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

项目总结

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.