Deciphering the Role of dNTP Metabolism in Innate Immunity

解读 dNTP 代谢在先天免疫中的作用

• 批准号: 10480862
• 负责人: Zhenyu Zhong
• 金额: $ 41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-03 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10480862
• 关键词: Affect; Aging; Alzheimer' s Disease; Apoptosis; Atherosclerosis; CASP1 gene; Cells; DNA; Disease; Enzymes; Genetic; Genomic Instability; Goals; Gouty Arthritis; Homeostasis; Immune; Inflammasome; Inflammation; Interleukin-1 beta; Knowledge; Macular degeneration; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Muscle Cells; NF-kappa B; Natural Immunity; Nuclear; Obesity; Pathogenicity; Production; Proteins; Research; Risk Factors; Role; Tissues; Virus; Virus Replication; cell growth; cell injury; cytokine; disorder risk; fitness; immune activation; immunoregulation; macrophage; marenostrin; mitochondrial genome; neoplastic cell; novel therapeutics; prevent; receptor; repaired; restoration; sensor; therapy development; tissue injury; tissue repair; tripolyphosphate

Project Summary A balanced supply of deoxynucleoside triphosphates (dNTPs), the building blocks for DNA, is vital for the synthesis or repair of both nuclear and mitochondrial genomes, whereas its imbalance results in genome instability that precipitates cellular damage and breach of homeostasis. Research on dNTP metabolism has been traditionally conducted in highly proliferative (e.g. tumor cells), metabolically active (e.g. muscle cells) or virus-infected cells due to the key roles of dNTPs in fulfilling demands for cell growth, energy production and viral replication. However, little is known regarding the role of dNTP metabolism in innate immunity, especially in the context of nonpathogen-induced immune activation. A hallmark of innate immune activation is the assembly of the Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome—a dominant innate immune sensor for tissue damage. The NLRP3 inflammasome is composed of the sensor NLRP3, the adaptor ASC (apoptosis associated spike-like protein) and the effector pro-caspase-1. Assembly of the NLRP3 inflammasome proceeds with two distinct steps: ‘priming’ and ‘activation’. Priming entails rapid NF-kB activation for initiating de novo synthesis of pro-IL-1β as well as increasing the amount of NLRP3. In contrast, activation involves the assembly of the NLRP3 inflammasome machinery, resulting in autocleavage and activation of caspase-1 which then converts immature pro-IL-1β into bioactive IL-1β—a powerful proinflammatory cytokine that ignites inflammation. Although properly controlled NLRP3 inflammasome activity allows for restoration of homeostasis after traumatic tissue injury by stimulating damage clearance and tissue repair, its aberrant and prolonged activation also promotes the rapid progression of many devastating disorders, including gouty arthritis, Alzheimer’s disease, atherosclerosis, macular degeneration and cancer. It is therefore crucial to understand how NLRP3 inflammasome activity is regulated in innate immune cells. Recently, we discovered that genetic deletion of CMPK2 or SAMHD1, two key enzymes within the dNTP metabolic pathways responsible for synthesizing or degrading dNTPs respectively, orchestrates NLRP3 inflammasome activation. Therefore, the ultimate goal of this MIRA R35 project is to establish dNTP metabolism as a new layer for innate immune regulation and further delineate its underlying mechanism of action. To achieve this goal, three major scientific questions will be pursued: (1) how does inflammasome priming regulate the function of dNTP metabolic enzymes? (2) how does dNTP metabolism control NLRP3 inflammasome activation? Lastly, since NLRP3 inflammasome overactivation is a shared pathogenic hallmark of many diseases, we further asked: (3) do common disease risk factors, such as aging and obesity, dysregulate macrophage dNTP metabolism, thereby permitting NLRP3 inflammasome overactivation? Completion of this project will not only fill an important knowledge gap in the innate immunity field, but may also guide new therapy development to prevent NLRP3 inflammasome hyperactivation.

项目摘要 脱氧核苷三磷酸（dNTPs）的平衡供应，DNA的基石，是至关重要的， 核和线粒体基因组的合成或修复，而其不平衡导致基因组 加速细胞损伤和破坏体内平衡的不稳定性。对dNTP代谢的研究 传统上在高度增殖（例如肿瘤细胞）、代谢活性（例如肌细胞）或 由于dNTPs在满足细胞生长、能量产生和代谢的需求中的关键作用， 病毒复制然而，关于dNTP代谢在先天免疫中的作用知之甚少，特别是 在非病原体诱导的免疫激活的情况下。先天免疫激活的标志是 Nod样受体pyrin结构域3（NLRP 3）炎性小体的组装--一种显性先天性 用于组织损伤免疫传感器。NLRP 3炎性小体由传感器NLRP 3、适配器 ASC（凋亡相关尖峰样蛋白）和效应物caspase-1原。NLRP的组装3 炎性小体以两个不同的步骤进行：“引发”和“激活”。引发需要快速的NF-kB 激活以启动pro-IL-1β的从头合成以及增加NLRP 3的量。与此相反， 活化涉及NLRP 3炎性体机制的组装，导致自裂解和 激活caspase-1，然后将未成熟的pro-IL-1β转化为具有生物活性的IL-1β-a， 引发炎症的促炎细胞因子。尽管适当控制了NLRP 3炎性体活性， 允许在创伤性组织损伤后通过刺激损伤清除和组织 修复，其异常和长期激活也促进了许多破坏性的疾病的快速发展。 这些疾病包括痛风性关节炎、阿尔茨海默病、动脉粥样硬化、黄斑变性和癌症。它 因此，了解NLRP 3炎性体活性如何在先天免疫细胞中调节至关重要。 最近，我们发现dNTP中的两个关键酶CMPK 2或SAMHD 1的基因缺失， 分别负责合成或降解dNTP的代谢途径，协调NLRP 3 炎性小体激活。因此，本MIRA R35项目的最终目标是建立dNTP 代谢作为先天免疫调节的新层，并进一步阐明其潜在的机制， 行动上为了实现这一目标，将追求三个主要的科学问题：（1）炎症体如何 引发调节dNTP代谢酶的功能？(2)dNTP代谢如何控制NLRP 3 炎性小体激活最后，由于NLRP 3炎性体过度活化是共同的致病标志， 在众多疾病中，我们进一步问：（3）常见的疾病危险因素，如衰老和肥胖， 巨噬细胞dNTP代谢失调，从而允许NLRP 3炎性小体过度活化？ 该项目的完成不仅将填补先天免疫领域的一个重要知识空白， 还指导新疗法的开发，以防止NLRP 3炎性小体过度活化。