Abstract

Nervous necrosis virus (NNV) is a lethal aquatic pathogen that activates NF-κB signaling to manipulate host immune responses, yet the underlying molecular mechanisms remain poorly defined. Here, we identify the NNV capsid protein (CP) as a novel viral SUMO E3 ligase that promotes SUMOylation of Lateolabrax japonicus mitochondrial antiviral signaling protein (MAVS) to drive NF-κB activation. We show that CP induces p65 nuclear translocation and upregulates proinflammatory cytokine expression in a MAVS-dependent manner. Mechanistically, CP interacts with SUMO2 and the E2 conjugating enzyme L. japonicus UBC9 to promote MAVS SUMOylation at lysine 325 (K325), which stabilizes MAVS, facilitates its aggregation, and amplifies downstream NF-κB signaling. Notably, disruption of this modification via the K325R mutation or SUMOylation inhibition abrogates MAVS aggregation and inflammatory responses. Our findings reveal a previously unrecognized strategy by which NNV hijacks the host SUMOylation machinery to fine-tune MAVS function, promoting immune evasion and viral persistence.