Tegument ICP0 and HSV Entry

皮层 ICP0 和 HSV 条目

• 批准号: 7708637
• 负责人: ANTHONY V NICOLA
• 金额: $ 21.86万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-19 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708637
• 关键词: 26S proteasome; Affect; Antiviral Agents; Area; Binding; Biochemical; Biochemistry; Biological; Blindness; Capsid; Cell Nucleus; Cell membrane; Cells; Cellular biology; Cytosol; Dependence; Deposition; Destinations; Disease; Doctor of Philosophy; Encephalitis; Event; Experimental Designs; Fingers; Genital system; Genome; Goals; Herpes Labialis; Herpes Simplex Infections; Human; Immediate-Early Proteins; Infection; Intervention; Kinetics; Knowledge; Lesion; Light; Minor; Molecular; Molecular Virology; Neonatal; Nuclear Outer Membrane; Nuclear Pore Complex; Nucleocapsid; Penetration; Process; Proteins; Research; Role; Simplexvirus; Staging; Techniques; Viral; Viral Proteins; Virion; Virus; Virus Diseases; Virus-Cell Membrane Interaction; Zinc; latent infection; multicatalytic endopeptidase complex; novel; novel strategies; novel therapeutic intervention; particle; pathogen; prevent; public health relevance; trafficking; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) is a common and significant human pathogen that causes lifelong latent infection and a variety of diseases, ranging from cold sores and genital lesions to blindness and fatal encephalitis. Proteins within the tegument layer of HSV are released into the cell upon entry when the viral envelope fuses with the cell membrane. HSV capsids and capsid-associated tegument proteins then utilize the host cytoskeletal machinery for transport to the nucleus. We recently showed that incoming HSV employs the 26S proteasome machinery at a postpenetration step to initiate infection. ICP0 is a multi-functional viral protein that is synthesized by the infected cell with immediate-early kinetics. ICP0 has a zinc binding RING finger motif that confers E3 ubiquitin ligase activity. ICP0 is also a component of the virion tegument and is brought into the cell with the infecting viral particle. The functional role of tegument ICP0 has been largely undetermined. Our preliminary studies indicate a role for ICP0 in proteasome-dependent viral entry. The long-term goal of this project is to understand the virus-cell interactions that HSV uses to gain access to the host cell nucleus during the earliest stages of infection. The objective of this proposal is to determine the fate and function of tegument ICP0 in the context of pre-immediate early events in HSV infection. Our central hypothesis is that tegument ICP0 modulates the proteasome-dependent delivery of the viral nucleocapsid from the cell periphery to the nucleus. Two aims are proposed. In Specific Aim 1, the precise step in the entry process that is affected by ICP0 will be defined. The role of the RING finger domain of ICP0 in the proteasome-dependent transport of capsids will also be analyzed. In Specific Aim 2, the stability and subcellular localization of tegument ICP0 will be determined. The roles of the proteasome and of ICP0 functional domains in these processes will be defined. A combination of molecular, biochemical and cell biological approaches will be used to achieve these goals. These studies will widen our understanding of the mechanism for capsid targeting to the nucleus to initiate productive infection. By identifying new requirements for virus entry into the host, the results will increase our knowledge of the early steps of HSV infection and reveal targets for novel therapeutic intervention. PUBLIC HEALTH RELEVANCE: Herpes simplex virus is a common cause of infections and can cause serious complications such as neonatal infections and fatal encephalitis. The purpose of this research is to determine how the herpes simplex virus initiates infection in humans by studying the virus interaction with host cells. Greater understanding of the virus entry process may help to develop novel approaches to prevent herpes infections.

描述（由申请人提供）：单纯疱疹病毒（HSV）是一种常见且重要的人类病原体，会引起终生潜在感染和多种疾病，从唇疱疹和生殖器病变到失明和致命性脑炎。当病毒包膜与细胞膜融合时，HSV的Tegument层中的蛋白质会释放到细胞中。然后，HSV衣壳和与衣壳相关的Tegument蛋白利用宿主细胞骨架机械将其运输到核。我们最近表明，传入的HSV在后期步骤中采用26S蛋白酶体机械来启动感染。 ICP0是一种多功能病毒蛋白，由感染的细胞与立即的动力学合成。 ICP0具有一个赋予E3泛素连接酶活性的锌结合环指数。 ICP0也是病毒素tegument的组成部分，并带有感染病毒颗粒进入细胞。 Tegument ICP0的功能作用在很大程度上尚不确定。我们的初步研究表明ICP0在蛋白酶体依赖性病毒进入中的作用。该项目的长期目标是了解HSV在最早的感染阶段使用HSV进入宿主细胞核的病毒 - 细胞相互作用。该提案的目的是确定在HSV感染中预先发生的早期事件的情况下，Tegument ICP0的命运和功能。我们的中心假设是Tegument ICP0调节病毒核蛋白酶从细胞周围到核的蛋白酶体依赖性递送。提出了两个目标。在特定的目标1中，将定义受ICP0影响的输入过程中的确切步骤。也将分析ICP0的环手指结构域在capsids的蛋白酶体依赖性转运中的作用。在特定的目标2中，将确定TEGUMEMER ICP0的稳定性和亚细胞定位。将定义蛋白酶体和ICP0功能域在这些过程中的作用。分子，生化和细胞生物学方法的结合将用于实现这些目标。这些研究将扩大我们对靶向核靶向启动生产性感染的机制的理解。通过确定对病毒进入宿主的新要求，结果将增加我们对HSV感染的早期步骤的了解，并揭示新的治疗干预措施的靶标。公共卫生相关性：单纯疱疹病毒是引起感染的常见原因，可能引起严重的并发症，例如新生儿感染和致命性脑炎。这项研究的目的是确定单纯疱疹病毒如何通过研究病毒与宿主细胞的相互作用来引发人类感染。对病毒进入过程的更多了解可能有助于开发新的方法以防止疱疹感染。