The small GTPase RAB1B promotes antiviral innate immunity by interacting with TNF receptor?associated factor 3 (TRAF3)
The small GTPase RAB1B promotes antiviral innate immunity by interacting with TNF receptor?associated factor 3 (TRAF3)
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DOI：
10.1074/jbc.ra119.007917
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发表时间：
2019-09-27
影响因子：
4.8
通讯作者：
Horner, Stacy M.
中科院分区：
文献类型：
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作者：
Beachboard, Dia C.;Park, Moonhee;Horner, Stacy M.
病毒感染期间对病毒核酸的先天免疫检测激活了一个信号级联反应，诱导I型和III型IFN以及其他细胞因子，以产生抗病毒反应。这种信号是由模式识别受体启动的，例如感知病毒RNA的RNA解旋酶维甲酸诱导基因I(RIG-I)。然后，这些传感器与适配器蛋白线粒体抗病毒信号蛋白(MAVS)相互作用，MAVS招募额外的信号蛋白，包括肿瘤坏死因子受体相关因子3(TRAF3)和坦克结合蛋白1(TBK1)，形成一个信号复合体，激活干扰素调节因子3(IRF3)，以转录诱导I型IFN。在这里，我们利用多种人类细胞类型中的几种免疫学和生化方法，证明了GTP酶运输蛋白RAB1B上调RIG-I途径信号，从而促进干扰素？诱导和抗病毒反应。我们观察到，RAB1B的过表达增加了RIG-I？介导的干扰素-1信号传导。RAB1B的缺失减少了这一途径的信号传递。此外，RAB1B的缺失抑制了抗病毒反应，表现为RAB1B缺失的细胞感染寨卡病毒的增强。重要的是，我们确定了RAB1B在抗病毒反应中的作用机制，发现它与TRAF3形成蛋白质复合体，促进TRAF3与线粒体抗病毒信号蛋白的相互作用。我们得出结论：在RNA病毒感染过程中，RAB1B调节TRAF3，并促进先天免疫信号复合体的形成，以响应核酸感应。
Innate immune detection of viral nucleic acids during viral infection activates a signaling cascade that induces type I and type III IFNs as well as other cytokines, to generate an antiviral response. This signaling is initiated by pattern recognition receptors, such as the RNA helicase retinoic acid-inducible gene I (RIG-I), that sense viral RNA. These sensors then interact with the adaptor protein mitochondrial antiviral signaling protein (MAVS), which recruits additional signaling proteins, including TNF receptor?associated factor 3 (TRAF3) and TANK-binding kinase 1 (TBK1), to form a signaling complex that activates IFN regulatory factor 3 (IRF3) for transcriptional induction of type I IFNs. Here, using several immunological and biochemical approaches in multiple human cell types, we show that the GTPase-trafficking protein RAB1B up-regulates RIG-I pathway signaling and thereby promotes IFN-? induction and the antiviral response. We observed that RAB1B overexpression increases RIG-I?mediated signaling to IFN-? and that RAB1B deletion reduces signaling of this pathway. Additionally, loss of RAB1B dampened the antiviral response, indicated by enhanced Zika virus infection of cells depleted of RAB1B. Importantly, we identified the mechanism of RAB1B action in the antiviral response, finding that it forms a protein complex with TRAF3 to facilitate the interaction of TRAF3 with mitochondrial antiviral signaling protein. We conclude that RAB1B regulates TRAF3 and promotes the formation of innate immune signaling complexes in response to nucleic acid sensing during RNA virus infection.