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首页> 外文期刊>Molecular and Cellular Biology >Regulation of MyD88-Dependent Signaling Events by S Nitrosylation Retards Toll-Like Receptor Signal Transduction and Initiation of Acute-Phase Immune Responses
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Regulation of MyD88-Dependent Signaling Events by S Nitrosylation Retards Toll-Like Receptor Signal Transduction and Initiation of Acute-Phase Immune Responses

机译：亚硝化阻滞MyD88依赖信号事件的规管收费象受体信号转导和急性期免疫反应的启动。

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Nitric oxide (NO) has been thought to regulate the immune system through S nitrosylation of the transcriptional factor NF-κB. However, regulatory effects of NO on innate immune responses are unclear. Here, we report that NO has a capability to control Toll-like receptor-mediated signaling through S nitrosylation. We found that the adaptor protein MyD88 was primarily S nitrosylated, depending on the presence of endothelial NO synthase (eNOS). S nitrosylation at a particular cysteine residue within the TIR domain of MyD88 resulted in slight reduction of the NF-κB-activating property. This modification could be restored by the antioxidant glutathione. Through S nitrosylation, NO could negatively regulate the multiple steps of MyD88 functioning, including translocation to the cell membrane after LPS stimulation, interaction with TIRAP, binding to TRAF6, and induction of IκBα phosphorylation. Interestingly, glutathione could reversely neutralize such NO-derived effects. We also found that an acute febrile response to LPS was precipitated in eNOS-deficient mice, indicating that eNOS-derived NO exerts an initial suppressive effect on inflammatory processes. Thus, NO has a potential to retard induction of MyD88-dependent signaling events through the reversible and oxidative modification by NO, by which precipitous signaling reactions are relieved. Such an effect may reflect appropriate regulation of the acute-phase inflammatory responses in living organisms.
机译：一氧化氮（NO）被认为通过转录因子NF-κB的S亚硝基化来调节免疫系统。然而，NO对先天免疫反应的调节作用尚不清楚。在这里，我们报道NO具有通过S亚硝化作用来控制Toll样受体介导的信号传导的能力。我们发现衔接蛋白MyD88主要被S亚硝化，具体取决于内皮NO合酶（eNOS）的存在。 MyD88的TIR域内特定半胱氨酸残基的亚硝基化导致NF-κB活化特性略有降低。抗氧化剂谷胱甘肽可以恢复这种修饰。通过亚硝基化，NO可以负面调节MyD88功能的多个步骤，包括LPS刺激后易位至细胞膜，与TIRAP相互作用，与TRAF6结合以及诱导IκBα磷酸化。有趣的是，谷胱甘肽可以反向中和这种源自NO的效应。我们还发现，在eNOS缺陷型小鼠中沉淀出了对LPS的急性发热反应，这表明eNOS衍生的NO对炎症过程起了最初的抑制作用。因此，NO可能通过NO的可逆和氧化修饰而延迟MyD88依赖性信号事件的诱导，从而缓解了剧烈的信号反应。这种作用可能反映了活生物体中急性期炎症反应的适当调节。

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