Inside-Out Signaling Pathways from Nuclear Reactive Oxygen Species Control Pulmonary Innate Immunity.
Inside-Out Signaling Pathways from Nuclear Reactive Oxygen Species Control Pulmonary Innate Immunity.
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DOI：
10.1159/000442254
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发表时间：
2016
影响因子：
5.3
通讯作者：
Brasier AR
中科院分区：
文献类型：
--
作者：
Choudhary S;Boldogh I;Brasier AR
气道粘膜负责在遇到病原体相关分子模式时产生强大的先天免疫反应（IIR）。 IIR 产生保护性基因网络，刺激邻近的上皮细胞和免疫系统的组成部分，从而触发适应性免疫。目前，人们对细胞活性氧 (ROS) 信号传导如何产生以及如何在 IIR 中发挥作用知之甚少。我们讨论了控制先天免疫的两条核 ROS 信号通路的最新发现。核 ROS 氧化鸟嘌呤碱基，产生诱变性 8-氧鸟嘌呤，这是一种被 8-氧鸟嘌呤 DNA 糖基化酶 1/AP 裂解酶 (OGG1) 切除的损伤。 OGG1与切除的碱基形成复合物，诱导其核输出。细胞质OGG1•8-oxoG复合物作为鸟嘌呤核苷酸交换因子发挥作用，触发小GTPase信号传导并激活NFκB/RelA转录因子的磷酸化以诱导立即早期基因表达。与此同时，共济失调毛细血管扩张突变 (ATM) 检测到核 ROS，ATM 是一种由 ROS 激活的 PI3 激酶，触发其核输出。 ATM 与核糖体 S6 激酶形成支架，诱导 RelA 磷酸化并导致 I 型和 III 型干扰素以及 CC 和 CXC 趋化因子的转录偶联合成。我们认为 ATM 和 OGG1 是内源性核 ROS 传感器，它们传输核信号，与由外向内的 PRR 信号传导相协调，调节 IIR。
The airway mucosa is responsible for mounting a robust innate immune response (IIR) upon encountering pathogen-associated molecular patterns. The IIR produces protective gene networks that stimulate neighboring epithelia and components of the immune system to trigger adaptive immunity. Little is currently known about how cellular reactive oxygen species (ROS) signaling is produced and cooperates in the IIR. We discuss recent discoveries on two nuclear ROS signaling pathways controlling innate immunity. Nuclear ROS oxidize guanine bases to produce mutagenic 8-oxoguanine, a lesion excised by 8-oxoguanine DNA glycosylase1/AP-lyase (OGG1). OGG1 forms a complex with the excised base, inducing its nuclear export. The cytoplasmic OGG1•8-oxoG complex functions as a guanine nucleotide exchange factor, triggering small GTPase signaling and activating phosphorylation of the NFκB/RelA transcription factor to induce immediate early gene expression. In parallel, nuclear ROS are detected by ataxia telangiectasia mutated (ATM), a PI3 kinase activated by ROS, triggering its nuclear export. ATM forms a scaffold with ribosomal S6 kinases, inducing RelA phosphorylation and resulting in transcription-coupled synthesis of type -I and –III interferons and CC and CXC chemokines. We propose that ATM and OGG1 are endogenous nuclear ROS sensors that transmit nuclear signals that coordinate with outside-in PRR signaling, regulating the IIR.