Geninthiocin promotes RIG-I-mediated anti-RNA viral signaling responses

RIG-I, the core RNA sensor of RIG-I-mediated type I IFNs (IFN-I) signaling, induces the innate antiviral response through recognizing RNA viruses. Upon RNA virus infection, RIG-I undergoes autophagic degradation to attenuate host innate immune response for immune evasion. Thus, we sought to discovery the lead compounds that promote RIG-I protein stability to enhance host antiviral ability. Natural compounds have a rich history for contributing to new therapeutic candidates. Up to now, there is rarely reported that natural compounds enhance RIG-I to clear RNA virus. By screening a natural compound library, we identified that Geninthiocin, a natural thiopeptide from a marine Streptomyces, potentiates RIG-I-IFN-I signaling to enhance IFN-I and antiviral ISGs expression through inhibiting RIG-I autophagic degradation. Both in human and murine cells, Geninthiocin promoted RIG-I-mediated IFN-I and antiviral ISGs expression upon Influenza A virus PR8 (IAV) infection or RNA mimics Poly(I:C) stimulation. In vivo, we observed that Geninthiocin significantly suppressed IAV PR8 induced death and enhance the expression of IFN-I and antiviral ISGs in C57BL/6 J mice. By performing molecular docking and biotin pull down assay, we observed that Geninthiocin interacted with RIG-I. Further, Geninthiocin repressed RIG-I autophagic degradation to positively regulate RIG-I-IFN-I signaling response. Together, we reveal the novel function of Geninthiocin in anti-RNA viral innate immune response by enhancing RIG-I-IFN-I signaling activation, which provides new insight in developing therapeutic strategy for IAVs or other RNA viral infectious diseases.