MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades.
MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades.
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DOI：
10.7554/elife.00785
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发表时间：
2013-08-14
期刊：
影响因子：
7.7
通讯作者：
Chen ZJ
中科院分区：
文献类型：
--
作者：
Liu S;Chen J;Cai X;Wu J;Chen X;Wu YT;Sun L;Chen ZJ
RNA病毒感染由RIG-I受体家族检测，其通过线粒体蛋白MAVS诱导I型干扰素。MAVS形成大的朊病毒样聚合物，其激活胞质激酶IKK和TBK 1，进而分别激活NF-κB和IRF 3，以诱导干扰素。在这里，我们表明，MAVS聚合物招募几个TRAF蛋白，包括TRAF 2，TRAF 5和TRAF 6，通过不同的TRAF结合基序。破坏MAVS与TRAF结合的这些基序的突变废除了其激活IRF 3的能力。在缺乏TRAF 2、5和6的细胞中，IRF 3活化也被消除。这些TRAF蛋白促进泛素化反应，将NEMO募集到MAVS信号复合物中，导致IKK和TBK 1的活化。这些结果描述了MAVS信号传导的机制，并揭示了TRAF 2、5和6，其通常与NF-κB活化相关，也在抗病毒免疫应答中的IRF 3活化中起关键作用。http://dx.doi.org/10.7554/eLife.00785.001先天免疫系统可以检测和摧毁进入人体的病毒、细菌和其他病原体。特别是在细胞内，病毒RNA可以结合并激活一种名为RIG-I的蛋白质。这种蛋白质会开启另一种称为MAVS的蛋白质，这种蛋白质可以激活自身的其他拷贝。然后，这些MAVS分子在线粒体膜上聚集在一起，并发出信号，导致产生称为细胞因子的小蛋白质，刺激炎症反应并最终中和病毒。虽然已经鉴定了MAVS在先天免疫信号传导途径中激活的许多蛋白质，但MAVS如何确切地传递这种信号尚不清楚。现在，Liu等人通过监测转录因子IRF 3和NF-κB（转录细胞因子基因）的激活，探索这种蛋白质如何在先天免疫应答中传播信号。以前的研究表明，需要一种称为泛素的蛋白质来激活RIG-I，并且这种蛋白质与MAVS合作，通过先天免疫途径发出信号。Liu等发现，包括TRAF 2、TRAF 5、TRAF 6和LUBAC在内的一组蛋白质通过与MAVS结合来传递抗病毒信号。这些所谓的“E3连接酶”将泛素串在称为聚泛素的链中，聚泛素对于激活MAVS之后或下游的信号传导是必需的;然而，这些E3连接酶与MAVS的关联还需要MAVS的多个拷贝簇在一起。MAVS、TRAF蛋白和LUBAC共同募集其他先天免疫途径蛋白以激活IRF 3和NF-κB，并因此转录控制先天免疫应答的基因。总之，这些结果显示了从体内消除病毒所需的蛋白质的复杂相互作用。DOI：http://dx.doi.org/10.7554/eLife.00785.002网站
RNA virus infections are detected by the RIG-I family of receptors, which induce type-I interferons through the mitochondrial protein MAVS. MAVS forms large prion-like polymers that activate the cytosolic kinases IKK and TBK1, which in turn activate NF-κB and IRF3, respectively, to induce interferons. Here we show that MAVS polymers recruit several TRAF proteins, including TRAF2, TRAF5, and TRAF6, through distinct TRAF-binding motifs. Mutations of these motifs that disrupted MAVS binding to TRAFs abrogated its ability to activate IRF3. IRF3 activation was also abolished in cells lacking TRAF2, 5, and 6. These TRAF proteins promoted ubiquitination reactions that recruited NEMO to the MAVS signaling complex, leading to the activation of IKK and TBK1. These results delineate the mechanism of MAVS signaling and reveal that TRAF2, 5, and 6, which are normally associated with NF-κB activation, also play a crucial role in IRF3 activation in antiviral immune responses. DOI: http://dx.doi.org/10.7554/eLife.00785.001 The innate immune system can detect and destroy viruses, bacteria and other pathogens that enter the human body. In particular, inside cells, viral RNA can bind to and activate a protein called RIG-I. This protein switches on another protein, called MAVS, which can activate other copies of itself. These MAVS molecules then aggregate together on the membrane of mitochondria and send a signal that leads to the production of small proteins, called cytokines, which stimulate an inflammatory response and ultimately neutralize the virus. Although many of the proteins that are activated by MAVS in the innate immunity signaling pathway have been identified, precisely how MAVS transmits this signal is unknown. Now, Liu et al. explore how this protein can propagate signals in the innate immune response by monitoring activation of the transcription factors IRF3 and NF-κB, which transcribe cytokine genes. Previous studies have suggested that a protein known as ubiquitin is needed to activate RIG-I, and that this protein collaborates with MAVS to signal through the innate immunity pathway. Liu et al. found that a group of proteins including TRAF2, TRAF5, TRAF6 and LUBAC relay the antiviral signal by binding to MAVS. These so-called ‘E3 ligases’ string ubiquitin together in chains called polyubiquitin, which is essential for activating signaling after, or downstream of, MAVS; however, the association of these E3 ligases with MAVS also requires that multiple copies of MAVS cluster together. MAVS, the TRAF proteins and LUBAC collectively recruit other innate immunity pathway proteins to activate IRF3 and NF-κB, and thus transcription of the genes that control the innate immunity response. Together, these results show the intricate interplay of proteins needed to eliminate viruses from the body. DOI: http://dx.doi.org/10.7554/eLife.00785.002