Abstract:
OBJECTIVE: Tuberculosis still remains a global burden and is one of the top infectious diseases from a single pathogen. Mycobacterium tuberculosis, the causative agent, has perfected many ways to replicate and persist within its host. While mycobacteria induce vacuole damage to evade the toxic environment and eventually escape into the cytosol, the host recruits repair machineries to restore the MCV membrane. However, how lipids are delivered for membrane repair is poorly understood. Using advanced fluorescence imaging and volumetric correlative approaches, we demonstrate that this involves the recruitment of the endoplasmic reticulum (ER)-Golgi lipid transfer protein OSBP8 in the Dictyostelium discoideum/Mycobacterium marinum system. Strikingly, depletion of OSBP8 affects lysosomal function accelerating mycobacterial growth. This indicates that an ER-dependent repair pathway constitutes a host defense mechanism against intracellular pathogens such as M. tuberculosis.
摘要:
几种细胞内病原体,如结核分枝杆菌,损伤内膜以进入细胞质并破坏先天免疫反应。宿主通过招募将病原体保留在液泡内的修复机器来抵消内膜损伤。这里,我们表明,内质网(ER)-高尔基体蛋白氧固醇结合蛋白(OSBP)及其盘基网柄菌同源物OSBP8被募集到含有分枝杆菌的液泡(MCV)依赖于ESX-1分泌系统的存在,表明它们的动员与膜损伤有关。缺乏OSBP8会导致磷脂酰肌醇-4-磷酸(PI4P)在MCV上的过度积累并降低细胞活力。OSBP8耗尽细胞的溶酶体和液泡的降解能力降低,有利于分枝杆菌的生长。与OSBP8在膜修复中的潜在作用一致,感染结核分枝杆菌的人巨噬细胞以ESX-1依赖性方式募集OSBP.这些发现确定了用于恢复MCV的ER依赖性修复机制,其中OSBP8起平衡受损膜上的PI4P水平的作用。重要性结核病仍然是全球负担,是单一病原体的主要传染病之一。结核分枝杆菌,病原体,已经完善了许多在其宿主内复制和持续存在的方法。虽然分枝杆菌诱导液泡损伤以逃避有毒环境并最终逃逸到细胞质中,宿主招募修复机器来恢复MCV膜。然而,脂质是如何递送用于膜修复的,人们知之甚少。使用先进的荧光成像和体积相关方法,我们证明,这涉及到内质网(ER)-高尔基脂质转移蛋白OSBP8在盘基网柄菌/分枝杆菌系统中的募集。引人注目的是,OSBP8的消耗影响溶酶体功能加速分枝杆菌生长。这表明ER依赖性修复途径构成了针对细胞内病原体如结核分枝杆菌的宿主防御机制。