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

Raul Sanchez David (1) , Chantal Combredet (1) , Valérie Najburg (1) , Gaël Millot (2) , Guillaume Beauclair (1) , Benno Schwikowski , Thibaut Léger (3) , Jean-Michel Camadro (3) , Yves Jacob (4) , Jacques Bellalou , Nolwenn Jouvenet (1) , Frédéric Tangy (1) , Anastassia Komarova (1)

1 Génomique virale et vaccination
2 C3BI - Centre de Bioinformatique, Biostatistique et Biologie Intégrative
3 IJM (UMR_7592) - Institut Jacques Monod
4 GMV-ARN (UMR_3569 / U-Pasteur_2) - Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses

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.

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Microbiology and Parasitology; Virology

Raul Sanchez David, Chantal Combredet, Valérie Najburg, Gaël Millot, Guillaume Beauclair, et al.. LGP2 binds to PACT to regulate RIG-I– and MDA5-mediated antiviral responses. Science Signaling, 2019, 12 (601), pp.eaar3993. ⟨10.1126/scisignal.aar3993⟩. ⟨hal-03100138⟩