Activation of the interferon response by HCV is mediated by MDA5 and potentiated by LGP2

Activation of the interferon (IFN) response is mediated by various intracellular pattern recognition receptors (PRRs). These sense non-self nucleic acids and trigger a signaling cascade that leads to the activation of the interferon (IFN) response. Two major cytosolic PRRs are RIG-I and MDA5 that contain an RNA binding/helicase domain and an N-terminal signaling domain that is required for binding to the adaptor protein MAVS. A third PRR is LGP2 that lacks this N-terminal domain but contains the RNA binding/helicase domain. Interestingly, MAVS is proteolytically cleaved by the hepatitis C virus (HCV) protease, yet HCV induces an IFN response.

In the present study we characterized the role of LGP2 in the activation of the IFN response by HCV. Using a panel of Huh7-derived cell lines expressing a MAVS variant that cannot be cleaved by HCV, and expressing various levels of LGP2, we found that LGP2 enhances MDA5-mediated ISG induction, but inhibits RIG-I mediated signaling after stimulation of the cells with the respective ligands. Upon infection with HCV, LGP2 enhanced the IFN response and this activation was mediated by MDA5. Consistent with this IFN activation, LGP2 inhibited HCV replication and infection rates in Huh7 cells.

These results show that HCV is sensed predominantly by MDA5 resulting in an activation of the IFN response that is potentiated by LGP2.