Mycobacterium tuberculosis Rv0927c promote Type I interferon responses by targeting host TUFM to trigger mitochondrial damage and increase intracellular survival

Mycobacterium tuberculosis (M. tuberculosis) deploys effector proteins to reprogram host immunity, but how it perturbs mitochondrial homeostasis during infection remains incompletely understood. Here, Rv0927c is identified as an M. tuberculosis effector that targets the host mitochondrial translation elongation factor TUFM. Rv0927c associates with TUFM and induces mitochondrial dysfunction, including membrane depolarization, oxidative stress, and PINK1 accumulation, followed by leakage of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA is accompanied by activation of STING-IRF3 signaling and increased production of IFN-β, which promotes intracellular mycobacterial survival. In infection models, genetic deletion of Rv0927c attenuates interferon induction, whereas Rv0927c expression enhances type I interferon responses. Consistently, in a mouse tail vein infection model using H37Ra, Rv0927c is associated with elevated IFN-β transcripts in spleen and liver and exacerbated tissue pathology. Together, these findings define an Rv0927c–TUFM axis that triggers mitochondrial stress and PINK1 accumulation. This response activates STING dependent type I interferon signaling and promotes disease associated inflammation.

结核分枝杆菌（Mycobacterium tuberculosis）可通过分泌效应蛋白（effector proteins）重编程宿主免疫，但该菌在感染过程中如何扰乱线粒体稳态（mitochondrial homeostasis），目前仍未完全阐明。本研究鉴定出结核分枝杆菌效应蛋白Rv0927c，其靶向宿主线粒体翻译延伸因子Tu（TUFM）。Rv0927c与TUFM结合并诱导线粒体功能障碍，包括膜去极化（membrane depolarization）、氧化应激（oxidative stress）及PTEN诱导激酶1（PINK1）积累，随后导致线粒体DNA（mtDNA）渗漏至细胞质（cytosol）中。胞质线粒体DNA伴随干扰素基因刺激因子（STING）-干扰素调节因子3（IRF3）信号通路激活以及干扰素β（IFN-β）生成增加，这一过程可促进胞内分枝杆菌的存活。在感染模型中，敲除Rv0927c可减弱干扰素诱导应答，而表达Rv0927c则可增强I型干扰素应答。一致的是，在采用H37Ra毒株的小鼠尾静脉感染模型中，Rv0927c可使脾脏与肝脏中的IFN-β转录本水平升高，并加剧组织病理损伤。综上，本研究明确了Rv0927c-TUFM轴可诱导线粒体应激与PINK1积累，该应答激活STING依赖型I型干扰素信号通路，并促进疾病相关炎症反应。