TRIM proteins polarize DNA sensing outcomes during the innate immune response to Mycobacterium tuberculosis

TRIM 蛋白在结核分枝杆菌先天免疫反应过程中使 DNA 传感结果极化

• 批准号: 9158187
• 负责人: Robert Owen Watson
• 金额: $ 37.13万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9158187
• 关键词: Affect; Anti-Bacterial Agents; Antiviral Agents; Autophagocytosis; Bacillus (bacterium); Bacteria; Bacterial DNA; Bacterial Infections; Binding; Biochemical; Cells; Complex; Coupled; Cytosol; DNA; DNA Viruses; Data; Detection; Deubiquitinating Enzyme; Development; Disease Outcome; Event; Genes; Goals; Growth; Human; Immune; Immune response; Immune system; Infection; Interferon Type I; Interferons; Lead; Life Cycle Stages; Lysine; Lysosomes; Membrane; Microscopy; Modeling; Mycobacterium tuberculosis; Outcome; Pathogenesis; Pathway interactions; Phosphotransferases; Population; Post-Translational Protein Processing; Process; Production; Protein Family; Proteins; Proteomics; RNA Viruses; Regulation; Role; Signal Transduction; TBK1 gene; TRIM Motif; Testing; Therapeutic; Tuberculosis; Ubiquitination; Viral; Work; antimicrobial; antiviral immunity; base; ds-DNA; killings; knock-down; macrophage; mouse model; pathogen; response; therapeutic target; ubiquitin-protein ligase; viral DNA

Project Summary Mycobacterium tuberculosis (Mtb) is an incredibly successful human pathogen that currently infects one-third of the world's population and kills 1.5 million people every year. While interaction of Mtb bacilli and macrophages activates numerous antimicrobial pathways, this bacterium has evolved an exquisite array of adaptations to counteract such responses in order to establish a niche and promote infection. As such, when Mtb is internalized into macrophages, innate immune sensing of bacterial DNA in the host cell cytosol triggers both anti-bacterial and pro-bacterial responses: selective autophagy destroys a population of bacilli and restricts Mtb growth, while activation of the antiviral type I interferon response promotes bacterial infection and pathogenesis. An innate immune kinase called TBK1 is central to both of these processes; however, the mechanism by which this kinase comprises both selective autophagy and type I interferon signaling complexes is unknown. Our new work has uncovered an important role for the tripartite motif protein TRIM14 in regulating the kinase TBK1 and eliciting the type I IFN response during Mtb infection. We hypothesize that TRIM14 is a key modulator of DNA sensing during Mtb infection and that post-translational modification of TRIM14 influences the shuttling of TBK1 away from selective autophagy to promote type I IFN production. Using biochemical, proteomic and microscopy-based approaches we will (1) determine the mechanism by which TRIM14 influences DNA sensing outcomes during Mtb infection (2) elucidate the role of post-translational modifications in regulating TRIM14 and (3) determine the role of TRIM30α in negatively regulating type I IFN production and controlling Mtb pathogenesis. Because these two DNA sensing pathways lead to such strikingly different disease outcomes, there is an obvious opportunity to develop therapeutics that target molecules like TRIMs, in hopes of activating selective autophagy while inhibiting the type I interferon response during Mtb infection.

项目摘要 结核分枝杆菌（Mtb）是一种非常成功的人类病原体，目前感染了三分之一的人， 占世界总人口的10%，每年造成150万人死亡。虽然Mtb杆菌和 巨噬细胞激活许多抗菌途径，这种细菌已经进化出一系列精致的 为了建立一个生态位和促进感染，适应性抵消这种反应。所以当 结核分枝杆菌被内化到巨噬细胞中，宿主细胞胞质溶胶中细菌DNA的先天免疫感应触发 抗细菌和促细菌反应：选择性自噬破坏杆菌群， 限制Mtb生长，而抗病毒I型干扰素应答的激活促进细菌感染， 发病机制一种称为TBK 1的先天免疫激酶对这两个过程都至关重要;然而， 这种激酶包含选择性自噬和I型干扰素信号复合物的机制 不明我们的新工作揭示了三重基序蛋白TRIM 14在调节 激酶TBK 1并在Mtb感染期间引发I型IFN应答。我们假设TRIM 14是一个 结核分枝杆菌感染过程中DNA传感关键调控因子及TRIM 14的翻译后修饰 影响TBK 1从选择性自噬中的穿梭以促进I型IFN的产生。使用 生物化学，蛋白质组学和显微镜为基础的方法，我们将（1）确定的机制， TRIM 14影响Mtb感染期间的DNA传感结果（2）阐明翻译后的作用 调节TRIM 14的修饰和（3）确定TRIM 30 α在负调节I型IFN中的作用 生产和控制Mtb致病。因为这两条DNA传感通路导致了如此惊人的 不同的疾病结果，有一个明显的机会，发展治疗的目标分子，如 TRIMs，希望在Mtb期间激活选择性自噬，同时抑制I型干扰素反应。 感染