Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710
J Biol Chem. 2019 Sep 27;294(39):14231-14240. doi: 10.1074/jbc.RA119.007917. Epub 2019 Aug 2.
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-β induction and the antiviral response. We observed that RAB1B overexpression increases RIG-I-mediated signaling to IFN-β 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.
病毒感染过程中，先天免疫系统对病毒核酸的检测会激活信号级联反应，诱导 I 型和 III 型干扰素以及其他细胞因子的产生，从而引发抗病毒反应。该信号级联反应由模式识别受体（如识别病毒 RNA 的 RNA 解旋酶视黄酸诱导基因 I（RIG-I））起始。这些传感器随后与衔接蛋白线粒体抗病毒信号蛋白（MAVS）相互作用，MAVS 招募其他信号蛋白，包括肿瘤坏死因子受体相关因子 3（TRAF3）和 TANK 结合激酶 1（TBK1），形成信号复合物，激活干扰素调节因子 3（IRF3），从而诱导 I 型干扰素的转录。在这里，我们使用多种人类细胞类型中的几种免疫学和生化方法表明，GTP 酶转运蛋白 RAB1B 上调 RIG-I 途径信号，从而促进 IFN-β 的诱导和抗病毒反应。我们观察到 RAB1B 过表达增加 RIG-I 介导的 IFN-β 信号，而 RAB1B 缺失则降低该途径的信号。此外，RAB1B 的缺失减弱了抗病毒反应，这表明 RAB1B 缺失的细胞中寨卡病毒的感染增强。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 形成蛋白复合物，促进 TRAF3 与线粒体抗病毒信号蛋白的相互作用。我们的结论是，RAB1B 调节 TRAF3，并促进 RNA 病毒感染时核酸感应引发的先天免疫信号复合物的形成。
