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，感染世界上超过 50% 的人口， HCMV 感染是个体中存在终生感染的一个主要问题。 幼稚的免疫系统，因为它可能导致一系列疾病，包括耳聋、呼吸道疾病和器官疾病 此外，近年来，HCMV 由于其对疾病的影响而引起了越来越多的关注。 慢性疾病的出现和进展是一个显着的特征，例如心血管疾病和癌症。 HCMV 感染的关键是细胞代谢的整体重新布线，以增加生物合成的产生 HCMV 感染过程中细胞代谢的失调是前体细胞和能量的调节。 它是其复制所必需的，并且与其许多病理学有关，包括其肿瘤调节 然而，我们目前对代谢改变的机制缺乏了解。 我们最近发现线粒体酶 Sirtuin 4 (SIRT4) 是一种有效的酶。 此外，我们将 SIRT4 确定为第一个已知的哺乳动物细胞。 脂酰胺酶，从丙酮酸脱氢酶中去除必需的翻译后修饰脂酰化 这一发现表明 SIRT4 是细胞代谢的关键调节因子，但 SIRT4 是如何发挥其作用的呢？ 抗病毒功能仍然未知。我认为 SIRT4 在 HCMV 感染期间在宿主防御中发挥作用。 通过对抗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。 我的初步结果是，我发现HCMV已经获得了抑制其功能的机制。 证明 SIRT4 是以前未表征的病毒蛋白 pUL13 的抑制目标。 在目标 1 中，我将讨论病毒与宿主相互作用的双方。 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 我将确定抗病毒所需的特定 SIRT4 酶活性。 在目标 2 中，我将揭示 pUL13 如何抑制 SIRT4，并描述其调节功能。 作为长期目标，阐明细胞代谢和线粒体生物能量学。 SIRT4 和 pUL13 之间的相互作用可以帮助解释 HCMV 如何诱导代谢变化，从而促进 这些知识可以指出恢复代谢健康和治疗 HCMV-的治疗目标。 这项研究将在普林斯顿大学分子生物学系进行。 该计划以其多学科研究和研究生培训的支持环境而闻名 职业发展。