Enhancer of Zeste Homolog 2 Is a Negative Regulator of Mitochondria-Mediated Innate Immune Responses
Enhancer of Zeste Homolog 2 Is a Negative Regulator of Mitochondria-Mediated Innate Immune Responses
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zeste 同源物 2 的增强剂是线粒体介导的先天免疫反应的负调节剂
DOI：
10.4049/jimmunol.1203143
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发表时间：
2013-09-01
影响因子：
4.4
通讯作者：
Huang, Wenlin
中科院分区：
文献类型：
--
作者：
Chen, Shuai;Sheng, Chunjie;Huang, Wenlin
细胞内RIG-I样受体识别5 '-三磷酸病毒基因组RNA，并通过线粒体接头VISA启动细胞因子的产生。这种信号通路的调节在很大程度上是未知的。在这项研究中，我们报告，组蛋白甲基转移酶增强子zeste同源物2（EZH 2）抑制RIG-I信号通路中的甲基转移酶非依赖性的方式。敲低EZH 2表达增强了VISA诱导的IFN-β启动子和NF-κ B信号传导的活化。胞质分布的EZH 2与VISA共定位并结合其半胱天冬酶募集结构域（CARD），从而阻断其与RIG-I的缔合。在甲型流感病毒（IAV）A/WSN/33株（WSN）感染过程中，EZH 2易位至RIG-I，并持续干扰RIG-I与VISA的相互作用。EZH 2的N和C末端都与VISA相互作用并减弱其下游信号传导。WSN病毒感染诱导的TNF-α、IFN-β和IL-8的表达被EZH 2及其催化死亡形式Delta SET抑制。EZH 2过表达促进IAV毒株WSN和A/波多黎各/8/34流感病毒的复制。敲低EZH 2表达激活感染诱导的IFN-β转录并抑制病毒复制。我们进一步提供的证据表明，EZH 2表达的抑制剂3-deazaneplanocin A的药理学破坏激活先天性免疫反应，并减弱WSN病毒在HeLa，MDCK和小鼠原代骨髓来源的巨噬细胞，但不是在IFN-缺陷的Vero细胞的复制。总的来说，这些结果揭示了EZH 2与VISA结合并干扰VISA和RIG-I之间的相互作用。靶向EZH 2可激活IAV介导的抗病毒先天免疫应答，从而抑制IAV在细胞中的复制。
The intracellular RIG-I-like receptors recognize 5'-triphosphate viral genomic RNA and initiate the production of cytokines through mitochondria adaptor VISA. The regulation of this signal pathway is largely unknown. In this study, we report that the histone methyltransferase enhancer of zeste homolog 2 (EZH2) inhibits RIG-I signal pathway in an methyltransferase-independent manner. Knockdown EZH2 expression enhances VISA-induced activation of IFN-beta promoter and NF-kappa B signaling. Cytosolic distributed EZH2 colocalizes with VISA and binds to its caspase recruitment domain (CARD), thus blocking its association with RIG-I. During the infection of influenza A virus (IAV) strain A/WSN/33 (WSN), EZH2 translocates to RIG-I and continuously interferes the interaction between RIG-I and VISA. Both N and C termini of EZH2 interact with VISA and attenuate its downstream signaling. WSN virus infection-induced expression of TNF-alpha, IFN-beta, and IL-8 is inhibited by EZH2 and its catalytic dead form Delta SET. EZH2 overexpression facilitates the replications of IAV strains WSN and A/Puerto Rico/8/34 influenza virus. Knockdown EZH2 expression activates infection-induced IFN-beta transcription and inhibits virus replication. We further provided evidence to show that pharmacological disruption of EZH2 expression by its inhibitor 3-deazaneplanocin A activates innate immune responses and attenuates the replication of WSN virus in HeLa, MDCK, and mouse primary bone marrow-derived macrophages, but not in IFN-deficient Vero cells. Collectively, these results revealed that EZH2 binds to VISA and interferes with the interaction between VISA and RIG-I. Targeting EZH2 activates mitochondria-mediated antiviral innate immune responses, and thus represses the replication of IAV in cells.