LGP2 binds to PACT to regulate RIG I and MDA5 mediated antiviral responses
The interaction between LGP2 and a component of the RNA silencing machinery enables coordination of innate immune responses. An antiviral PACT The RIG I like receptors (RLRs) RIG I and MDA5 sense cytosolic viral RNAs during infection and activate signaling pathways that culminate in the production of type I interferons (IFNs) and proinflammatory cytokines as part of the antiviral immune response. LGP2, another member of the RLR family, inhibits RIG I mediated responses while enhancing MDA5 signaling. Sanchez David et al. found that this differential effect of LGP2 depended on its binding to PACT, a cofactor of DICER in the processing of microRNAs. Mutation of a residue in LGP2 required for the LGP2 PACT interaction resulted in loss of the regulatory effect of LGP2 over the other RLRs. Together, these data provide evidence of a connection between the RNA silencing machinery and the innate immune response. 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.
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