Translation Regulation by Enterovirus Proteinase

肠道病毒蛋白酶的翻译调控

• 批准号: 7538415
• 负责人: Richard E Lloyd
• 金额: $ 37.5万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7538415
• 关键词: Affect; Apoptosis; Binding; Biochemical; Cells; Cellular Stress; Cellular Stress Response; Cleaved cell; Coxsackie Viruses; Cytopathology; Cytoplasmic Granules; Enterovirus; Family Picornaviridae; Gene Expression; Gene Expression Regulation; Goals; Human; Human poliovirus; Interruption; Invaded; Knowledge; Learning; Malignant Neoplasms; Mammalian Cell; Mediating; Messenger RNA; MicroRNAs; Pathway interactions; Peptide Hydrolases; Peptide Initiation Factors; Polioviruses; Poly(A)-Binding Proteins; Polyribosomes; Proteins; RNA Viruses; RNA chemical synthesis; RNA replication; Recycling; Regulation; Repression; Research; Ribosomes; Role; Stress; Translations; Untranslated Regions; Viral; Viral Gene Expression Regulation; Viral Genome; Virus; Virus Diseases; Work; cell killing; cellular targeting; disorder prevention; insight; mRNA Decay; mRNA capping; overexpression; pathogen; prevent; prototype; research study; viral RNA

DESCRIPTION (provided by applicant): The long term goal of this research is to understand the mechanism by which enteroviruses such as poliovirus (PV) and Coxsackievirus (CVB3) inactivate translation of nearly all cellular mRNA while stimulating efficient translation of viral mRNA in infected cells. We have shown that cleavage of the translation initiation factor eIF4G will block assembly of new capped mRNA on ribosomes, and that cleavage of PABP is required in concert with eIF4G to completely block translation. PABP cleavage affects late steps in translation that are presently undefined, however likely interrupt ribosome recycling via 5'-3' interactions on mRNA. The mechanism of ribosome recycling and its biochemical requirements are unknown. In addition, enteroviruses and probably most other plus strand RNA viruses must abruptly shut down translation of the infecting viral genome before viral RNA synthesis can begin. We hypothesize that PABP cleavage is also required for inhibition of viral translation. Translation regulation mechanisms involving PABP are now thought to interface with mRNA decay mechanisms on several levels. In addition, microRNAs, which bind to 3' UTR of targeted cellular mRNAs, also silence translation by unknown mechanisms that somehow result in transit of mRNAs from polysomes to other cell compartments called P-bodies and stress granules. We have discovered that G3BP, a key factor that nucleates formation of stress granules, is cleaved in PV-infected cells by 3C protease. Thus, the virus is attacking the overall translation regulatory apparatus at a new level. The aims in this proposal will determine the role of PABP cleavage in the switch from viral translation to RNA replication, will determine the role of ribosome recycling in this switch, and will investigate the function of G3BP cleavage on the viral replication cycle and microRNA-translation silencing. These results will provide new fundamental information on how cells regulate gene expression at the translation level, and the interplay between translation initiation factors and mRNA silencing/decay pathways that will be useful in studies of viral regulation of gene expression and cellular stress responses in cancer and apoptosis. This work investigates new ways that poliovirus, the prototype human picornavirus, interferes with host translation and regulation of gene expression by stress granules and microRNAs. These mechanisms are fundamental for cell gene regulation and are disrupted in cancer and numerous non-viral diseases. These experiments will give us more insight how a large class of human pathogens invade and kill cells (cytopathology) and potentially provide new avenues for disease prevention and we will learn more about gene regulation in human cells.

描述（由申请方提供）：本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））抑制几乎所有细胞mRNA翻译同时刺激感染细胞中病毒mRNA有效翻译的机制。我们已经表明，翻译起始因子eIF 4G的切割将阻断新的加帽mRNA在核糖体上的组装，并且PABP的切割需要与eIF 4G协同作用以完全阻断翻译。PABP切割影响翻译中的晚期步骤，这些步骤目前尚不明确，但可能通过mRNA上的5 '-3'相互作用中断核糖体再循环。核糖体再循环的机制及其生化要求尚不清楚。此外，肠道病毒和可能大多数其他正链RNA病毒必须在病毒RNA合成开始之前突然关闭感染病毒基因组的翻译。我们推测PABP裂解也是抑制病毒翻译所必需的。现在认为涉及PABP的翻译调节机制在几个水平上与mRNA衰变机制相互作用。此外，与靶细胞mRNA的3' UTR结合的microRNA也通过未知机制沉默翻译，该机制以某种方式导致mRNA从多核糖体转运到称为P体和应激颗粒的其他细胞区室。我们已经发现，G3 BP，一个关键的因素，核形成的压力颗粒，被切割在PV感染的细胞由3C蛋白酶。因此，病毒正在一个新的水平上攻击整个翻译调节装置。该提案的目的将确定PABP切割在从病毒翻译到RNA复制的转换中的作用，将确定核糖体再循环在该转换中的作用，并将研究G3 BP切割对病毒复制周期和microRNA翻译沉默的功能。这些结果将提供关于细胞如何在翻译水平上调节基因表达的新的基本信息，以及翻译起始因子和mRNA沉默/衰变途径之间的相互作用，这将有助于研究病毒对基因表达的调节以及癌症和凋亡中的细胞应激反应。 这项工作研究了脊髓灰质炎病毒（原型人类小核糖核酸病毒）通过应激颗粒和microRNA干扰宿主翻译和基因表达调控的新途径。这些机制是细胞基因调控的基础，在癌症和许多非病毒性疾病中被破坏。这些实验将使我们更深入地了解一大类人类病原体如何入侵和杀死细胞（细胞病理学），并可能为疾病预防提供新的途径，我们将更多地了解人类细胞中的基因调控。