LGP2 binds to PACT to regulate RIG-I– and MDA5-mediated antiviral responses

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Sanchez David, Raul | Combredet, Chantal | Najburg, Valérie | Millot, Gaël | Beauclair, Guillaume | Schwikowski, Benno | Léger, Thibaut | Camadro, Jean-Michel | Jacob, Yves | Bellalou, Jacques | Jouvenet, Nolwenn | Tangy, Frédéric | Komarova, Anastassia

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. 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 proteinprotein 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.

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