Nectin4 antagonises type I interferon production by targeting TRAF3 for autophagic degradation and disrupting TRAF3-TBK1 complex formation

Autophagy, a conserved cellular degradative process, plays a crucial role in innate immunity during viral infections. Nervous necrosis virus (NNV), a leading cause of fish diseases with morbidity and mortality, triggers cell autophagy to promote viral replication; however, the details of how NNV utilises autophagy to facilitate its own replication remain largely unexplored. Here, we investigated the mechanism by which the sea perch Nectin4 (LjNectin4), a receptor of NNV, regulates autophagy and the innate immune system by targeting TNFR-associated factor 3 (TRAF3). Our data demonstrated that LjNectin4 directly binds to the NNV capsid protein and facilitates NNV entry, indicating that LjNectin4 functions as an NNV receptor. Moreover, LjNectin4 promoted NNV replication by inhibiting key elements of the RLR signalling pathway (MDA5, MAVS, TRAF3, TBK1, and IRF3)induced IFN response. Mechanistically, LjNectin4 directly interacted with TRAF3 and promoted its autophagymediated lysosomal degradation. Domain mapping of the interaction between TRAF3 and LjNectin4 or TBK1 showed that both LjNectin4 and TBK1 interacted with the ZF2 and TRAF-C domains of TRAF3, suggesting that LjNectin4 blocked TRAF3-TBK1 complex formation. Collectively, our study revealed that NNV utilises LjNectin4 to suppress IFN production by mediating TRAF3 autophagic degradation and disrupting the TRAF3-TBK1 complex, thereby promoting NNV replication.

Automated summary

In this study, the researchers explored how nervous necrosis virus (NNV) utilizes autophagy to promote its replication. They found that the sea perch Nectin4 (LjNectin4), as a receptor of NNV, facilitates NNV entry by directly binding to NNV capsid protein. Furthermore, LjNectin4 inhibits key elements of the RLR signaling pathway to suppress interferon (IFN) response and promote NNV replication.