in membrane trafficking are best understood for building replication compartments and sites of assembly for RNA viruses. However, much less is known about how DNA viruses influence membrane remodeling in the host. Human cytomegalovirus (CMV) is a complex DNA virus and a member of the herpesvirus family that establishes a lifelong infection in the host. During infection, CMV induces alterations in membrane trafficking that results in increased biogenesis of multivesicular bodies (MVBs), organelles important for signaling and exocytosis or degradation of cargo. During infection, MVBs become loaded with virus particles and dense bodies (vesicles of viral tegument protein). The mechanisms by which CMV controls host membrane trafficking pathways, and particularly MVB biogenesis, are not understood. Therefore, defining the viral proteins and host targets important for the regulation of membrane trafficking is an important goal with important implications for host and virus biology. We have identified two CMV proteins, pUL135 and pUL136, which regulate MVB biogenesis. Recombinant viruses lacking UL135 or UL136 genes exhibit profound alterations in MVB biogenesis and the incorporation of viral cargo into MVB. Consistent with these phenotypes, we have identified host interacting proteins for both pUL135 and pUL136 proteins that are important for membrane trafficking and MVB biogenesis. The discovery of two viral proteins and their host interactions strongly position us to define the mechanisms by which CMV modulates membrane trafficking and MVB biogenesis. We hypothesize that UL135- and UL136-host interactions co-opt host membrane trafficking and MVB pathways to modulate virus replication. Three aims are proposed to address this hypothesis. We will define the association of UL135 and UL136 with subcellular membrane compartments and host proteins in Aim 1. In Aim 2, we will define the significance of host interactions to virus replication, membrane trafficking, and incorporation of cargo into MVBs to understand the mechanistic basis of CMV- mediated control of host trafficking. Finally, we will investigate the role of UL135 and UL136 and their host interacting partners in regulating MVB biogenesis and determine how this regulation impacts viral egress. Our studies will define the virus-host interactions and trafficking pathways targeted by CMV and their significance to infection. Furthermore, we anticipate that our findings will uncover common strategies used by many viruses to manipulate trafficking pathways.

项目总结/摘要 病毒强占宿主细胞膜以促进病毒复制。虽然这是一个关键的控制点， 对于病毒感染，病毒如何劫持宿主蛋白质和途径以促进感染是不完全的， 明白病毒介导的膜运输的改变是最好的理解为建设复制 区室和RNA病毒的组装位点。然而，我们对DNA病毒如何 影响宿主的膜重塑。人巨细胞病毒（CMV）是一种复杂的DNA病毒， 疱疹病毒家族中的一员，在宿主中建立终身感染。在感染过程中，CMV 诱导膜运输的改变，导致多泡体的生物发生增加 （MVB），对于信号传导和胞吐或货物降解重要的细胞器。感染期间，MVB 病毒颗粒和致密体（病毒被膜蛋白的囊泡）被装载。的机制 CMV控制宿主膜运输途径，特别是MVB生物发生， 明白因此，确定病毒蛋白和宿主靶点对于膜的调节是重要的， 贩运是一个重要目标，对宿主和病毒生物学具有重要意义。我们已经确定了两个 CMV蛋白，pUL 135和pUL 136，其调节MVB生物发生。缺乏UL 135或 UL 136基因在MVB生物发生和将病毒货物掺入MVB中方面表现出深刻的改变。 与这些表型一致，我们已经鉴定了pUL 135和pUL 136的宿主相互作用蛋白 这些蛋白质对于膜运输和MVB生物发生是重要的。两种病毒蛋白质的发现 它们与宿主的相互作用使我们能够确定CMV调节细胞膜的机制 贩运和MVB生物发生。我们假设UL 135和UL 136与宿主的相互作用 膜运输和MVB途径来调节病毒复制。提出了三个目标， 这个假设。我们将定义UL 135和UL 136与亚细胞膜区室的关联 和宿主蛋白质。在目标2中，我们将定义宿主相互作用对病毒复制的重要性， 膜运输，并将货物纳入MVB，以了解CMV的机制基础- 通过中介控制宿主贩运。最后，我们将研究UL 135和UL 136及其宿主的作用 相互作用的合作伙伴在调节MVB生物发生，并确定如何调节影响病毒的出口。我们 研究将确定CMV靶向的病毒-宿主相互作用和运输途径及其对 感染此外，我们预计我们的发现将揭示许多病毒使用的共同策略， 操纵贩运途径。