TorsinA and Nuclear Envelope Function in HSV Infection

TorsinA 和核膜在 HSV 感染中的功能

• 批准号: 8424221
• 负责人: RICHARD J ROLLER
• 金额: $ 18.88万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-13 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424221
• 关键词: Antiviral Therapy; Biochemical; Biology; Bone Tissue; Cardiac; Cell physiology; Cells; Cellular biology; Connective Tissue Diseases; Data; Defect; Disease; Dystonia Musculorum Deformans; Gene Mutation; Genes; Genetic; Glycoproteins; Hereditary Disease; Herpes Simplex Infections; Herpesviridae; Herpesvirus 1; Human; Human Genetics; Infection; Inherited; Knock-out; Mediating; Membrane Fusion; Molecular Biology; Muscular Dystrophies; Neuromuscular Diseases; Nuclear; Nuclear Envelope; Nuclear Outer Membrane; Pathogenesis; Perforation; Plant Roots; Process; Proteins; Recording of previous events; Regulation; Role; Simplexvirus; Testing; TorsinA; Viral Proteins; Virion; Virus; Virus Replication; disease-causing mutation; early onset; genetic manipulation; human disease; insight; interest; knock-down; mutant; nervous system disorder; news; protein function; tool

DESCRIPTION (provided by applicant): Nuclear egress of herpesviruses is an essential and conserved process in virus replication. Over the past decade, viral proteins required for this process have been identified and functionally characterized. Progress in identification of cellular factors that participate in nuclear egress has been slower. Identification of cellular factors that participate in nuclear egress is highly significant from two points of view. On one hand, identification of essential factors might yield targets for antiviral therapy. On the other, characterization of the function of these factors will certainly provide insight into their normal functions in the uninfected cell. This is an important problem in human disease biology because many interesting inherited diseases are caused by mutations in genes that encode proteins of the nuclear envelope and its underlying lamina. These diseases include muscular dystrophies, cardiac, and bone and connective tissue disorders and torsion dystonias. In no case is the relationship between the mutant protein and disease pathogenesis completely clear. Here, we propose to explore the function of the torsinA gene product in HSV infection. Mutation of the gene encoding torsinA results in a neuromuscular disease called early-onset torsion dystonia, and the mechanism of disease is unclear. We have found preliminary evidence for a functional interaction between torsinA and herpes simplex type 1, and evidence specifically for a role for torsinA in regulation of membrane fusion at the nuclear envelope. We propose to fully characterize the interaction between torsinA and HSV pursuing two specific aims. Aim 1. Phenotypic characterization of the function of TorsinA in HSV-1 infection. We will use complementary approaches of TorsinA over-expression and knock-down/knock-out to test the hypothesis that normal Torsin expression is required for efficient HSV infection and to test the hypothesis that Torsin A is specifically required for efficient nuclear egress of HSV. Aim 2. Identification of the mechanism of TorsinA function in HSV infection. TorsinA function is thought to be mediated by interaction with, and regulation of, the activity of other proteins. Our preliminary data suggest that Torsin A might regulate HSV nuclear egress either by regulating the activity of previously identified cellular proteins or by directly regulating the function of HV glycoproteins in the nuclear envelope or the primary virion envelope. We will test both of these hypotheses using a combination of genetic and biochemical approaches.

描述（由申请方提供）：疱疹病毒的核逃逸是病毒复制中的一个重要和保守的过程。在过去的十年中，这个过程所需的病毒蛋白质已被确定和功能特征。细胞鉴定的研究进展 参与核出口的因素已经变慢了。鉴定细胞因子， 从两个角度来看，参与核出口具有非常重要的意义。一方面，识别关键因素可能产生抗病毒治疗的目标。另一方面，对这些因子功能的表征肯定会提供对它们在未感染细胞中的正常功能的深入了解。这是人类疾病生物学中的一个重要问题，因为许多有趣的遗传性疾病是由编码核膜及其下层蛋白质的基因突变引起的。这些疾病包括肌营养不良、心脏、骨骼和结缔组织疾病以及扭转肌张力障碍。在任何情况下，突变蛋白和疾病发病机制之间的关系都不完全清楚。 在这里，我们建议探索torsinA基因产物在HSV感染中的功能。编码torsinA的基因突变导致一种称为早发性扭转肌张力障碍的神经肌肉疾病，其发病机制尚不清楚。我们已经发现了初步的证据torsinA和单纯疱疹1型之间的功能相互作用，和证据，特别是torsinA在调节核膜融合的作用。我们建议充分表征torsinA和HSV追求两个特定目标之间的相互作用。目标1.扭转蛋白A在HSV-1感染中功能的表型表征我们将使用TorsinA过表达和敲低/敲除的互补方法来检验正常Torsin表达是有效HSV感染所需的假设，并检验TorsinA是HSV有效核出口所特异性需要的假设。目标2.扭转蛋白A在单纯疱疹病毒感染中作用机制的鉴定扭转蛋白A的功能被认为是通过与其他蛋白质的相互作用和调节其他蛋白质的活性来介导的。我们的初步数据表明，扭转蛋白A可能通过调节以前鉴定的细胞蛋白的活性或通过直接调节核膜或初级病毒体包膜中的HV糖蛋白的功能来调节HSV核出口。我们将使用遗传和生物化学方法的组合来测试这两种假设。