Insulin-like growth factor binding protein 1 facilitates nervous necrosis virus replication through m6A methylation and suppression of antiviral immune response

Nervous necrosis virus (NNV) is a major pathogen in aquaculture, leading to devastating neurological damage and high mortality in fishes; however, its pathogenic mechanism has not been fully elucidated. Insulin-like growth factor binding protein 1 (IGFBP1) is a member of the IGFBP family and acts as a critical modulator in viral infections. Here, we explore the potential role of marine medaka ( Oryzias melastigma ) IGFBP1 during NNV infection. We found that overexpression of IGFBP1 in marine medaka embryonic stem cells significantly increased NNV capsid protein levels, whereas IGFBP1 knockdown dramatically reduced it, confirming IGFBP1's pro-viral function. Further, we found that m 6 A methylation, particularly mediated by the Wilm's tumor 1-associated protein complex, is crucial for the post-transcriptional enhancement of IGFBP1 expression. Moreover, IGFBP1 overexpression downregulated the expression levels of key components (IRF3, MAVS, TBK1, and TRAF3) in the retinoic acid-inducible gene I-like receptor signaling pathway. This suppression led to reduced activity of the interferon (IFN) 1 promoter and lower expression of IFN and IFN-stimulated genes. Our findings underscore IGFBP1's role in enhancing viral replication and weakening host immune defenses, providing a potential target for therapeutic intervention against NNV infections. • Marine medaka IGFBP1 promoted nervous necrosis virus (NNV) replication. • IGFBP1 expression was enhanced by m6A methylation mediated by the WTAP complex. • IGFBP1 inhibits the RLR signaling pathway and IFN response to promote NNV replication.