The retinoic acid–inducible gene I (RIG-I)–like receptors (RLRs) RIG-I, MDA5, and LGP2 stimulate inflammatory and antiviral responses by sensing nonself RNA molecules produced during viral replication. Here, we investigated how LGP2 regulates the RIG-I– and MDA5-dependent induction of type I interferon (IFN) signaling and showed that LGP2 interacted with different components of the RNA-silencing machinery. We identified a direct protein-protein interaction between LGP2 and the IFN-inducible, double-stranded RNA binding protein PACT. The LGP2-PACT interaction was mediated by the regulatory C-terminal domain of LGP2 and was necessary for inhibiting RIG-I–dependent responses and for amplifying MDA5-dependent responses. We described a point mutation within LGP2 that disrupted the LGP2-PACT interaction and led to the loss of LGP2-mediated regulation of RIG-I and MDA5 signaling. These results suggest a model in which the LGP2-PACT interaction regulates the inflammatory responses mediated by RIG-I and MDA5 and enables the cellular RNA-silencing machinery to coordinate with the innate immune response.

视黄酸诱导型基因I（RIG-I）样受体（RLR）RIG-1，MDA5和LGP2通过检测病毒复制过程中产生的非自身RNA分子来刺激炎症反应和抗病毒反应。在这里，我们研究了LGP2如何调节RIG-I和MDA5依赖性的I型干扰素（IFN）信号传导，并表明LGP2与RNA沉默机制的不同组成部分相互作用。我们确定了LGP2和IFN诱导型，双链RNA结合蛋白PACT之间的直接蛋白相互作用。LGP2-PACT相互作用是由LGP2的调节性C末端结构域介导的，对于抑制RIG-I依赖性反应和放大MDA5依赖性反应是必需的。我们描述了LGP2内的一个点突变，该突变破坏了LGP2-PACT相互作用并导致LGP2介导的RIG-I和MDA5信号传导调节丧失。这些结果提示了一个模型，其中LGP2-PACT相互作用调节RIG-1和MDA5介导的炎症反应，并使细胞RNA沉默机制与先天免疫反应协调。