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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >Phosphatidylinositol-3-kinase and Akt are required for RIG-I-mediated anti-viral signalling through cross-talk with IPS-1
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Phosphatidylinositol-3-kinase and Akt are required for RIG-I-mediated anti-viral signalling through cross-talk with IPS-1

机译：RIG-I介导的抗病毒信号通过与IPS-1的串扰而需要磷脂酰肌醇3-激酶和Akt

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摘要

Retinoic acid-inducible gene I (RIG-I) is a cytosolic pattern-recognition receptor that recognizes viruses and triggers anti-viral immune responses. Activation of intracellular RIG-I signalling is mediated through interferon- (IFN-) promoter stimulator-1 (IPS-1), an adaptor of RIG-I, which induces IFN regulatory factor (IRF) 3 activation and type I IFN expression. The phosphatidylinositol-3-kinase (PI3K) and Akt pathway is activated in host immune cells upon viral infection. However, the mechanism as to how they work in RIG-I signalling has not been fully elucidated. Therefore, we investigated the role of PI3K and Akt in the regulation of RIG-I-mediated IRF3 activation and type I IFN expression in macrophages. Our results show that Sendai virus infection, which is recognized by RIG-I, led to IRF3 activation and IFN- expression and these responses were attenuated by the PI3K inhibitor (LY294002) and an Akt dominant-negative mutant in the macrophage cell line(RAW264.7). IRF3 phosphorylation and dimerization as well as IFN- expression induced by a synthetic RIG-I agonist, short poly(I:C), were suppressed by LY294002 or siRNA-Akt in bone marrow-derived macrophages. Suppression of PI3K and Akt using a dominant-negative mutant and siRNA knockdown resulted in attenuation of IRF3 activation and IFN- expression induced by RIG-I itself or its adaptor, IPS-1. Association of Akt with IPS-1 increased with short poly(I:C) stimulation and required the pleckstrin homology domain of Akt and caspase-recruitment domain in IPS-1. Collectively, our results show that PI3K and Akt are required downstream of IPS-1 for RIG-I-mediated anti-viral immune responses. The results describe a novel, interactive relationship between RIG-I downstream signalling molecules resulting in efficient anti-viral immunity.
机译：维甲酸诱导基因I（RIG-I）是一种胞浆模式识别受体，可识别病毒并触发抗病毒免疫反应。细胞内RIG-I信号的激活是通过干扰素（IFN-）启动子刺激物1（IPS-1）（RIG-1的衔接子）介导的，它可以诱导IFN调节因子（IRF）3激活和I型IFN表达。病毒感染后，宿主免疫细胞中的磷脂酰肌醇-3-激酶（PI3K）和Akt途径被激活。但是，关于它们如何在RIG-I信令中工作的机制尚未完全阐明。因此，我们调查了PI3K和Akt在RIG-I介导的IRF3激活和巨噬细胞中I型IFN表达调控中的作用。我们的结果表明，RIG-I识别的仙台病毒感染导致IRF3激活和IFN-α表达，并且这些应答被PI3K抑制剂（LY294002）和巨噬细胞系（RAW264）的Akt显性阴性突变体减弱.7）。 LY294002或siRNA-Akt在骨髓衍生的巨噬细胞中抑制了合成RIG-I激动剂短聚（I：C）诱导的IRF3磷酸化和二聚化以及IFN-表达。使用显性阴性突变体和siRNA抑制来抑制PI3K和Akt导致RIG-1本身或其适配器IPS-1诱导的IRF3激活和IFN-表达的减弱。短聚（I：C）刺激会增加Akt与IPS-1的关联，并且需要IPS-1中Akt的pleckstrin同源结构域和caspase招聘结构域。总体而言，我们的结果表明，PI-1K介导的抗病毒免疫应答在IPS-1的下游需要PI3K和Akt。结果描述了RIG-1下游信号分子之间的新型相互作用关系，从而产生了有效的抗病毒免疫力。

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