Mammalian Peptidoglycan Recognition Proteins (PGRPs) kill bacteria through induction of synergistic oxidative, thiol, and metal stress. PGRPs induce oxidative stress in bacteria through a block in the respiratory chain, which results in decreased respiration and incomplete reduction of oxygen (O2) to hydrogen peroxide (H2O2). In this study we identify the site of PGRP-induced generation of H2O2 in Escherichia coli. Tn-seq screening of E. coli Tn10 insertion library revealed that mutants in formate dehydrogenase (FDH) genes had the highest survival following PGRP treatment. Mutants lacking functional FDH-O had abolished PGRP-induced H2O2 production and the highest resistance to PGRP-induced killing, and formate enhanced PGRP-induced killing and H2O2 production in an FDH-dependent manner. Mutants in ubiquinone synthesis (but not menaquinone and demethylmenaquinone) and cytochrome bd-I (but not cytochromes bo3 and bd-II) also had completely abolished PGRP-induced H2O2 production and high resistance to PGRP-induced killing. Because electrons in the respiratory chain flow from dehydrogenases' substrates through quinones and then cytochromes to O2, these results imply that the site of PGRP-induced incomplete reduction of O2 to H2O2 is downstream from dehydrogenases and ubiquinone at the level of cytochrome bd-I, which results in oxidative stress. These results reveal several essential steps in PGRP-induced bacterial killing.

译文

:哺乳动物肽聚糖识别蛋白(PGRP)通过诱导协同氧化,硫醇和金属胁迫杀死细菌。 PGRP通过呼吸链中的阻滞诱导细菌中的氧化应激,导致呼吸减少,氧气(O2)还原为过氧化氢(H2O2)的过程不完全。在这项研究中,我们确定了PGRP诱导大肠杆菌中H2O2生成的位点。大肠杆菌Tn10插入文库的Tn-seq筛选显示,在进行PGRP处理后,甲酸脱氢酶(FDH)基因中的突变体具有最高的存活率。缺乏功能性FDH-0的突变体废除了PGRP诱导的H2O2产生和对PGRP诱导的杀灭的最高抗性,甲酸盐以FDH依赖性方式增强了PGRP诱导的杀灭和H2O2的产生。泛醌合成中的突变体(但不是甲萘醌和去甲基甲萘醌)和细胞色素bd-I(但不是细胞色素bo3和bd-II)的突变体也完全消除了PGRP诱导的H2O2产生,并且对PGRP诱导的杀灭具有很高的抵抗力。由于呼吸链中的电子从脱氢酶的底物流经醌,然后从细胞色素流向O2,因此这些结果表明,PGRP诱导的O2不完全还原为H2O2的位点在脱氢酶和泛醌的下游位于细胞色素bd-I的水平,导致氧化应激。这些结果揭示了PGRP诱导的细菌杀伤中的几个基本步骤。

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