| DDX41 is a highly conserved DEAD‑box helicase that contains two RecA‑like helicase domains with the signature Asp‑Glu‑Ala‑Asp (DEAD) motif, flanked by N‑ and C‑terminal regulatory regions, and it participates both in RNA metabolism and in innate immune sensing by acting as a bispecific receptor for double‑stranded DNA and cyclic dinucleotides upstream of STING. Structural studies of the human DDX41 DEAD domain show an ATP‑binding cleft that undergoes conformational rearrangement on nucleotide binding and a distinct overlapping surface that binds dsDNA and cyclic di‑GMP/di‑AMP, demonstrating that the same DEAD domain provides ATP‑powered recognition of DNA and bacterial second messengers while leaving the ATP pocket structurally segregated from the ligand interface to enable rapid ADP release and turnover during signaling. In myeloid and dendritic cells, cytosolic DDX41 detects foreign or mislocalized self nucleic acids and cyclic dinucleotides produced during microbial infection, then directly engages the adaptor STING via its DEAD domain; this DDX41–STING complex recruits TBK1 and activates IRF3 and NF‑κB, driving type I interferon production and pro‑inflammatory cytokine expression as part of a STING‑dependent DNA‑sensing pathway. The BTK–DDX41 axis further refines this mechanism: Bruton’s tyrosine kinase phosphorylates DDX41 and promotes its interaction with STING, and during human cytomegalovirus infection this BTK‑dependent activation of DDX41 facilitates STING dimerization, ER‑to‑Golgi translocation and full engagement of the TBK1–IRF3 module, positioning DDX41 as a critical upstream node in antiviral STING signaling. Beyond its sensor role, DDX41 binds DNA/RNA hybrids in transcription‑associated R‑loops and maintains genome stability by preventing their accumulation; DDX41 deficiency increases R‑loop levels, triggers chronic inflammatory responses and perturbs hematopoietic stem and progenitor cell production, indicating that DDX41 integrates nucleic acid surveillance with control of hematopoietic homeostasis. At the level of RNA metabolism, DDX41 associates with spliceosomal components and ribonucleoprotein complexes involved in pre‑mRNA splicing, ribosome biogenesis and translational regulation, and recent work shows that it selectively modulates alternative splicing of genes implicated in cell transformation and immune responses, providing a mechanistic link between its helicase activity and transcriptional programs that govern proliferation and antigen presentation. Germline and somatic mutations in the DEAD domain and other regions of DDX41 are recurrent in familial and sporadic myelodysplastic syndrome and acute myeloid leukemia; loss‑of‑function or frameshift variants compromise its DNA/CDN sensing, RNA processing and R‑loop control and are associated with increased inflammatory signaling and clonal myeloid expansion, supporting a tumor‑suppressor role for DDX41 in myeloid malignancies. Functional analyses in leukemic and solid tumor models indicate that intact DDX41 expression inhibits proliferation, promotes apoptosis and down‑regulates oncogenes while up‑regulating tumor suppressors and antigen‑presentation genes, whereas knockdown or mutant DDX41 fosters tumor growth, emphasizing that the helicase’s combined roles in innate immunity, splicing and genome maintenance shape both anti‑pathogen defenses and cancer progression. |
