Sindbis nonstructural protein nsP2: Interaction with cellular proteins

Sindbis 非结构蛋白 nsP2：与细胞蛋白的相互作用

• 批准号: 7364821
• 负责人: ELENA I FROLOVA
• 金额: $ 12.38万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2009-01-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364821
• 关键词: Alphavirus; Animals; Antiviral Agents; Antiviral Response; Antiviral Therapy; Binding; Biological; Biological Process; Birds; Blood Circulation; Capsid Proteins; Cell Communication; Cell Nucleus; Cell physiology; Cells; Chikungunya virus; Complex; Culicidae; Cytoplasm; Data; Development; Disease; Disease Outbreaks; Distant; Down-Regulation; Encephalitis Viruses; Environment; Equilibrium; Equus caballus; Evolution; Genes; Genetic Transcription; Goals; Human; Immune response; Infection; Investigation; Knock-out; Knowledge; Lead; Life; Modification; Molecular; None or Not Applicable; Nonstructural Protein; Nuclear Localization Signal; Pathogenesis; Play; Process; Protein Biosynthesis; Proteins; Public Health; RNA chemical synthesis; Research; Role; Serological; Sindbis Virus; Source; Therapeutic; Variant; Viral; Viral Nonstructural Proteins; Viral Pathogenesis; Virus; Virus Activation; Virus Replication; base; biological adaptation to stress; chikungunya; forest; insight; member; pathogen; response; tool; virus development; virus pathogenesis

DESCRIPTION (provided by applicant): This project represents our continuing investigation into the mechanism of alphavirus replication and interaction with cells. Sindbis virus (SINV) is the most valuable tool for examining fundamental issues pertaining to alphavirus replication and pathogenesis on the molecular and cellular levels. However, despite great efforts by several research groups, our knowledge of these processes is far from complete. SINV nonstructural protein nsP2 is not only a component of the replicative complexes (RCs), but is also distributed in the cytoplasm outside of the RCs and is present at high concentrations in the nuclei of infected cells. We hypothesize, on the basis of our preliminary data, that SINV nsP2 plays critical roles not only in the processing of viral nonstructural proteins and synthesis of virus-specific RNAs, but also in controlling the development of the virus-induced stress response by inhibiting transcription of cellular genes. Thus, this protein is one of the viral factors critically involved in development of cytopathic effect and downregulation of the antiviral cell response during SINV replication. Our specific aims are: 1. To identify protein complexes formed by SINV nsP2 in different cellular compartments. 2. To study biological functions of the nsP2-binding cellular proteins. 3. To identify domains and sequences in SINV nsP2 playing critical roles in virus-host cell interactions. The results of this application will provide detailed information about the interaction of SINV nsP2 with cellular proteins in different cellular compartments. We will generate new data about the functions of cellular proteins in SINV replication and elucidate the mechanism of interference of SINV replication with cellular transcription. Using a variety of approaches, we will analyze the biological significance of these data and identify the nsP2 domains and sequences that are critical in the functioning of nsP2 in virus-host cell interactions. This information will advance our understanding of SINV pathogenesis on cellular level, and it will be mostly applicable, not only to SINV, but also to other Old World alphaviruses. The identified host proteins interacting with SINV nsP2 and involved in SINV RC formation and inhibition of cellular transcription might be used as targets for the antiviral therapy. Alphaviruses is a group of widely distributed human and animal pathogens; some of them induce highly debilitating diseases and represent a serious public health treat in the US. The goal of this application is to elucidate the role of one of the viral nonstructural protein in suppression of the antiviral response. Understanding of the virus-specific mechanisms of interference with antiviral response will lead to development of new antiviral therapeutic strategies.

描述（由申请人提供）：该项目代表了我们对α病毒复制机制和与细胞相互作用的机制的持续研究。信德氏病毒（SINV）是检查与分子和细胞水平上的α病毒复制和发病机理有关的基本问题的最有价值的工具。但是，尽管有几个研究小组的努力，但我们对这些过程的了解远非完整。 SINV非结构蛋白NSP2不仅是复制络合物（RC）的组成部分，而且还分布在RC之外的细胞质中，并且在感染细胞的核中以高浓度存在。我们根据我们的初步数据假设，SINV NSP2不仅在病毒非结构蛋白的加工过程中起着关键作用，并且在控制病毒胁迫反应的发展中通过抑制细胞基因的转录来控制病毒诱导的应激反应的发展。因此，该蛋白是在SINV复制过程中严重涉及细胞病毒作用发展和抗病毒细胞反应下调的病毒因素之一。我们的具体目的是：1。确定在不同细胞室中SINV NSP2形成的蛋白质复合物。 2。研究NSP2结合细胞蛋白的生物学功能。 3。识别SINV NSP2中的域和序列在病毒宿主相互作用中起关键作用。该应用的结果将提供有关SINV NSP2与不同细胞室中细胞蛋白相互作用的详细信息。我们将生成有关细胞蛋白在SINV复制中功能的新数据，并阐明SINV复制与细胞转录的干扰机理。使用多种方法，我们将分析这些数据的生物学意义，并确定NSP2域和序列在病毒宿主宿主相互作用中NSP2的功能至关重要。这些信息将提高我们对细胞水平上的SINV发病机理的理解，并且它不仅适用于SINV，而且还适用于其他旧世界α病毒。与SINV NSP2相互作用并参与SINV RC形成和抑制细胞转录的确定宿主蛋白可以用作抗病毒治疗的靶标。 α病毒是一组广泛分布的人和动物病原体。他们中的一些人诱发了高度令人衰弱的疾病，并代表了美国的一种严重的公共卫生待遇。该应用的目的是阐明病毒非结构蛋白之一在抑制抗病毒反应中的作用。了解干扰抗病毒反应的病毒特异性机制将导致新的抗病毒治疗策略的发展。