Control of Translation in Herpesvirus Infected Cells

疱疹病毒感染细胞中翻译的控制

• 批准号: 8671831
• 负责人: Ian J Mohr
• 金额: $ 33.81万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8671831
• 关键词: 7-methylguanosine triphosphate; Acquired Immunodeficiency Syndrome; Affect; Alleles; Animals; Attenuated; Binding; Binding Proteins; Biological Models; Biological Process; Bone Marrow; Cells; Complex; Congenital Abnormality; Cues; Cultured Cells; Cytomegalovirus; Cytomegalovirus Infections; Diabetes Mellitus; Disease; Ensure; Family member; Fibroblasts; Fostering; Gene Expression; Gene Expression Regulation; Genes; Genetic Translation; Growth and Development function; Health; Herpesviridae; Homeostasis; Human; Immune system; Immunocompromised Host; Individual; Investigation; Knock-in Mouse; Learning; Malignant Neoplasms; Measures; Mediating; Memory; Messenger RNA; Multiprotein Complexes; Murid herpesvirus 1; Mus; Newborn Infant; Normal Cell; Organ Transplantation; Pathogenesis; Pathway interactions; Patients; Peptide Initiation Factors; Phosphorylation; Phosphotransferases; Physiological; Poly A; Polyribosomes; Process; Production; Protein Biosynthesis; Protein Complex Subunit; Protein Isoforms; Proteins; Recruitment Activity; Regulation; Ribosomes; Role; Signal Pathway; Signal Transduction; Solid; Stress; Transcript; Translational Activation; Translations; Transplant Recipients; Viral; Viral Proteins; Virus; Virus Diseases; cell growth; design; gammaherpesvirus; genetic regulatory protein; human disease; inhibitor/antagonist; inorganic phosphate; insight; mRNA capping; pathogen; polyadenylated messenger RNA; polypeptide; reactivation from latency; research study; response; vaccine development; 7-methylguanosine triphosphate; Acquired Immunodeficiency Syndrome; Affect; Alleles; Animals; Attenuated; Binding; Binding Proteins; Biological Models; Biological Process; Bone Marrow; Cells; Complex; Congenital Abnormality; Cues; Cultured Cells; Cytomegalovirus; Cytomegalovirus Infections; Diabetes Mellitus; Disease; Ensure; Family member; Fibroblasts; Fostering; Gene Expression; Gene Expression Regulation; Genes; Genetic Translation; Growth and Development function; Health; Herpesviridae; Homeostasis; Human; Immune system; Immunocompromised Host; Individual; Investigation; Knock-in Mouse; Learning; Malignant Neoplasms; Measures; Mediating; Memory; Messenger RNA; Multiprotein Complexes; Murid herpesvirus 1; Mus; Newborn Infant; Normal Cell; Organ Transplantation; Pathogenesis; Pathway interactions; Patients; Peptide Initiation Factors; Phosphorylation; Phosphotransferases; Physiological; Poly A; Polyribosomes; Process; Production; Protein Biosynthesis; Protein Complex Subunit; Protein Isoforms; Proteins; Recruitment Activity; Regulation; Ribosomes; Role; Signal Pathway; Signal Transduction; Solid; Stress; Transcript; Translational Activation; Translations; Transplant Recipients; Viral; Viral Proteins; Virus; Virus Diseases; cell growth; design; gammaherpesvirus; genetic regulatory protein; human disease; inhibitor/antagonist; inorganic phosphate; insight; mRNA capping; pathogen; polyadenylated messenger RNA; polypeptide; reactivation from latency; research study; response; vaccine development

Regulation of gene expression at the level of translation is fundamentally important for the control of normal cell growth, development, differentiation, learning, memory, and the response to environmental stress, including viral infection. In particular, the translation of many eukaryotic capped, polyadenylated mRNAs is controlled at the initiation step, where the regulated assembly of a specialized, multiprotein complex is required to recruit the small ribosome subunit to the mRNA 5' terminus. The translation initiation factor components of this complex are capable of responding to different cellular signaling cascades, enabling a rapid response to diverse physiological effectors. Viral model systems have proven to be particularly useful in elaborating cellular translational control strategies because their successful replication absolutely requires viral mRNA translation. In their continued efforts to capture and engage the cellular protein synthesis machinery, viruses must effectively control the cellular signaling cascades that regulate translation. This investigation utilizes a herpes virus family member, human cytomegalovirus (HCMV), as a probe to explore the complex circuitry regulating the initiation of mRNA translation. Although innocuous in most healthy individuals, HCMV is a widespread, opportunistic pathogen responsible for severe disease among the immunocompromised, including bone marrow and solid organ transplant recipients along with AIDS patients. In addition, congenital HCMV infection is the leading viral cause of birth defects in newborns. Our long-term overall objective is to understand how HCMV manipulates cellular translational control pathways to ensure that viral mRNAs can compete effectively with cellular mRNAs for access to translation initiation factors. As this process is critical for productive replication and reactivation from latency, our investigation is likely to reveal new targets for interfering with viral replication and new strategies for creating weakened, attenuated strains useful for vaccine development. In addition, these studies will provide insight into basic mechanisms of translational control that are likely to prove important in many human diseases, including cancer and diabetes, where the regulation of protein production is abnormal. We specifically propose to i) determine how HCMV infection affects eIF4F-core and associated components; ii) define the mechanism(s) by which PABP abundance is controlled translationally in HCMV-infected cells; and iii) evaluate the role of cellular eIF4E-kinases & eIF4E phosphorylation on viral replication & pathogenesis

基因表达在翻译水平上的调节对于控制正常细胞生长，发育，分化，学习，记忆以及对环境压力（包括病毒感染）的反应至关重要。特别地，在开始步骤中控制了许多真核封顶的翻译，多腺苷酸化的mRNA受到控制，在该步骤中，需要专门的多蛋白复合物的调节组装来募集小核糖体亚基到mRNA 5'末端。该复合物的翻译起始因子成分能够对不同的细胞信号级联反应，从而可以快速响应各种生理效应子。事实证明，病毒模型系统在阐述细胞翻译控制策略方面特别有用，因为它们的成功复制绝对需要病毒mRNA翻译。在他们持续捕获和参与细胞蛋白合成机制的努力中，病毒必须有效控制调节翻译的细胞信号传导级联。这项研究利用疱疹病毒家族成员人类巨细胞病毒（HCMV）作为探索探索调节mRNA翻译启动的复杂电路。尽管在大多数健康的个体中，HCMV是一种普遍的，机会性病原体，负责免疫功能低下的严重疾病，包括骨髓和固体器官移植受者以及艾滋病患者。此外，先天性HCMV感染是新生儿出生缺陷的主要病毒原因。我们的长期整体目标是了解HCMV如何操纵细胞翻译控制途径，以确保病毒mRNA可以有效地与细胞mRNA竞争，以获取转化起始因子。由于此过程对于潜伏期的生产复制和重新激活至关重要，因此我们的研究很可能揭示了干扰病毒复制的新目标，以及创建有用的弱化，减弱菌株有用的新策略。此外，这些研究将提供对翻译控制的基本机制的洞察力，这些机制可能在许多人类疾病中很重要，包括癌症和糖尿病，而蛋白质产生的调节是异常的。我们特别建议i）确定HCMV感染如何影响EIF4F核和相关组件； ii）定义了在HCMV感染的细胞中控制PABP丰度翻译的机制； iii）评估细胞EIF4E激酶和EIF4E磷酸化对病毒复制和发病机理的作用