The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-β promoter
The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-β promoter
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DOI：
10.1073/pnas.0407639101
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发表时间：
2004-12-07
影响因子：
11.1
通讯作者：
Randall, RE
中科院分区：
文献类型：
--
作者：
Andrejeva, J;Childs, KS;Randall, RE
大多数帕托病毒通过阻止IFN信号传导并限制了通过病毒感染的细胞的IFN产生来规避IFN响应。在这里，我们报告说，多种帕托病毒的V蛋白的高度保守的富含半胱氨酸的C末端结构域结合黑色素瘤分化相关基因5（MDA-5）产物。 MDA-5是IFN诱导的宿主细胞DEXD/H盒解旋酶，其在其N末端包含caspase募集域。 MDA-5的过表达刺激了记者基因测定中IFN-β启动子的基础活性，并通过细胞内DSRNA显着增强了IFN-β启动子的激活。这两种活性都通过邻苯二甲酸病毒5的V蛋白的共表达，人parainfluenza病毒2，腮腺炎病毒，仙台病毒和亨德拉病毒的共表达抑制。通过测量IFN产生获得与记者测定的相似结果。通过RNA干扰对MDA-5的抑制作用或主要干扰MDA-5的抑制作用可显着抑制DSRNA对IFN-β启动子的激活。因此，MDA-5似乎在细胞内信号转导途径中起着核心作用，该途径可以导致IFN-β启动子的激活，并且Paramyxoviruses的V蛋白与MDA-5相互作用以阻止其活性。
Most paramyxoviruses circumvent the IFN response by blocking IFN signaling and limiting the production of IFN by virus-infected cells. Here we report that the highly conserved cysteine-rich C-terminal domain of the V proteins of a wide variety of paramyxoviruses binds melanoma differentiation-associated gene 5 (mda-5) product. mda-5 is an IFN-inducible host cell DExD/H box helicase that contains a caspase recruitment domain at its N terminus. Overexpression of mda-5 stimulated the basal activity of the IFN-beta promoter in reporter gene assays and significantly enhanced the activation of the IFN-beta promoter by intracellular dsRNA. Both these activities were repressed by coexpression of the V proteins of simian virus 5, human parainfluenza virus 2, mumps virus, Sendai virus, and Hendra virus. Similar results to the reporter assays were obtained by measuring IFN production. inhibition of mda-5 by RNA interference or by dominant interfering forms of mda-5 significantly inhibited the activation of the IFN-beta promoter by dsRNA. It thus appears that mda-5 plays a central role in an intracellular signal transduction pathway that can lead to the activation of the IFN-beta promoter, and that the V proteins of paramyxoviruses interact with mda-5 to block its activity.