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

项目摘要 结核分枝杆菌是一种令人难以置信的成功的人类病原体，目前感染了三分之一的人。 每年造成150万人死亡。结核分枝杆菌与结核分枝杆菌的相互作用 巨噬细胞激活了许多抗菌途径，这种细菌进化出了一系列精巧的 为了建立利基和促进感染而进行的适应以抵消这种反应。因此，当 结核分枝杆菌内化成巨噬细胞，先天免疫感应宿主细胞胞浆中的细菌DNA触发 抗菌和亲细菌反应：选择性自噬摧毁一群杆菌和 限制结核分枝杆菌的生长，而抗病毒I型干扰素反应的激活促进细菌感染和 发病机制。一种名为TBK1的天然免疫激酶对这两个过程都是至关重要的；然而， 该激酶包括选择性自噬和I型干扰素信号复合体的机制 是未知的。我们的新工作发现了三聚体基序蛋白TRIM14在调节 在结核分枝杆菌感染过程中，蛋白酪氨酸激酶1和I型干扰素反应。我们假设TRIM14是一个 结核分枝杆菌感染过程中DNA传感关键调控因子及TRIM14的翻译后修饰 影响TBK1的穿梭远离选择性自噬，以促进I型干扰素的产生。vbl.使用 生物化学、蛋白质组学和基于显微镜的方法我们将(1)确定 TRIM14对结核分枝杆菌感染过程中DNA传感结果的影响(2)阐明翻译后的作用 调节TRIM14的修饰和(3)确定TRIM30α在负调控I型干扰素中的作用 产生和控制结核分枝杆菌的发病机制。因为这两条DNA感知通路导致了如此惊人的 不同的疾病结果，显然有机会开发针对分子的治疗方法，如 TRIMS，希望在结核分枝杆菌感染期间激活选择性自噬，同时抑制I型干扰素反应 感染。

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.