DDX21 nuclear-cytoplasmic shuttling recruits RPS18 to viral dsRNA to promote CSFV replication

Cellular pathogens exploit host machinery by forcibly relocalizing and repurposing nuclear proteins. Here, we reveal that Classic Swine Fever Virus (CSFV) hijacks DEAD-box helicase 21 (DDX21)，dynamically translocating it from nucleus to cytoplasm and converts it into a non-enzymatic scaffold that recruits ribosomal protein S18 (RPS18) onto viral double-stranded RNA (dsRNA). This virus-induced DDX21-RPS18 axis creates a self-amplifying loop: DDX21 upregulates RPS18 via its helicase domain, while RPS18 suppresses DDX21 levels. Crucially, RPS18 dose-dependently enhances viral NS4A protein synthesis, with DDX21's pro-viral activity being strictly RPS18-dependent. By orchestrating RPS18-dsRNA binding independent of its helicase activity, cytoplasmic DDX21 spatially co-opts ribosomal components to selectively drive viral protein translation. Our findings reveal a mechanism in which CSFV-triggered relocalization of DDX21 enables viral hijacking of host translation, illustrating how spatial control of RNA-binding proteins can be exploited to redirect cellular functions for pathogen replication.