Defining the regulation of mitochondrial bioenergetics during virus infection

定义病毒感染期间线粒体生物能的调节

• 批准号: 10231667
• 负责人: Cora Nicole Betsinger
• 金额: $ 4.6万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231667
• 关键词: Address; Antiviral Agents; Antiviral Response; Bioenergetics; Biological Assay; Biology; Birth; Carbon; Cardiovascular Diseases; Cell physiology; Cells; Chronic; Chronic Disease; Citric Acid Cycle; Congenital Abnormality; Cytomegalovirus; Defense Mechanisms; Development; Disease; Drug Design; Enzymes; Fellowship; Generations; Glycolysis; Goals; Health; Herpesviridae; Host Defense; Host Defense Mechanism; Human; Immune system; Immunocompromised Host; Impairment; Individual; Infection; Interdisciplinary Study; Knowledge; Lead; Link; Lung diseases; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methods; Microscopy; Mitochondria; Molecular Biology; Molecular Virology; Monitor; Organ failure; Oxidative Phosphorylation; Pathology; Pathway interactions; Population; Post-Translational Protein Processing; Prevalence; Production; Proteins; Proteomics; Pyruvate Dehydrogenase Complex; Regulation; Research; Risk; Role; Side; Sirtuins; Structure; Testing; Therapeutic; Universities; Up-Regulation; Vaccines; Viral; Viral Proteins; Virus; Virus Assembly; Virus Diseases; Virus Replication; base; career development; cell growth regulation; deafness; enzyme activity; fatty acid biosynthesis; graduate student; human disease; human pathogen; interdisciplinary approach; interest; lipid biosynthesis; lipoamidase; metabolomics; mitochondrial metabolism; new therapeutic target; obligate intracellular parasite; pathogen; prevent; programs; student training; supportive environment; therapeutic target; therapy development; virology

PROJECT SUMMARY/ABSTRACT. Human cytomegalovirus (HCMV) is a ß-herpesvirus that infects over 50% of the world’s population and establishes lifelong infection in individuals. HCMV infection is a major concern in individuals with impaired or naïve immune systems, as it can lead to a range of diseases, including deafness, respiratory disease, and organ failure. Additionally, HCMV has garnered increased interest in recent years due to its implication in the emergence and progression of chronic diseases, such as cardiovascular disease and cancer. A striking feature of HCMV infection is the global rewiring of cellular metabolism for the increased production of biosynthetic precursors and energy for replication. The dysregulation of cellular metabolism during HCMV infection is necessary for its replication and has been linked to many of its pathologies, including its oncomodulatory capacity. However, we currently lack an understanding of the mechanisms underlying the metabolic alterations observed during infection. We recently discovered that the mitochondrial enzyme sirtuin 4 (SIRT4) is a potent antiviral factor during HCMV infection. Furthermore, we established SIRT4 as the first known mammalian cellular lipoamidase, removing the essential posttranslational modification lipoylation from the pyruvate dehydrogenase complex. This discovery points to SIRT4 as a critical regulator of cellular metabolism, but how SIRT4 exerts its antiviral function remains unknown. I hypothesize that SIRT4 functions in host defense during HCMV infection by opposing viral-induced changes in cellular metabolism. Further supporting the critical role of SIRT4 in antiviral response, I discovered that HCMV has acquired a mechanism to suppress its functions. My preliminary results demonstrate that SIRT4 is targeted for inhibition by the previously uncharacterized viral protein, pUL13. In my proposal, I will address both sides of this virus-host interplay. In Aim 1, a combination of molecular virology, microscopy, proteomics and metabolomics will be used to define SIRT4-mediated mechanisms of defense against HCMV infection. I will determine which specific SIRT4 enzymatic activities are required for antiviral response. In Aim 2, I will uncover how pUL13 inhibits SIRT4, as well as characterize its function in regulating cellular metabolism and mitochondrial bioenergetics. As a long-term objective, elucidating the functional interaction between SIRT4 and pUL13 can help explain how HCMV induces metabolic changes that promote disease. This knowledge can point to therapeutic targets for restoring metabolic health and for treating HCMV- linked pathologies. This research will take place in the Molecular Biology Department of Princeton University, a program known for its multidisciplinary research and supportive environment for graduate student training and career development.

项目摘要/摘要。 人类巨细胞病毒（HCMV）是一种ß-疱疹病毒，感染了世界50％以上的人口和 建立个体终身感染。 HCMV感染是受损或 天真的免疫系统，因为它可能导致一系列疾病，包括死亡，呼吸道疾病和器官 失败。此外，由于HCMV在 慢性疾病的出现和进展，例如心血管疾病和癌症。罢工功能 HCMV感染是细胞代谢的全球重新布线，用于增加生物合成的产生 前体和复制能量。 HCMV感染期间细胞代谢的失调是 复制所必需的，并与许多病理有关 容量。但是，我们目前缺乏对代谢改变的机制的理解 在感染期间观察到。我们最近发现线粒体酶Sirtuin 4（Sirt4）是有效的 HCMV感染期间的抗病毒因子。此外，我们将SIRT4建立为第一个已知的哺乳动物细胞 脂肪酰胺酶，从丙酮酸脱氢酶中去除基本的翻译后修饰脂酰化 复杂的。该发现指出SIRT4是细胞代谢的关键调节剂，但Sirt4如何导出它 抗病毒功能仍然未知。我假设在HCMV感染期间，SIRT4在宿主防御中起作用 通过反对病毒诱导的细胞代谢变化。进一步支持SIRT4在抗病毒中的关键作用 响应，我发现HCMV已经获得了一种抑制其功能的机制。我的初步结果 证明SIRT4是针对先前未表征的病毒蛋白PUL13抑制的。在我的 提案，我将解决此病毒宿主相互作用的两面。在AIM 1中，分子病毒学的结合， 显微镜，蛋白质组学和代谢组学将用于定义SIRT4介导的防御机制 针对HCMV感染。我将确定抗病毒需要哪些特定的SIRT4酶活性 回复。在AIM 2中，我将发现PUL13如何抑制SIRT4，并表征其在调节中的功能 细胞代谢和线粒体生物能学。作为一个长期目标，阐明功能 SIRT4和PUL13之间的相互作用可以帮助解释HCMV如何影响促进的代谢变化 疾病。这些知识可以指出用于恢复代谢健康和治疗HCMV-的治疗靶标。 链接的病理。这项研究将在普林斯顿大学分子生物学系进行 以其多学科研究和研究生培训的支持环境而闻名的计划 职业发展。