At the crossroads of immunity and hijacking: dual roles of DDX proteins during host–virus interactions

Abstract

The DEAD-box (DDX) protein family, constituting a critical subgroup of the Superfamily 2 (SF2) helicase family, plays extensive roles in nucleic acid metabolism, gene expression regulation and innate immune signaling, and exerts a key regulatory role during viral infection. During viral infection, DDX proteins function as both RNA helicases and host restriction factors, exerting antiviral effects by recognizing viral nucleic acids, regulating signaling pathways and maintaining the host immune response. Conversely, through complex and diverse mechanisms, viruses can hijack or antagonize DDX proteins to facilitate their replication, transcription, translation and immune evasion. Focusing on the DDX protein family, this review systematically elucidates their molecular mechanisms of action across the life cycles of various viruses. Specifically, it examines the regulation of viral nucleic acid metabolism by DDX proteins, their influence on innate immune signaling pathways, and the molecular strategies employed by viruses to antagonize DDX proteins, while synthesizing the functional similarities and differences among members of the DDX protein family across distinct viral infections. This review aims to establish a theoretical framework for the in-depth analysis of virus–host interactions and the discovery of novel antiviral targets.