Ubiquitin-induced oligomerization of the RNA sensors RIG-I and MDA5 activates antiviral innate immune response.
Ubiquitin-induced oligomerization of the RNA sensors RIG-I and MDA5 activates antiviral innate immune response.
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DOI：
10.1016/j.immuni.2012.03.022
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发表时间：
2012-06-29
期刊：
影响因子：
32.4
通讯作者：
Chen ZJ
中科院分区：
文献类型：
--
作者：
Jiang X;Kinch LN;Brautigam CA;Chen X;Du F;Grishin NV;Chen ZJ
RIG-I和MDA5检测细胞质中的病毒RNA，并激活信号级联，导致I型干扰素的产生。RIG-I通过病毒RNA和未锚定的赖氨酸-63(K63)多泛素链的顺序结合而激活，但多泛素如何激活RIG-I以及MDA5是否通过类似的机制激活仍未解决。在这里，我们证明了MDA5的卡域与K63多聚泛素结合，这种结合是MDA5激活转录因子IRF3所必需的。MDA5和RIG-I保守残基的突变破坏了它们的泛素结合，也破坏了它们激活IRF3的能力。多泛素结合诱导形成一个由四个rig-I和四个泛素链组成的大复合体。这个异四聚体复合体在激活抗病毒信号级联方面非常有效。这些结果提示了RIG-I和MDA5激活的统一机制，并揭示了泛素调节细胞信号和免疫反应的独特机制。
RIG-I and MDA5 detect viral RNA in the cytoplasm and activate signaling cascades leading to the production of type-I interferons. RIG-I is activated through sequential binding of viral RNA and unanchored lysine-63 (K63) polyubiquitin chains, but how polyubiquitin activates RIG-I and whether MDA5 is activated through a similar mechanism remain unresolved. Here we showed that the CARD domains of MDA5 bound to K63 polyubiquitin and that this binding was essential for MDA5 to activate the transcription factor IRF3. Mutations of conserved residues in MDA5 and RIG-I that disrupt their ubiquitin binding also abrogated their ability to activate IRF3. Polyubiquitin binding induced the formation of a large complex consisting of four RIG-I and four ubiquitin chains. This hetero-tetrameric complex was highly potent in activating the antiviral signaling cascades. These results suggest a unified mechanism of RIG-I and MDA5 activation and reveal a unique mechanism by which ubiquitin regulates cell signaling and immune response.
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