Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2
Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2
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DOI：
10.1073/pnas.0606699104
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发表时间：
2007-01-09
影响因子：
11.1
通讯作者：
Gale, Michael, Jr.
中科院分区：
文献类型：
--
作者：
Saito, Takeshi;Hirai, Reiko;Gale, Michael, Jr.
RIG-I 是一种 RNA 解旋酶，含有 caspase 激活和募集结构域 (CARD)。 RIG-I 的 RNA 结合和信号传导涉及病原体识别和 IFN-α/β 免疫防御的触发，从而影响细胞对丙型肝炎病毒 (HCV) 的耐受性。在这里，我们评估了控制 RIG-I 信号传输的过程。 RNA结合研究和对缺乏RIG-I或相关MDA5蛋白的细胞的分析表明，RIG-I而非MDA5能够有效结合二级结构HCV RNA以诱导IFN-β表达。我们还发现 LGP2 是一种与 RIG-I 和 MDA5 相关但缺乏 CARD 且充当宿主防御负调节因子的解旋酶，可结合 HCV RNA。在静息细胞中，RIG-I 作为单体维持在自动抑制状态，但在病毒感染和 RNA 结合过程中，它会发生构象转变，促进自我缔合以及 CARD 与 IPS-1 接头蛋白的相互作用，从而向 IFN 调节因子 3 和 NF-κ B 反应基因发出信号。该反应由控制 RIG-I 多聚化和 IPS-1 相互作用的内部阻遏结构域 (RD) 控制。 RIG-I RD 的缺失导致对 IFN-β 启动子的组成型信号传导，而单独的 RD 表达则阻止信号传导并增加细胞对 HCV 的许可性。我们在 LGP2 内发现了一个类似的 RD，它与 RIG-I 反式相互作用以消除自关联和信号传导。因此，RIG-I 是 HCV 的细胞质传感器，受 RD 相互作用控制，RD 相互作用与 LGP2 共享，作为控制先天防御的开关。 RIG-I/LGP2 相互作用动力学的调节可能对免疫调节具有治疗意义。
RIG-I is an RNA helicase containing caspase activation and recruitment domains (CARDs). RNA binding and signaling by RIG-I are implicated in pathogen recognition and triggering of IFN-alpha/beta immune defenses that impact cell permissiveness for hepatitis C virus (HCV). Here we evaluated the processes that control RIG-I signaling. RNA binding studies and analysis of cells lacking RIG-I, or the related MDA5 protein, demonstrated that RIG-I, but not MDA5, efficiently binds to secondary structured HCV RNA to confer induction of IFN-beta expression. We also found that LGP2, a helicase related to RIG-I and MDA5 but lacking CARDs and functioning as a negative regulator of host defense, binds HCV RNA. In resting cells, RIG-I is maintained as a monomer in an autoinhibited state, but during virus infection and RNA binding it undergoes a conformation shift that promotes self-association and CARD interactions with the IPS-1 adaptor protein to signal IFN regulatory factor 3- and NF-kappa B- responsive genes. This reaction is governed by an internal repressor domain (RD) that controls RIG-I multimerization and IPS-1 interaction. Deletion of the RIG-I RD resulted in constitutive signaling to the IFN-beta promoter, whereas RD expression alone prevented signaling and increased cellular permissiveness to HCV. We identified an analogous RD within LGP2 that interacts in trans with RIG-I to ablate self-association and signaling. Thus, RIG-I is a cytoplasmic sensor of HCV and is governed by RD interactions that are shared with LGP2 as an on/off switch controlling innate defenses. Modulation of RIG-I/LGP2 interaction dynamics may have therapeutic implications for immune regulation.