Abstract

DEAD/H-box RNA helicases are critical regulators of host antiviral innate immunity. In this study, we utilized an RNA-binding protein knockout sub-library to identify DDX46, a member of the DEAD/H-box RNA helicase family, as an essential proviral host factor for RNA virus replication. While DDX46 has been shown to sequester demethylated innate immune transcripts in the nucleus and dampen interferon (IFN) production, the mechanisms underlying its regulation during viral infection remain unclear. Here, we report that RNA virus infection induces caspase-dependent cleavage of DDX46, triggering its translocation from the nucleus to the cytoplasm. This translocation unchains innate immune transcripts from nuclear retention, licensing their rapid translation and potentiating robust IFN responses. Our findings reveal a novel regulatory mechanism by which post-translational modification and subcellular relocalization of DDX46 fine-tune the host antiviral response, highlighting the functional versatility of RNA helicases in host-virus interactions.