Fish <i>Snx27</i> promotes viral products by modulating the innate immune response and exosomal machinery

Viral nervous necrosis caused by the nervous necrosis virus (NNV) poses a significant threat to the global aquaculture industry. Developing preventive methods to minimize economic losses due to NNV infections is crucial. This study explored the role of the sorting nexin 27 (<i>Snx27</i>) gene, encoded by the orange-spotted grouper (<i>Epinephelus coioides</i>) and referred to as <i>EcSnx27</i>, as an immune regulator affecting red-spotted grouper nervous necrosis virus (RGNNV) infection <i>in vitro</i>. Our findings revealed that <i>EcSnx27</i> negatively regulates interferon (IFN)-related cytokines and the promoter activities of fish ISRE and NF-κB. Furthermore, we identified the SNX-FERM and SNX-FERM-like domains as responsible for the interaction between <i>EcSnx27</i> and RGNNV coat protein. Through the detection of viable virions associated with <i>EcSnx27</i>-containing exosomes, we propose that <i>EcSnx27</i> may contribute to the release process of RGNNV by influencing the apoptosis-linked gene 2-interacting protein X (ALIX)-associated exosomal pathway. Consequently, our study suggests that <i>EcSnx27</i> promotes RGNNV replication by inhibiting the IFN immune response and facilitating virus production and release through ALIX-mediated exosomal machinery.IMPORTANCERed grouper nervous necrosis virus (RGNNV), a member of the <i>Nodaviridae</i> family, has emerged as a significant cause of fish diseases worldwide, leading to high morbidity and mortality rates. This study investigated the sorting nexin 27 (<i>Snx27</i>) gene encoded by the orange-spotted grouper (<i>Epinephelus coioides</i>) on RGNNV infection in grouper kidney cells. Our findings revealed that <i>EcSnx27</i> negatively regulated the interferon pathway, resulting in the promotion of RGNNV replication. Additionally, we observed that <i>EcSnx27</i> could interact with apoptosis-linked gene 2-interacting protein X (ALIX) and the RGNNV coat protein, suggesting its potential involvement in viral release processes through modulation of the exosomal pathway. Our study identified <i>EcSnx27</i> as a key target that RGNNV exploits to enhance viral production. This finding offers valuable insights into the immune evasion and viral release mechanisms of non-enveloped RNA viruses.