Mitochondrial-localized activities of HHV-8 vIRF-1

HHV-8 vIRF-1 的线粒体定位活性

• 批准号: 8413784
• 负责人: John Nicholas
• 金额: $ 20.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413784
• 关键词: Antiviral Agents; Apoptosis; Apoptotic; BH3 Domain; Binding; Biological; Biological Assay; Biology; Cell Cycle Arrest; Cells; Cessation of life; Data; Development; EP300 gene; Endothelial Cells; Future; Goals; Homologous Gene; Human Herpesvirus 8; Immune response; In Vitro; Individual; Infection; Interferons; Maps; Mediating; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Molecular; Mutagenesis; Nuclear; Nuclear Translocation; Pathway interactions; Peptides; Peripheral; Property; Protein Binding Domain; Protein Family; Proteins; Research; Role; Site; Specific qualifier value; Specificity; Stimulus; Stress; Variant; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; base; cell growth regulation; gain of function; genetic regulatory protein; in vivo; loss of function; member; mutant; novel; overexpression; pro-apoptotic protein; research study; response; transcription factor; viral interferon regulatory factor; viral resistance

DESCRIPTION (provided by applicant): Human herpesvirus 8 (HHV-8) specifies four viral interferon regulatory factor homologues (vIRFs 1-4) that function to inhibit cellular IRFs in addition to other components of cellular defense pathways that promote cell cycle arrest and apoptosis in response to virus infection. Cellular proteins targeted for inhibition by vIRF-1 include p53, ATM, GRIM19, Smad transcription factors, and p300/CBP transcriptional co-activators required for IRF-mediated responses. We have identified an entirely novel class of interaction, between vIRF-1 and stress-responsive, pro-apoptotic BH3-only proteins (BOPs) Bim and Bid. Interactions of vIRF-1 with Bim and Bid occur via residues 170-187 (BOP-binding domain, BBD) of the viral protein and the functional BH3 domains of the BOPs. Both Bim and Bid are induced during HHV-8 productive replication, each is inhibited functionally by vIRF-1 association, and we have identified partial localization of vIRF-1 to mitochondria, consistent with the hypothesis that direct targeting and inactivation of BOPs at their site of action is biologicaly important. For Bim, a demonstrated powerful negative regulator of HHV-8 replication, we have also shown that vIRF-1 binding leads to nuclear translocation, representing a secondary mode of inactivation. These properties of vIRF-1 represent new paradigms of viral control of host responses to infection. This application is focused on examining: (1) the structural requirements of vIRF-1 mitochondrial localization and associated activities; (2) the molecular basis of BOP/BH3 targeting by vIRF-1; (3) the functional significance of individual vIRF-1:BOP interactions and of vIRF-1 mitochondrial localization in HHV-8 biology. The project will characterize unique properties and activities of vIRF-1, thereby expand understanding of viral evasion from host cell defenses, and potentially enabling future development of novel antiviral agents.

描述（由申请人提供）：人类疱疹病毒 8 (HHV-8) 指定了四种病毒干扰素调节因子同源物 (vIRF 1-4)，除了响应病毒感染而促进细胞周期停滞和细胞凋亡的细胞防御途径的其他成分外，还具有抑制细胞 IRF 的功能。 vIRF-1 抑制的目标细胞蛋白包括 IRF 介导的反应所需的 p53、ATM、GRIM19、Smad 转录因子和 p300/CBP 转录共激活因子。我们已经确定了 vIRF-1 和应激反应性促凋亡 BH3 蛋白 (BOP) Bim 和 Bid 之间一类全新的相互作用。 vIRF-1 与 Bim 和 Bid 的相互作用通过病毒蛋白的残基 170-187（BOP 结合结构域，BBD）和 BOP 的功能性 BH3 结构域发生。 Bim 和 Bid 均在 HHV-8 生产性复制过程中被诱导，每种都受到 vIRF-1 关联的功能性抑制，并且我们已经确定 vIRF-1 部分定位于线粒体，这与 假设 BOP 在其作用位点直接靶向并失活具有重要的生物学意义。对于 Bim（已证明的 HHV-8 复制的强大负调节因子），我们还表明 vIRF-1 结合会导致核易位，代表第二种失活模式。 vIRF-1 的这些特性代表了病毒控制宿主感染反应的新范例。该应用的重点是检查：（1）vIRF-1线粒体定位和相关活性的结构要求； (2) vIRF-1靶向BOP/BH3的分子基础； (3)个体vIRF-1:BOP相互作用和vIRF-1线粒体定位在HHV-8生物学中的功能意义。该项目将表征 vIRF-1 的独特性质和活性，从而扩大对病毒逃避宿主细胞防御的了解，并有可能促进未来新型抗病毒药物的开发。