Translation Regulation by Enterovirus Proteinase

肠道病毒蛋白酶的翻译调控

• 批准号: 10447044
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447044
• 关键词: Amino Acids; Area; Arginine; Avidity; Biology; C-terminal; Cells; 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; antiviral drug development; 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道病毒 如脊髓灰质炎病毒（PV）和柯萨奇病毒（CVB 3）控制细胞和病毒翻译， 感染的细胞，进而了解翻译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）和翻译抑制（例如，微RNA）。 RNA颗粒、应激颗粒（SG）和P体（PB）的动态组装/拆卸， 含有预防性沉默的mRNP。这些结构有助于细胞在压力下的自我平衡 并作为mRNP的临时储存/分类位点，在PB的情况下，作为mRNA的位点 腐烂我们发现PV和CVB 3破坏-分散SGs和PBs，前者通过 G3 BP 1的切割，这是促成应力颗粒形成的关键因素。我们新兴 有证据表明，压力反应与先天免疫反应在几个层面上有关， 形成一个整合的压力/先天免疫反应。在这个融资期内，我们发现， SGs是应激激活的平台，用于发出先天免疫信号，并且G3 BP 1介导 PKR和NF-kB的激活。我们还发现，G3 BP 1组装的SGs是 通过G3 BP 1上的可逆精氨酸甲基化介导，并将甲基化与功能性 SG的先天免疫输出。在这个建议中，我们将阐明蛋白质精氨酸的作用， 甲基化在先天免疫激活中的作用，因为我们现在已经发现了一个关键的甲基- 阅读器蛋白TDRD 3和几种先天免疫因子对SGs依赖于甲基化 G3 BP 1的状态。我们已经发现甲基阅读器TDRD 3是抗病毒的，目的2将阐明甲基阅读器TDRD 3的抗病毒性。 TDRD 3在缺乏G3 BP 1的先天免疫因子的募集和激活中的作用 以及病毒蛋白酶对其切割的影响。目标3将确定 非甲基化依赖的PKR和NF-κ B都被G3 BP 1激活。这项建议 是创新的，因为（i）SG作为先天免疫中的信号平台的作用和（ii） 蛋白质甲基化在先天免疫激活中作用是新的。拟议的工作是 因为它与促进SG的广泛的DNA和RNA病毒相关， 形成，并有望揭示前所未有的见解，新的蛋白质mRNP 将压力信号与先天免疫激活联系起来的相互作用。这将开启新的概念 开发抗病毒药物的途径。

项目成果

Regulation of stress granules in virus systems.

• DOI: 10.1016/j.tim.2012.02.001
• 发表时间: 2012-04
• 期刊: TRENDS IN MICROBIOLOGY
• 影响因子: 15.9
• 作者: White, James P.;Lloyd, Richard E.
• 通讯作者: Lloyd, Richard E.

How do viruses interact with stress-associated RNA granules?

• DOI: 10.1371/journal.ppat.1002741
• 发表时间: 2012
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Lloyd RE

Cytoplasmic RNA Granules and Viral Infection.

• DOI: 10.1146/annurev-virology-031413-085505
• 发表时间: 2014-11
• 期刊: Annual review of virology
• 影响因子: 11.3
• 作者: Tsai WC;Lloyd RE
• 通讯作者: Lloyd RE

TDRD3 is an antiviral restriction factor that promotes IFN signaling with G3BP1.

• DOI: 10.1371/journal.ppat.1010249
• 发表时间: 2022-01
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Deater M;Tamhankar M;Lloyd RE
• 通讯作者: Lloyd RE

Norovirus-Mediated Modification of the Translational Landscape via Virus and Host-Induced Cleavage of Translation Initiation Factors.

• DOI: 10.1074/mcp.m116.062448
• 发表时间: 2017-04
• 期刊: Molecular & cellular proteomics : MCP
• 作者: Emmott E;Sorgeloos F;Caddy SL;Vashist S;Sosnovtsev S;Lloyd R;Heesom K;Locker N;Goodfellow I
• 通讯作者: Goodfellow I