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

基本信息

批准号：
9174898
负责人：
John S Parker
金额：
$ 38.6万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
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/9174898
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 Individual Infection Knowledge Mammalian Orthoreovirus Mediating Messenger RNA Modeling Nonstructural Protein Outcome Pathogenicity Peptide Initiation Factors Phosphorylation Process Protein Biosynthesis Protein Synthesis Inhibition Protein phosphatase Proteins Recruitment Activity Reoviridae Reoviridae Infections Reovirus Resources Ribosomes Role Site Stress Stress Response Signaling Testing Translational Regulation 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

项目摘要

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（由适用提供）：作为强制性细胞内病原体，病毒需要宿主生物合成机械。基本要求是用于合成新病毒蛋白的宿主翻译机制。病毒选择宿主翻译机制并避免降低病毒mRNA并减少细胞蛋白合成以防止或更少的可预防病毒蛋白合成的机制。该项目的目的是定义机制，哺乳动物丙卷病毒将宿主翻译机制重新编程为优先合成病毒蛋白。特别是，该项目将集中于转化机制的病毒介导的分隔，这是一种新型的致病机制，在感染诱导的应激期间可以维持病毒蛋白质合成。要测试的假设是，依孢病毒通过以下方式促进其病毒mRNA的翻译：（1）在称为病毒工厂的细胞溶胶中定义的病毒复制位点的分隔翻译因子和核糖体亚基；（2）通过隔离GADD34/蛋白质磷酸酶1复合物，该复合物使病毒因子内的EIF2α脱磷酸化，从而保护病毒mRNA的翻译免受应激诱导的蛋白质合成的抑制作用；（3）通过直接修饰核糖体并改变其功能以促进非经典病毒mRNA的翻译。提出了三个目的：（1）确定宿主细胞平移机制在嗜孢病毒感染细胞中的病毒式工厂内被分隔的机制；（2）确定在依孢病毒工厂内的细胞GADD34和蛋白质磷酸酶1的综合应力反应和隔室化的激活是否促进了嗜孢病毒mRNA的翻译；（3）确定病毒非结构蛋白σns在增强感染细胞中葡萄病毒mRNA翻译中的作用。 Expected outcomes of this work are identification of the viral factors required for compartmentalization of the host translational machinery within viral factors, 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.我们预计该提案的重要结果将是有关克服先天宿主防御的病毒策略的新基本信息。