Dynamin like proteins mediate extracellular vesicle secretion in Mycobacterium tuberculosis

Abstract Mycobacterium tuberculosis (Mtb) secretes extracellular vesicles (EVs) containing a variety of proteins, lipoproteins and lipoglycans. While emerging evidence suggests that EVs contribute to tuberculosis pathogenesis, the factors and molecular mechanisms involved in mycobacterial EV production have not been identified. In this study, we use a genetic approach to identify Mtb proteins that mediate vesicle release in response to iron limitation and antibiotic exposure. We uncover a critical role for the isoniazid induced, dynamin-like proteins, IniA and IniC in mycobacterial EV biogenesis. Further characterization of a Mtb iniA mutant shows that the production of EVs enables intracellular Mtb to export bacterial components into the extracellular environment to communicate with host cells and potentially modulate the immune response. The findings advance our understanding of the biogenesis and functions of mycobacterial EVs and provide an avenue for targeting vesicle production in vivo.

摘要 结核分枝杆菌（Mycobacterium tuberculosis, Mtb）可分泌含有多种蛋白质、脂蛋白及脂聚糖的细胞外囊泡（extracellular vesicles, EVs）。尽管越来越多的研究证据表明EVs参与结核发病进程，但目前尚未明确分枝杆菌EV产生过程中涉及的关键因子与分子机制。本研究采用遗传学方法，筛选出可响应铁限制与抗生素暴露、介导囊泡释放的Mtb蛋白。我们发现异烟肼诱导的动力蛋白样蛋白IniA与IniC在分枝杆菌EV生物发生中发挥关键作用。对Mtb iniA突变体的进一步表征显示，EV的产生可使胞内Mtb将细菌组分分泌至胞外环境，从而与宿主细胞进行交流并潜在调控免疫应答。本研究结果加深了我们对分枝杆菌EV生物发生与功能的理解，并为靶向体内囊泡生成提供了新的研究途径。