Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
Cell Host Microbe. 2010 Mar 18;7(3):210-20. doi: 10.1016/j.chom.2010.02.006.
Mycobacterium tuberculosis uses the ESX-1 secretion system to deliver virulence proteins during infection of host cells. Here we report a mechanism of posttranscriptional control of ESX-1 mediated by MycP1, a M. tuberculosis serine protease. We show that MycP1 is required for ESX-1 secretion but that, unexpectedly, genetic inactivation of MycP1 protease activity increases secretion of ESX-1 substrates. We demonstrate that EspB, an ESX-1 substrate required for secretion, is a target of MycP1 in vitro and in vivo. During macrophage infection, an inactive MycP1 protease mutant causes hyperactivation of ESX-1-stimulated innate signaling pathways. MycP1 is required for growth in mice during acute infection, while loss of its protease activity leads to attenuated virulence during chronic infection. As the key ESX-1 substrates ESAT-6 and CFP-10 are highly immunogenic, fine-tuning of their secretion by MycP1 may balance virulence and immune detection and be essential for successful maintenance of long-term M. tuberculosis infection.
结核分枝杆菌利用 ESX-1 分泌系统在感染宿主细胞时输送毒力蛋白。在这里，我们报告了一种由 M. tuberculosis 丝氨酸蛋白酶 MycP1 介导的 ESX-1 介导的转录后控制机制。我们表明 MycP1 是 ESX-1 分泌所必需的，但出乎意料的是，MycP1 蛋白酶活性的遗传失活增加了 ESX-1 底物的分泌。我们证明 EspB，一种 ESX-1 分泌所需的底物，是 MycP1 的体外和体内靶标。在巨噬细胞感染过程中，无活性的 MycP1 蛋白酶突变体导致 ESX-1 刺激的先天信号通路过度激活。MycP1 在急性感染期间是小鼠生长所必需的，而其蛋白酶活性的丧失导致慢性感染期间毒力减弱。由于关键的 ESX-1 底物 ESAT-6 和 CFP-10 具有高度免疫原性，因此 MycP1 对其分泌的精细调节可能平衡了毒力和免疫检测，对于成功维持长期结核分枝杆菌感染至关重要。
