DEAD-box RNA helicase (DDX helicases acting as innate immune receptors) (DDX helicases)

DEAD-box (DDX) RNA helicases are a family of multifunctional enzymes characterized by a conserved helicase core with RecA-like domains that bind and unwind RNA structures in an ATP-dependent manner, enabling roles in RNA metabolism, genome stability, and innate immunity. Several members, such as DDX41, act as cytosolic sensors for foreign nucleic acids like viral DNA, bacterial cyclic dinucleotides, or self-DNA/RNA hybrids (R-loops), activating the STING-TBK1-IRF3 pathway to induce type I interferon responses and anti-pathogen defenses. DDX41 exemplifies this by recognizing cytosolic DNA independently of cGAS, binding STING to trigger IFN production during infections like HSV or adenovirus, while also resolving R-loops to prevent replication stress and maintain hematopoietic stem cell function. Beyond immunity, DDX helicases like DDX1, DDX5, and DDX21 regulate splicing, DNA repair, and ribosome biogenesis, with deficiencies causing DNA damage or aberrant transcripts. In disease, DDX41 loss-of-function mutations are linked to myeloid malignancies (MDS/AML), promoting inflammation, genome instability, and disrupted erythropoiesis via elevated R-loops and cGAS-STING signaling. No direct drugs target these helicases clinically, but their roles highlight therapeutic potential in modulating innate immunity or cancer, balanced against risks like hematopoietic toxicity.

Other names

DExD/H-box helicasesDEAD/H-box RNA helicasesRNA helicases (innate immune sensors)