HACE1 Negatively Regulates Virus-Triggered Type I IFN Signaling by Impeding the Formation of the MAVS-TRAF3 Complex.
HACE1 Negatively Regulates Virus-Triggered Type I IFN Signaling by Impeding the Formation of the MAVS-TRAF3 Complex.
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HACE1 通过阻碍 MAVS-TRAF3 复合物的形成来负调节病毒触发的 I 型 IFN 信号传导。
DOI：
10.3390/v8050146
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发表时间：
2016-05-21
期刊：
影响因子：
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通讯作者：
Zhang J
中科院分区：
文献类型：
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作者：
Mao HT;Wang Y;Cai J;Meng JL;Zhou Y;Pan Y;Qian XP;Zhang Y;Zhang J
在病毒感染过程中，导致促炎细胞因子产生的级联信号通路在多个水平上受到控制，以避免有害的过度反应。HACE 1是一种重要的肿瘤抑制因子。在这里，我们确定了HACE 1作为病毒触发的I型IFN信号传导的重要负调节因子。过表达的HACE 1抑制仙台病毒或聚（I：C）诱导的信号转导，并导致减少IFNB 1的生产和增强病毒复制。HACE 1表达的敲低表现出相反的效果。死亡突变体HACE 1/C876 A的泛素E3连接酶活性具有与WT HACE 1相当的抑制功能，表明HACE 1对病毒诱导的信号传导的抑制功能不依赖于其E3连接酶活性。进一步的研究表明，HACE 1作用于MAVS的下游和TBK 1的上游。机制研究表明，HACE 1通过破坏MAVS-TRAF 3复合物对病毒诱导的信号传导发挥其抑制作用。因此，我们发现了一个新的功能，在先天免疫调节的HACE 1。
During virus infection, the cascade signaling pathway that leads to the production of proinflammatory cytokines is controlled at multiple levels to avoid detrimental overreaction. HACE1 has been characterized as an important tumor suppressor. Here, we identified HACE1 as an important negative regulator of virus-triggered type I IFN signaling. Overexpression of HACE1 inhibited Sendai virus- or poly (I:C)-induced signaling and resulted in reduced IFNB1 production and enhanced virus replication. Knockdown of HACE1 expression exhibited the opposite effects. Ubiquitin E3 ligase activity of the dead mutant HACE1/C876A had a comparable inhibitory function as WT HACE1, suggesting that the suppressive function of HACE1 on virus-induced signaling is independent of its E3 ligase activity. Further study indicated that HACE1 acted downstream of MAVS and upstream of TBK1. Mechanistic studies showed that HACE1 exerts its inhibitory role on virus-induced signaling by disrupting the MAVS-TRAF3 complex. Therefore, we uncovered a novel function of HACE1 in innate immunity regulation.