DEAD-box helicase gcDDX56 disrupts IRF3 nuclear import complex and promotes nuclear IRF3 degradation for enhancing GCRV replication

DEAD-box helicases exhibit versatile cellular roles in antiviral defense, functioning both as sentinels detecting viral invaders and as regulators of immune signaling. The present study reveals that teleost fish have evolved unique strategies using a related protein called gcDDX56. Unlike previously studied DEAD-box helicases, we demonstrate for the first time that gcDDX56 hijacks an importin β's (gcKPNB3) dual functions (IRF3 transport/degradation) via domain-specific interaction, acting as a "switch" to tilt gcKPNB3 toward pro-viral degradation. This novel regulatory axis (gcDDX56-gcKPNB3-IRF3) reveals a "triple hit" mechanism (cytoplasmic degradation + nuclear clearance + import blockade) that maximizes IRF3 suppression, a strategy not reported for other viruses. Beyond advancing basic knowledge of vertebrate innate immunity (expanding DEAD-box helicase/importin β functional repertoires), these findings provide actionable targets (e.g., gcDDX56-Helicase C/gcKPNB3-KAP95 interface) for developing anti-GCRV therapies, addressing a pressing need in aquaculture to mitigate GCRV-induced losses.