Nucleotide oligomerization domain-like receptors (NLRs) and RIG-I-like receptors (RLRs) detect diverse pathogen-associated molecular patterns to activate the innate immune response. The role of mammalian NLR NOD1 in sensing bacteria is well established. Although several studies suggest NOD1 also plays a role in sensing viruses, the mechanisms behind this are still largely unknown. In this study, we report on the synergism and antagonism between NOD1 and MDA5 isoforms in teleost. In zebrafish, the overexpression of NOD1 enhances the antiviral response and mRNA abundances of key antiviral genes involved in RLR-mediated signaling, whereas the loss of NOD1 has the opposite effect. Notably, spring viremia of carp virus-infected NOD1 2/2 zebrafish exhibit reduced survival compared with wild-type counterparts. Mechanistically, NOD1 targets MDA5 isoforms and TRAF3 to modulate the formation of MDA5-MAVS and TRAF3-MAVS complexes. The cumulative effects of NOD1 and MDA5a (MDA5 normal form) were observed for the binding with poly(I:C) and the formation of the MDA5a-MAVS complex, which led to increased transcription of type I IFNs and ISGs. However, the antagonism between NOD1 and MDA5b (MDA5 truncated form) was clearly observed during proteasomal degradation of NOD1 by MDA5b. In humans, the interactions between NOD1-MDA5 and NOD1-TRAF3 were confirmed. Furthermore, the roles that NOD1 plays in enhancing the binding of MDA5 to MAVS and poly(I:C) are also evolutionarily conserved across species. Taken together, our findings suggest that mutual regulation between NOD1 and MDA5 isoforms may play a crucial role in the innate immune response and that NOD1 acts as a positive regulator of MDA5/MAVS normal form-mediated immune signaling in vertebrates.

Aquareoviruses (AqRVs) can infect various wild or cultured bony fishes with serious muscle and viscera haemorrhage syndrome and have caused severe economic losses worldwide. Accumulating evidences have revealed the functions of viral proteins of AqRVs in RNA transcription, virion assembly, cell attachment and/or viral replication. In addition, structural information and transcription mechanism of AqRVs have been in‐depth studied through cryo‐electron microscopy combined with three‐dimensional image reconstruction. Although far from enough, structural and functional studies of AqRVs provide substantial insights into how viral proteins coordinate the replication of AqRVs and escape the host immune response. Grass carp reovirus (GCRV) is the most pathogenic AqRV isolated from aquatic animals. The completion of GCRV lifecycle requires the participation of host proteins. So far, many host factors involved in the entry and replication of GCRV have been identified. Based on the function of viral proteins and the viral lifecycle, many vaccines and antiviral agents have been developed to prevent the replication and infection of GCRV. This review summarises the structural characteristics and the composition of core proteins of AqRVs, as well as synergistic mechanisms of structural proteins on genome transcription and virus entry of AqRVs. In addition, the review highlights our current knowledge for the infection and replication, functions of non‐structural proteins, immune escape mechanisms, as well as the vaccines and antiviral agents of AqRVs, especially for GCRV. A better understanding of structure, function and immune evasion strategies of AqRVs will offer new targets for prevention and control of AqRVs in aquaculture.