The Endoplasmic Reticulum Stress Sensor Inositol-Requiring Enzyme 1α Augments Bacterial Killing through Sustained Oxidant Production.
The Endoplasmic Reticulum Stress Sensor Inositol-Requiring Enzyme 1α Augments Bacterial Killing through Sustained Oxidant Production.
复制标题
DOI：
10.1128/mbio.00705-15
复制
发表时间：
2015-07-14
期刊：
影响因子：
6.4
通讯作者：
O'Riordan MX
中科院分区：
文献类型：
--
作者：
Abuaita BH;Burkholder KM;Boles BR;O'Riordan MX
细菌感染可以触发细胞应激程序，例如未折叠蛋白反应（UPR），当错误折叠的蛋白质在内质网（ER）内积累时发生。在这里，我们使用人类病原体耐甲氧西林金黄色葡萄球菌（MRSA）作为感染模型，以探讨ER应激如何促进抗菌功能。MRSA感染激活了最高度保守的未折叠蛋白反应传感器，肌醇需要酶1α（IRE 1 α），这是体外和体内强大的细菌杀伤所必需的。巨噬细胞IRE 1依赖的杀菌活性需要活性氧（ROS）。活的MRSA细胞从新生吞噬体中排除ROS，并强烈触发IRE 1激活，导致ROS的持续产生，这些ROS在很大程度上不依赖于Nox 2。相比之下，死亡的MRSA显示早期与ROS共定位，但IRE 1的激活剂较差，不会引发持续的ROS产生。由IRE 1信号刺激的全局ROS对于MRSA杀伤是必要的，但不是足够的，这也需要ER驻留SNARE Sec 22 B用于吞噬体隔室中ROS的积累。综上所述，这些结果表明，IRE 1介导的持续ROS产生可能作为一种故障安全机制，以杀死逃避初始巨噬细胞氧化爆发的细菌病原体。细胞应激程序已经被认为是对感染的先天免疫应答的重要组成部分。ER应激反应的IRE 1途径在免疫分泌功能（例如抗体产生）中的作用已得到充分证实，但其对先天免疫的贡献尚不清楚。在这里，我们表明，感染的巨噬细胞与可行的MRSA诱导IRE 1激活，导致细菌杀伤。IRE 1依赖性杀菌活性需要在感染数小时内持续产生活性氧。SNARE蛋白Sec 22 B，这是以前证明控制ER-吞噬体运输，是IRE 1驱动的全球ROS生产，但必须在含细菌的吞噬体后期ROS积累。我们的研究强调了IRE 1在促进巨噬细胞杀菌能力方面的关键作用，并揭示了导致巨噬细胞吞噬体中抗菌效应分子浓度的故障安全机制。
Bacterial infection can trigger cellular stress programs, such as the unfolded protein response (UPR), which occurs when misfolded proteins accumulate within the endoplasmic reticulum (ER). Here, we used the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) as an infection model to probe how ER stress promotes antimicrobial function. MRSA infection activated the most highly conserved unfolded protein response sensor, inositol-requiring enzyme 1α (IRE1α), which was necessary for robust bacterial killing in vitro and in vivo. The macrophage IRE1-dependent bactericidal activity required reactive oxygen species (ROS). Viable MRSA cells excluded ROS from the nascent phagosome and strongly triggered IRE1 activation, leading to sustained generation of ROS that were largely Nox2 independent. In contrast, dead MRSA showed early colocalization with ROS but was a poor activator of IRE1 and did not trigger sustained ROS generation. The global ROS stimulated by IRE1 signaling was necessary, but not sufficient, for MRSA killing, which also required the ER resident SNARE Sec22B for accumulation of ROS in the phagosomal compartment. Taken together, these results suggest that IRE1-mediated persistent ROS generation might act as a fail-safe mechanism to kill bacterial pathogens that evade the initial macrophage oxidative burst. Cellular stress programs have been implicated as important components of the innate immune response to infection. The role of the IRE1 pathway of the ER stress response in immune secretory functions, such as antibody production, is well established, but its contribution to innate immunity is less well defined. Here, we show that infection of macrophages with viable MRSA induces IRE1 activation, leading to bacterial killing. IRE1-dependent bactericidal activity required generation of reactive oxygen species in a sustained manner over hours of infection. The SNARE protein Sec22B, which was previously demonstrated to control ER-phagosome trafficking, was dispensable for IRE1-driven global ROS production but necessary for late ROS accumulation in bacteria-containing phagosomes. Our study highlights a key role for IRE1 in promoting macrophage bactericidal capacity and reveals a fail-safe mechanism that leads to the concentration of antimicrobial effector molecules in the macrophage phagosome.