Teleost-Specific MxG, a Traitor in the Mx Family, Negatively Regulates Antiviral Responses by Targeting IPS-1 for Proteasomal Degradation and STING for Lysosomal Degradation

Abstract IFN-β promoter stimulator-1 (IPS-1)– and stimulator of IFN genes (STING)-mediated type I IFNs play a critical role in antiviral responses. Myxovirus resistance (Mx) proteins are pivotal components of the antiviral effectors induced by IFNs in many species. An unprecedented expansion of Mx genes has occurred in fish. However, the functions and mechanisms of Mx family members remain largely unknown in fish. In this study, we found that grass carp (Ctenopharyngodon idella) MxG, a teleost-specific Mx protein, is induced by IFNs and viruses, and it negatively regulates both IPS-1- and STING-mediated antiviral responses to facilitate grass carp reovirus, spring viremia of carp virus, and cyprinid herpesvirus-2 replication. MxG binds and degrades IPS-1 via the proteasomal pathway and STING through the lysosomal pathway, thereby negatively regulating IFN1 antiviral responses and NF-κB proinflammatory cytokines. MxG also suppresses the phosphorylation of STING IFN regulatory factor 3/7, and it subsequently downregulates IFN1 and NF-κB1 at the promoter, transcription, and protein levels. GTPase and GTPase effector domains of MxG contribute to the negative regulatory function. On the contrary, MxG knockdown weakens virus replication and cytopathic effect. Therefore, MxG can be an ISG molecule induced by IFNs and viruses, and degrade IPS-1 and STING proteins in a negative feedback manner to maintain homeostasis and avoid excessive immune responses after virus infection. To our knowledge, this is the first identification of a negative regulator in the Mx family, and our findings clarify a novel mechanism by which the IFN response is regulated.