NRROS negatively regulates reactive oxygen species during host defence and autoimmunity
NRROS negatively regulates reactive oxygen species during host defence and autoimmunity
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DOI：
10.1038/nature13152
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发表时间：
2014-05-08
期刊：
影响因子：
64.8
通讯作者：
Ouyang, Wenjun
中科院分区：
文献类型：
--
作者：
Noubade, Rajkumar;Wong, Kit;Ouyang, Wenjun
由吞噬细胞产生的活性氧（ROS）对宿主防御细菌和真菌感染至关重要。ROS产生机制有缺陷的个体会发展成慢性肉芽肿病（1,2）。相反，过多的ROS会在炎症过程中引起侧支组织损伤，因此需要严格调节。在这里，我们描述了一种蛋白质，我们称之为ROS的负调节因子（NRROS），它限制了炎症反应期间吞噬细胞产生ROS。炎症信号可抑制吞噬细胞内NRROS的表达。缺乏NRROS的吞噬细胞在炎症攻击时产生更多的ROS，并且在其吞噬细胞中缺乏NRROS的小鼠对大肠杆菌和单核增生李斯特菌的杀菌活性增强。相反，由于中枢神经系统的氧化组织损伤，这些小鼠发展为严重的实验性自身免疫性脑脊髓炎。在机制上，NRROS定位于内质网，在那里它直接与新生的NOX2（也称为gp91（phox）并由Cybb编码）单体相互作用，后者是NADPH氧化酶复合物的膜结合亚基之一，并通过内质网相关降解途径促进NOX2的降解。因此，NRROS提供了一种迄今尚未定义的调节ROS产生的机制——如果需要控制入侵的病原体，NRROS可以使吞噬细胞产生更多的ROS，同时最大限度地减少不必要的附带组织损伤。
Reactive oxygen species (ROS) produced by phagocytes are essential for host defence against bacterial and fungal infections. Individuals with defective ROS production machinery develop chronic granulomatous disease(1,2). Conversely, excessive ROS can cause collateral tissue damage during inflammatory processes and therefore needs to be tightly regulated. Here we describe a protein, we termed negative regulator of ROS (NRROS), which limits ROS generation by phagocytes during inflammatory responses. NRROS expression in phagocytes can be repressed by inflammatory signals. NRROS-deficient phagocytes produce increased ROS upon inflammatory challenges, and mice lacking NRROS in their phagocytes show enhanced bactericidal activity against Escherichia coli and Listeria monocytogenes. Conversely, these mice develop severe experimental autoimmune encephalomyelitis owing to oxidative tissue damage in the central nervous system. Mechanistically, NRROS is localized to the endoplasmic reticulum, where it directly interactswith nascent NOX2 (also known as gp91(phox) and encoded by Cybb) monomer, one of the membrane-bound subunits of the NADPH oxidase complex, and facilitates the degradation of NOX2 through the endoplasmic-reticulum-associated degradation pathway. Thus, NRROS provides a hitherto undefined mechanism for regulating ROS prodution-one that enables phagocytes to produce higher amounts of ROS, if required to control invading pathogens, while minimizing unwanted collateral tissue damage.