FTR85 negatively regulates type I IFN antiviral signaling pathway by promoting K48-linked polyubiquitination of IRF3

Abstract

The finTRIM (FTR) subfamily, a group of fish-specific tripartite motif proteins, has arisen through gene duplication events specific to particular genera or species. However, the regulatory mechanisms of FTR in antiviral immune response remains largely unknown. In the present study, we identified a fish novel tripartite motif member (finTRIM, FTR) in common carp (Cyprinus carpio L.) and named it CcFTR85, which contains a RING (really interesting new gene) domain, a coiled-coil region, and a PRY/SPRY domain. Its expression can be induced following spring viremia of carp virus (SVCV) infection and poly(I:C) stimulation. Overexpression of CcFTR85 significantly inhibits the expression of IFNφ1 and IFN-stimulated genes, thereby facilitating SVCV replication. Mechanistically, CcFTR85 binds to interferon regulatory factor 3 (IRF3) and promotes its K48-linked polyubiquitination at K329, causing a proteasomal degradation of IRF3 and consequent suppression of IRF3-mediated antiviral immune responses. In addition, ftr85-deficient zebrafish are more resistant to SVCV infection. Our study reveals a role for FTR85 in the regulation of antiviral responses, suggesting that it may serve as a potential target for controlling fish viral infections.