Translation Regulation by Enterovirus Proteinase

肠道病毒蛋白酶的翻译调控

• 批准号: 10216998
• 负责人: Richard E Lloyd
• 金额: $ 48万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216998
• 关键词: Amino Acids; Antiviral Agents; Area; Arginine; Avidity; Biology; C-terminal; Cells; Cleaved cell; Complex; Coxsackie Viruses; Cytoplasmic Granules; DNA Viruses; Data; Development; Disease; Enterovirus; Exhibits; Functional disorder; Funding; Future; G3BP1 gene; Gene Expression; Goals; Homeostasis; Human; Human poliovirus; Hydrophobic Interactions; IRF3 gene; Immune; Immune signaling; Immunity; Immunologic Factors; Infection; Innate Immune Response; Interruption; Link; MAPK8 gene; Malignant Neoplasms; Mammalian Cell; Mediating; Methylation; MicroRNAs; Modification; Molecular; NF-kappa B; Natural Immunity; Nature; Neurodegenerative Disorders; Organelles; Output; Pathway interactions; Pattern; Peptide Hydrolases; Plants; Post-Translational Protein Processing; Protein Methylation; Proteins; RNA; RNA Viruses; RNA-Binding Proteins; Reader; Regulation; Regulator Genes; Reporting; Reproduction; Research; Role; Signal Pathway; Signal Transduction; Site; Stress; Structure; Surface; TBK1 gene; Translations; Triage; Viral; Virus; Virus Diseases; Work; Yeasts; arm; biological adaptation to stress; functional outcomes; human disease; immune activation; immunoregulation; innate immune function; innovation; insight; mRNA Decay; messenger ribonucleoprotein; methylation pattern; mutant; novel; recruit; stress granule; tool

The long term goal of this research is to understand the mechanism by which enteroviruses such as poliovirus (PV) and Coxsackievirus (CVB3) control cellular and viral translation in infected cells and in turn, discern how translation and gene expression are regulated normally. Translation regulation mechanisms now encompass translation silencing (e.g. microRNAs) and dynamic assembly/disassembly of RNA granules, stress granules (SG) and P-bodies (PB) that contain translationally-silenced mRNPs. These structures assist cell homeostasis during stress and serve as temporary storage/triage sites for mRNPs, and in the case of PBs, sites for mRNA decay. We discovered that PV and CVB3 destroys-disperses both SGs and PBs, the former by cleavage of G3BP1, a key factor that nucleates formation of stress granules. Our emerging evidence suggests stress responses are linked to innate immune responses at several levels to form an integrated stress/innate immune response. In this funding period we discovered that SGs are stress-activated platforms to signal innate immunity and that G3BP1 mediates activation of PKR and NF-kB. We have also discovered that G3BP1 assembly of SGs is mediated by reversible arginine methylation on G3BP1 and have linked methylation to functional innate immunity output of SGs. In this proposal we will elucidate the role of protein arginine methylation in innate immune activation as we have now found recruitment of a key methyl- reader protein TDRD3 and several innate immune factors to SGs is dependent on methylation state of G3BP1. We have found the methyl-reader TDRD3 is antiviral, Aim 2 will elucidate the role of TDRD3 in recruitment and activation of innate immune factors in the absence of G3BP1 and the impact of its cleavage by virus protease. Aim 3 will determine molecular mechanisms of activation of both PKR that is non-methylation dependent and NF-kB by G3BP1. This proposal is innovative since the both the (i) role SGs as a signaling platforms in innate immunity and (ii) the role of protein methylation in innate immune activation are novel. The proposed work is significant since it is relevant to a broad range of DNA and RNA viruses that promote SG formation and it promises to uncover unprecedented insights into novel protein-mRNP interactions that link stress signaling to innate immune activation. This will open new conceptual avenues for antiviral development.

这项研究的长期目标是了解肠病毒的机制 例如脊髓灰质炎病毒（PV）和Coxsackievivirus（CVB3）控制细胞和病毒翻译 感染细胞，然后辨别平移和基因表达如何正常调节。 翻译调节机制现在包括翻译沉默（例如microRNA）和 RNA颗粒，应力颗粒（SG）和P-Bodies（PB）的动态组装/拆卸 包含翻译成的mRNP。这些结构在压力下有助于细胞稳态 并充当mRNP的临时存储/分流点，在PBS的情况下 衰变。我们发现PV和CVB3破坏了SG和PBS，前者是 G3BP1的切割，这是核定应力颗粒形成的关键因素。我们的新兴 有证据表明，压力反应与几个级别的先天免疫反应有关 形成综合应力/先天免疫反应。在此资助期间，我们发现 SG是压力激活的平台，以信号先天免疫，而G3BP1介导 PKR和NF-KB的激活。我们还发现SG的G3BP1组装是 通过在G3BP1上可逆精氨酸甲基化介导，并将甲基化与功能 SGS先天免疫输出。在此提案中，我们将阐明蛋白质精氨酸的作用 先天免疫激活中的甲基化，因为我们现在发现募集了关键的甲基 读取器蛋白TDRD3和SGS的几种先天免疫因子取决于甲基化 G3BP1的状态。我们已经发现甲基读取器TDRD3是抗病毒，AIM 2将阐明 在没有G3BP1的情况下，TDRD3在募集和激活先天免疫因子中的作用 以及其通过病毒蛋白酶裂解的影响。 AIM 3将确定分子机制 G3BP1的非甲基化依赖性PKR的激活和NF-KB的激活。这个建议 具有创新性，因为（i）角色sgs作为先天免疫中的信号平台和（ii） 蛋白甲基化在先天免疫激活中的作用是新颖的。拟议的工作是 很重要，因为它与促进SG的广泛DNA和RNA病毒有关 形成及其有望发现对新型蛋白质MRNP的前所未有的见解 将应力信号传导与先天免疫激活联系起来的相互作用。这将打开新的概念 抗病毒发育的途径。