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.

视黄酸诱导基因 I (RIG-I) 样受体 (RLR) RIG-I、MDA5 和 LGP2 通过感知病毒复制过程中产生的非自身 RNA 分子来刺激炎症和抗病毒反应。在这里，我们研究了 LGP2 如何调节 I 型干扰素 (IFN) 信号传导的 RIG-I 和 MDA5 依赖性诱导，并表明 LGP2 与 RNA 沉默机制的不同组件相互作用。我们确定了 LGP2 和 IFN 诱导型双链 RNA 结合蛋白 PACT 之间的直接蛋白质-蛋白质相互作用。 LGP2-PACT 相互作用由 LGP2 的 C 端调节域介导，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 信号传导丧失。这些结果提出了一个模型，其中 LGP2-PACT 相互作用调节 RIG-I 和 MDA5 介导的炎症反应，并使细胞 RNA 沉默机制能够与先天免疫反应协调。