Nervous necrosis virus capsid protein antagonizes methyltransferase-like 14-mediated mA modification of mitochondrial antiviral signaling protein to evade antiviral immunity in Lateolabrax japonicus.

Abstract

N-methyladenosine (mA) modification plays crucial roles in diverse cellular processes, including the regulation of innate immune responses; however, its specific role in antiviral defense mechanisms in aquatic organisms remains incompletely understood. This study identifies LjMETTL14, a core mA methyltransferase in sea perch (Lateolabrax japonicus), as a key regulator of antiviral immunity against nervous necrosis virus (NNV), a major pathogen threatening aquaculture. Our findings show that LjMETTL14 expression was significantly upregulated in response to NNV infection, and overexpression of LjMETTL14 suppresses viral replication by enhancing retinoic acid-inducible gene I-like receptor (RLRs) signaling and type I interferon (IFN) production. In contrast, LjMETTL14 knockdown leads to impaired RLRs signaling and markedly increased viral replication, underscoring its essential antiviral function. Mechanistically, LjMETTL14 interacts specifically with transmembrane domain of mitochondrial antiviral signaling protein (LjMAVS), promoting its mA methylation, protein stability, and multimeric aggregation, thereby enhancing LjMAVS-mediated type I IFN signaling. Conversely, NNV capsid protein (CP) interacts with LjMETTL14, suppressing its expression and impeding the LjMAVS-dependent IFN response, thereby facilitating viral replication. These findings reveal a novel epitranscriptomic regulatory mechanism involving LjMETTL14 and LjMAVS that orchestrates antiviral immunity in fish, highlighting LjMETTL14 as a potential therapeutic target for controlling NNV infection in aquaculture.