Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
J Bacteriol. 2019 Jun 21;201(14). doi: 10.1128/JB.00760-18. Print 2019 Jul 15.
The ESX-1 (ESAT-6 system 1) secretion system plays a conserved role in the virulence of diverse mycobacterial pathogens, including the human pathogen and , an environmental mycobacterial species. The ESX-1 system promotes the secretion of protein virulence factors to the extracytoplasmic environment. The secretion of these proteins triggers the host response by lysing the phagosome during macrophage infection. Using proteomic analyses of the secretome in the presence and absence of a functional ESX-1 system, we and others have hypothesized that MMAR_2894, a PE family protein, is a potential ESX-1 substrate in We used genetic and quantitative proteomic approaches to determine if MMAR_2894 is secreted by the ESX-1 system, and we defined the requirement of for ESX-1-mediated secretion and virulence. We show that MMAR_2894 is secreted by the ESX-1 system in and is itself required for the optimal secretion of the known ESX-1 substrates in Moreover, we found that MMAR_2894 was differentially required for hemolysis and cytolysis of macrophages, two lytic activities ascribed to the ESX-1 system. Both , the cause of human tuberculosis (TB), and , a pathogen of ectotherms, use the ESX-1 secretion system to cause disease. There are many established similarities between the ESX-1 systems in and in Yet the two bacteria infect different hosts, hinting at species-specific functions of the ESX-1 system. Our findings demonstrate that MMAR_2894 is a PE protein secreted by the ESX-1 system of We show that MMAR_2894 is required for the optimal secretion of mycobacterial proteins required for disease. Because the gene is not conserved in , our findings demonstrate that MMAR_2894 may contribute to a species-specific function of the ESX-1 system in , providing new insight into how the and systems differ.
ESX-1（ESAT-6 系统 1）分泌系统在多种分枝杆菌病原体的毒力中发挥保守作用，包括人类病原体 和 ，一种环境分枝杆菌物种。ESX-1 系统促进蛋白质毒力因子向细胞外环境的分泌。这些蛋白质的分泌通过在巨噬细胞感染期间裂解吞噬体来触发宿主反应。通过在存在和不存在功能 ESX-1 系统的情况下对 分泌组进行蛋白质组学分析，我们和其他人假设，PE 家族蛋白 MMAR_2894 是 中 ESX-1 的潜在底物。我们使用遗传和定量蛋白质组学方法来确定 MMAR_2894 是否通过 ESX-1 系统分泌，并确定 对 ESX-1 介导的分泌和毒力的要求。我们表明，MMAR_2894 在 中通过 ESX-1 系统分泌，并且本身是 中已知 ESX-1 底物的最佳分泌所必需的。此外，我们发现 MMAR_2894 对巨噬细胞的溶血和细胞溶解有不同的要求，这两种溶酶活性归因于 ESX-1 系统。人类结核病（TB）的病原体 和 ，一种变温动物病原体，都使用 ESX-1 分泌系统来引起疾病。 和 中的 ESX-1 系统有许多已确立的相似之处。然而，两种细菌感染不同的宿主，暗示 ESX-1 系统具有种特异性功能。我们的研究结果表明，MMAR_2894 是 中 ESX-1 系统分泌的一种 PE 蛋白。我们表明，MMAR_2894 是疾病所需的分枝杆菌蛋白最佳分泌所必需的。由于 基因在 中不保守，我们的研究结果表明，MMAR_2894 可能在 中 ESX-1 系统的种特异性功能中发挥作用，为 ESX-1 系统和 系统的差异提供了新的见解。
