Department of Biomedicine, Aarhus University, Aarhus, Denmark.
PLoS Pathog. 2011 Sep;7(9):e1002250. doi: 10.1371/journal.ppat.1002250. Epub 2011 Sep 15.
The innate immune response constitutes the first line of defense against infections. Pattern recognition receptors recognize pathogen structures and trigger intracellular signaling pathways leading to cytokine and chemokine expression. Reactive oxygen species (ROS) are emerging as an important regulator of some of these pathways. ROS directly interact with signaling components or induce other post-translational modifications such as S-glutathionylation, thereby altering target function. Applying live microscopy, we have demonstrated that herpes simplex virus (HSV) infection induces early production of ROS that are required for the activation of NF-κB and IRF-3 pathways and the production of type I IFNs and ISGs. All the known receptors involved in the recognition of HSV were shown to be dependent on the cellular redox levels for successful signaling. In addition, we provide biochemical evidence suggesting S-glutathionylation of TRAF family proteins to be important. In particular, by performing mutational studies we show that S-glutathionylation of a conserved cysteine residue of TRAF3 and TRAF6 is important for ROS-dependent activation of innate immune pathways. In conclusion, these findings demonstrate that ROS are essential for effective activation of signaling pathways leading to a successful innate immune response against HSV infection.
先天免疫反应构成了抵御感染的第一道防线。模式识别受体识别病原体结构，并触发细胞内信号通路，导致细胞因子和趋化因子的表达。活性氧（ROS）正成为这些途径的一个重要调节剂。ROS 直接与信号成分相互作用，或诱导其他翻译后修饰，如 S-谷胱甘肽化，从而改变靶功能。通过应用活细胞显微镜技术，我们已经证明单纯疱疹病毒（HSV）感染诱导 ROS 的早期产生，这对于 NF-κB 和 IRF-3 途径的激活以及 I 型干扰素和 ISG 的产生是必需的。所有已知参与 HSV 识别的受体都被证明依赖于细胞的氧化还原水平来成功地进行信号传递。此外，我们提供了生化证据，表明 TRAF 家族蛋白的 S-谷胱甘肽化是重要的。特别是，通过进行突变研究，我们表明 TRAF3 和 TRAF6 中一个保守半胱氨酸残基的 S-谷胱甘肽化对于 ROS 依赖性先天免疫途径的激活是重要的。总之，这些发现表明 ROS 对于有效激活导致对 HSV 感染的成功先天免疫反应的信号通路是必需的。
