Mechanisms of virus-mediated compartmentalization of the host translational machinery

病毒介导的宿主翻译机制区室化机制

• 批准号: 9010465
• 负责人: John S Parker
• 金额: $ 36.4万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-11-05 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9010465
• 关键词: Anabolism; Animals; Biology; Biosynthetic Proteins; Cells; Cellular Stress; Complex; Cytoplasm; Cytosol; Defense Mechanisms; Environment; Eukaryotic Cell; GADD34 protein; Genetic Translation; Goals; Health; Host Defense; Human; Infection; Knowledge; Mammalian Orthoreovirus; Mediating; Messenger RNA; Modeling; Nonstructural Protein; Outcome; Peptide Initiation Factors; Phosphorylation; Process; Protein Biosynthesis; Protein Synthesis Inhibition; Protein phosphatase; Proteins; Recruitment Activity; Reoviridae Infections; Reovirus; Resources; Ribosomes; Role; Site; Stress; Stress Response Signaling; Testing; Translations; Viral; Viral Nonstructural Proteins; Viral Pathogenesis; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; base; biological adaptation to stress; cell growth regulation; insight; new therapeutic target; novel; pathogen; prevent; public health relevance; stressor; translation factor

 DESCRIPTION (provided by applicant): As obligate intracellular pathogens, viruses require the host biosynthetic machinery. A fundamental requirement is the host translational machinery for the synthesis of new viral proteins. The mechanisms by which viruses co-opt the host translational machinery and avoid the innate host defenses that act to degrade viral mRNA and diminish cellular protein synthesis to prevent or lessen the synthesis of viral proteins are not understood. The goal of this project is to define mechanisms by which mammalian reoviruses reprogram the host translational machinery to preferentially synthesize viral proteins. In particular, the project will focus on virus-mediated compartmentalization of the translational machinery, a novel pathogenic mechanism by which viral protein synthesis can be maintained during infection-induced stress. The hypotheses to be tested are that reovirus promotes the translation of its viral mRNAs by: (1) compartmentalizing translation factors and ribosomal subunits within defined sites of viral replication in the cytosol called viral factories; (2) by sequestering the GADD34/protein phosphatase 1 complex that dephosphorylates eIF2α within viral factories, thus, protecting translation of viral mRNAs from stress-induced inhibition of protein synthesis; and (3) by directly modifying the ribosome and altering its function to promote translation of non-canonical viral mRNA. Three Aims are proposed: (1) To identify mechanism(s) by which the host cell translational machinery is compartmentalized within viral factories in reovirus-infected cells; (2) To determine whether activation of the integrated stress response and compartmentalization of cellular GADD34 and protein phosphatase 1 within reovirus factories promotes translation of reovirus mRNAs; and (3) To determine the role of the viral nonstructural protein σNS in enhancing the translation of reovirus mRNA in infected cells. Expected outcomes of this work are identification of the viral factors required for compartmentalization of the host translational machinery within viral factories, an understanding of the mechanisms by which reoviruses replicate in the face of ongoing phosphorylated eIF2α and activation of the integrated stress response, and a greater understanding of the role of the reovirus protein σNS in co-opting the host translational machinery and modifying ribosome function. We expect that an important outcome of this proposal will be new basic information regarding viral strategies to overcome innate host defenses.

 描述（由申请方提供）：作为专性细胞内病原体，病毒需要宿主生物合成机制。一个基本的要求是宿主的翻译机器的新病毒蛋白质的合成。病毒利用宿主翻译机制并避免先天宿主防御的机制尚不清楚，先天宿主防御可降解病毒mRNA并减少细胞蛋白质合成，以防止或减少病毒蛋白质的合成。本项目的目标是确定哺乳动物呼肠孤病毒重编程宿主翻译机器优先合成病毒蛋白的机制。特别是，该项目将重点关注病毒介导的翻译机制的区室化，这是一种新的致病机制，通过这种机制，病毒蛋白质的合成可以在感染诱导的应激期间维持。待检验的假设是呼肠孤病毒通过以下方式促进其病毒mRNA的翻译：（1）在细胞质中称为病毒工厂的病毒复制的限定位点内将翻译因子和核糖体亚基区室化;（2）通过隔离病毒工厂内使eIF 2 α去磷酸化的GADD 34/蛋白磷酸酶1复合物，因此，保护病毒mRNA的翻译免受应激诱导的蛋白质合成抑制;和（3）通过直接修饰核糖体并改变其功能以促进非典型病毒mRNA的翻译。提出了三个目标：（2）确定呼肠孤病毒工厂内整合的应激反应的激活和细胞GADD 34和蛋白磷酸酶1的区室化是否促进呼肠孤病毒mRNA的翻译;（3）研究病毒非结构蛋白σNS在增强呼肠孤病毒mRNA翻译中的作用。这项工作的预期成果是鉴定病毒工厂内宿主翻译机制区室化所需的病毒因子，了解呼肠孤病毒在持续磷酸化eIF 2 α和激活整合应激反应的情况下复制的机制，以及更好地了解呼肠孤病毒蛋白σNS在选择宿主翻译机制和修饰核糖体功能中的作用。我们预计，这一建议的一个重要成果将是新的基本信息的病毒策略，以克服先天宿主防御。