Spatiotemporal dynamics of innate immune signaling via RIG-I-like receptors
Spatiotemporal dynamics of innate immune signaling via RIG-I-like receptors
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DOI：
10.1073/pnas.1921861117
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发表时间：
2020-07-07
影响因子：
11.1
通讯作者：
Gale, Michael, Jr.
中科院分区：
文献类型：
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作者：
Esser-Nobis, Katharina;Hatfield, Lauren D.;Gale, Michael, Jr.
RIG-I、MDA5 和 LGP2 包含 RIG-I 样受体 (RLR)。 RIG-I 和 MDA5 是感知病毒感染的重要病原体识别受体，而 LGP2 被描述为 RLR 辅助因子和负调节因子。在感测并结合病毒 RNA（包括双链 RNA (dsRNA)）后，RIG-I 和 MDA5 经历胞质到膜的重新定位，通过细胞内膜上的 MAVS 接头蛋白结合并发出信号，从而指导下游 IRF3 和先天免疫的激活。在这里，我们报告了对 dsRNA 和 RNA 病毒感染的细胞内反应中所有三个 RLR 的动态亚细胞定位的检查。高分辨率生化分级分离和电子显微镜的观察，再加上蛋白质相互作用和 IRF3 激活的分析，表明，在静息细胞中，微粒体而不是线粒体组分含有启动先天免疫信号传导的核心成分。 LGP2 与微粒体中的 MAVS 相互作用，阻断 RIG-I/MAVS 相互作用。值得注意的是，响应 dsRNA 治疗或 RNA 病毒感染，LGP2 迅速从 MAVS 释放并重新分布到线粒体，与 IRF3 激活在时间上相关。我们发现 IRF3 激活并不发生在线粒体上，而是发生在内质网 (ER) 衍生的膜上。我们的观察表明，ER 衍生膜是通过 LGP2 与 MAVS 结合的抑制作用控制的关键 RLR 信号平台，其中 LGP2 易位到线粒体释放 MAVS 抑制，以促进先天免疫的 RLR 介导的信号传导。
RIG-I, MDA5, and LGP2 comprise the RIG-I-like receptors (RLRs). RIG-I and MDA5 are essential pathogen recognition receptors sensing viral infections while LGP2 has been described as both RLR cofactor and negative regulator. After sensing and binding to viral RNA, including double-stranded RNA (dsRNA), RIG-I and MDA5 undergo cytosol-to-membrane relocalization to bind and signal through the MAVS adaptor protein on intracellular membranes, thus directing downstream activation of IRF3 and innate immunity. Here, we report examination of the dynamic subcellular localization of all three RLRs within the intracellular response to dsRNA and RNA virus infection. Observations from high resolution biochemical fractionation and electron microscopy, coupled with analysis of protein interactions and IRF3 activation, show that, in resting cells, microsome but not mitochondrial fractions harbor the central components to initiate innate immune signaling. LGP2 interacts with MAVS in microsomes, blocking the RIG-I/MAVS interaction. Remarkably, in response to dsRNA treatment or RNA virus infection, LGP2 is rapidly released from MAVS and redistributed to mitochondria, temporally correlating with IRF3 activation. We reveal that IRF3 activation does not take place on mitochondria but instead occurs at endoplasmic reticulum (ER)-derived membranes. Our observations suggest ER-derived membranes as key RLR signaling platforms controlled through inhibitory actions of LGP2 binding to MAVS wherein LGP2 translocation to mitochondria releases MAVS inhibition to facilitate RLR-mediated signaling of innate immunity.