Tripartite motif (TRIM) family proteins have come forth as important modulators of innate signaling dependent on of E3 ligase activity. Recently, several human TRIM proteins have been identified as unorthodox RNA-binding proteins by RNA interactome analyses; however, their targets and functions remain largely unknown. FTRCA1 is a crucian carp (Carassius auratus)–specific finTRIM (fish novel TRIM) member and negatively regulates the IFN antiviral response by targeting two retinoic acid–inducible gene-I (RIG-I)–like receptor (RLR) pathway molecules, that is, TANK-binding kinase 1 (TBK1) and IFN regulatory factor 7 (IRF7). In this study, we identify FTRCA1 as an RNA-binding E3 ligase and characterize the contribution of its RNA-binding activity and E3 ligase activity to fish IFN response. Besides targeting TBK1 and IRF7, FTRCA1 downregulates fish IFN response also by targeting stimulator of IFN response cGAMP interactor 1 (STING1). E3 ligase activity is required for full inhibition on the TBK1- and IRF7-mediated IFN response, but partial inhibition on the STING1-mediated IFN response. However, FTRCA1 has a general binding potential to mRNAs in vitro, it selectively binds STING1 and IRF7 mRNAs in vivo to attenuate mRNA levels, and it directly interacts with TBK1 protein to target protein degradation for downregulating the IFN response. Our results present an interesting example of a fish species–specific finTRIM protein that has acquired RNA-binding activity and E3 ligase activity to fine-tune fish IFN response.

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