Src interacts with TRAF5 and promotes NF-κB-associated antiviral responses against iridovirus in marine teleost.

Abstract

Src, a prototypical non-receptor tyrosine kinase and central signaling hub, is well documented to play complex, and even opposing, roles in mammalian viral infections-both restricting viral replication and being hijacked by viruses to facilitate their own life cycles. However, its role in aquatic viral infections remains largely unexplored. Here, we characterized a novel Src homolog from Epinephelus coioides, designated EcSrc, and investigated its function during Singapore grouper iridovirus (SGIV) infection. EcSrc exhibited high sequence conservation with vertebrate orthologs from mammals to teleosts. In healthy fish, EcSrc transcripts predominated in head kidney and spleen, but were markedly downregulated upon SGIV challenge. Under basal conditions, EcSrc displayed a diffuse cytoplasmic distribution without discernible organelle-specific enrichment; however, at late stages of infection, it also localized to the nucleus and virus assembly sites. Overexpression of EcSrc significantly suppressed SGIV replication, and treatment with a Src family kinase inhibitor (PP2) enhanced viral replication, together indicating that EcSrc functions as a host restriction factor. EcSrc activated NF κB signaling by promoting IκBα and p65 phosphorylation and facilitating p65 nuclear translocation, which in turn induced inflammatory cytokine gene transcription. Notably, EcSrc could interact with TRAF5, an interaction that has not been previously reported. While TRAF5 alone exerted a suppressive effect on NF-κB, EcSrc overexpression possibly counteracted this inhibition, suggesting that EcSrc may relieve the TRAF5-imposed restriction on NF-κB activation. Together, our findings indicate that EcSrc promotes NF-κB-associated antiviral responses against SGIV and identify an EcSrc-TRAF5 interaction potentially involved in teleost antiviral immunity.