Negative regulation of MDA5-but not RIG-I-mediated innate antiviral signaling by the dihydroxyacetone kinase
Negative regulation of MDA5-but not RIG-I-mediated innate antiviral signaling by the dihydroxyacetone kinase
复制标题
二羟基丙酮激酶对 MDA5 而非 RIG-I 介导的先天抗病毒信号进行负调节
DOI：
10.1073/pnas.0700544104
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发表时间：
2007-07-10
影响因子：
11.1
通讯作者：
Shu, Hong-Bing
中科院分区：
文献类型：
--
作者：
Diao, Feici;Li, Shu;Shu, Hong-Bing
病毒感染导致转录因子干扰素调节因子-3和NF-κ B的激活，它们协同诱导I型IFN。RNA解旋酶蛋白RIG-I和MDA 5最近被鉴定为两种细胞质病毒RNA传感器，其识别在病毒复制期间产生的不同种类的病毒RNA。在这项研究中，我们确定DAK，一个功能未知的二氢丙酮激酶，作为一个特定的MDA 5相互作用蛋白。在生理条件下，DAK与MDA 5相关，但与RIG-I无关。DAK的过表达抑制MDA 5介导的IFN-β诱导，但不抑制RIG-I或TLR 3介导的IFN-β诱导。DAK的过表达也抑制了胞质dsRNA和SeV诱导的IFN-β启动子的激活，而通过RNAi敲低内源性DAK激活了IFN-β启动子，并增加了胞质dsRNA或SeV触发的IFN-β启动子的激活。此外，DAK过表达抑制MDA 5介导的抗病毒活性，但不抑制RIG-I介导的抗病毒活性，而DAK RNAi增加细胞质dsRNA触发的抗病毒活性。这些发现表明DAK是MDA 5的生理抑制剂，并且特异性地抑制MDA 5介导的先天性抗病毒信号传导，但不抑制RIG-I介导的先天性抗病毒信号传导。
Viral infection leads to activation of the transcription factors interferon regulatory factor-3 and NF-kappa B, which collaborate to induce type I IFNs. The RNA helicase proteins RIG-I and MDA5 were recently identified as two cytoplasmic viral RNA sensors that recognize different species of viral RNAs produced during viral replication. In this study, we identified DAK, a functionally unknown dihydroacetone kinase, as a specific MDA5-interacting protein. DAK was associated with MDA5, but not RIG-I, under physiological conditions. Overexpression of DAK inhibited MDA5-but not RIG-I- or TLR3-mediated IFN-beta induction. Overexpression of DAK also inhibited cytoplasmic dsRNA and SeV-induced activation of the IFN-P promoter, whereas knockdown of endogenous DAK by RNAi activated the IFN-beta promoter, and increased cytoplasmic dsRNA- or SeV-triggered activation of the IFN-P promoter. In addition, overexpression of DAK inhibited MDA5- but not RIG-I- mediated antiviral activity, whereas DAK RNAi increased cytoplasmic dsRNA-triggered antiviral activity. These findings suggest that DAK is a physiological suppressor of MDA5 and specifically inhibits MDA5- but not RIG-I-mediated innate antiviral signaling.