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（由申请人提供）：疱疹病毒的核排出是病毒复制中必需且保守的过程。在过去的十年中，这一过程所需的病毒蛋白已被鉴定并进行了功能表征。细胞鉴定研究进展 参与核排放的因素较慢。鉴定细胞因子 从两个角度来看，参与核排放具有非常重要的意义。一方面，识别重要因素可能会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深入了解它们在未感染细胞中的正常功能。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底层蛋白的基因突变引起的。这些疾病包括肌肉营养不良、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，突变蛋白与疾病发病机制之间的关系都还不是完全清楚的。 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的基因突变会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torsinA和1型单纯疱疹之间功能相互作用的初步证据，以及torsinA在核膜膜融合调节中的作用的具体证据。我们建议充分表征 torsinA 和 HSV 之间的相互作用，以实现两个特定目标。目标 1. TorsinA 在 HSV-1 感染中的功能的表型特征。我们将使用 TorsinA 过表达和敲除/敲除的互补方法来检验有效 HSV 感染需要正常 Torsin 表达的假设，并检验 HSV 有效核排出特别需要 Torsin A 的假设。目的 2. 鉴定 TorsinA 在 HSV 感染中的功能机制。 TorsinA 功能被认为是通过与其他蛋白质的相互作用和对其活性的调节来介导的。我们的初步数据表明，Torsin A 可能通过调节先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 HV 糖蛋白的功能来调节 HSV 核排出。我们将结合遗传和生化方法来测试这两个假设。