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Interferon (IFN) system is considered as the first defense line against viral infection, and it has been extensively studied in vertebrates from fish to mammals. In invertebrates, Vagos from arthropod and IFN-like protein ( Cg IFNLP) from  Crassostrea gigas  appeared to function as IFN-like antiviral cytokines. In the present study, the  Cg IFNLP protein in hemocytes was observed to increase after Poly (I:C) stimulation. After  Cg IFNLP was knocked down by RNAi, the mRNA expression of IFN-stimulated genes ( Cg ISGs) was significantly inhibited. Both cyclic GMP-AMP synthase ( Cg cGAS) and stimulator of interferon gene ( Cg STING) identified from oyster were able to recognize the double-stranded nucleic acid [Poly (I:C) and dsDNA] and expressed at high level after Poly (I:C) stimulation. The expression of  Cg IFNLP and interferon regulatory factors ( Cg IRF1/8) and the nuclear translocation of  Cg IRF8 were all suppressed in  Cg cGAS-RNAi or  Cg STING-RNAi oysters after Poly (I:C) stimulation. The expression level of  Cg STING and TANK binding kinase1 ( Cg TBK1) did not decrease in  Cg cGAS-RNAi oysters. After  Cg STING was knocked down, the high expression of  Cg TBK1 induced by Poly (I:C) was prevented significantly. These results indicated that there was a primitive IFN-like antiviral mechanism dependent on the cGAS/STING–TBK1–IRFs regulatory axis in mollusks, which was different from the classic cGAS–STING–TBK1 signal pathway in mammals.

The cGAS/STING–TBK1–IRF Regulatory Axis Orchestrates a Primitive Interferon-Like Antiviral Mechanism in Oyster