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）：疱疹病毒的核出口是病毒复制的必不可少的过程。在过去的十年中，已经确定并在功能上表征了此过程所需的病毒蛋白。鉴定细胞的进展 参与核出口的因素较慢。鉴定细胞因素 从两个角度来看，参与核出口非常重要。一方面，鉴定基本因素可能会产生抗病毒治疗的靶标。另一方面，这些因素功能的表征肯定会洞悉其在未感染的细胞中的正常功能。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疾病是由编码核包膜及其潜在薄片的基因突变引起的。这些疾病包括肌肉营养不良，心脏和骨骼以及结缔组织疾病和扭转肌肌张力障碍。在任何情况下，突变蛋白与疾病发病机理之间的关系都完全清晰。 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的基因的突变导致一种称为早发扭曲肌张力障碍的神经肌肉疾病，疾病的机理尚不清楚。我们发现了Torsina与单纯疱疹1型之间的功能相互作用的初步证据，并专门证明了Torsina在调节核包膜上膜融合中作用的作用。我们建议充分表征Torsina和HSV之间追求两个特定目标的相互作用。 AIM 1。Torsina在HSV-1感染中的功能的表型表征。我们将使用Torsina过表达和敲除/敲除的互补方法来检验以下假设：有效的HSV感染需要正常的Torsin表达，并检验了Torsin a是有效地出现HSV核核能所需的假设。 AIM 2。鉴定HSV感染中Torsina功能的机理。 Torsina功能被认为是通过与其他蛋白质的活性相互作用和调节来介导的。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直接调节核包膜中HV糖蛋白的功能或原发性病毒素外壳的功能来调节HSV核出口。我们将使用遗传和生化方法的结合来检验这两个假设。