Master of many: cellular functions of DDX41. DDX41 localizes to both cytoplasmic and nuclear compartments and plays distinct roles in each location. In the nucleus, DDX41 functions in at least 3 processes. Via its association with the catalytically active spliceosome, DDX41 regulates pre-mRNA splicing. Here, it also modulates snoRNA processing, potentially via promoting excision of snoRNA-containing introns found in ribosomal protein genes. DDX41 can also modify pre-rRNA processing, either indirectly via its control of snoRNA processing or perhaps directly via an unknown mechanism. In the nucleus, DDX41 also interacts with R-loops, which comprise RNA:DNA hybrids and ssDNAs. DDX41 insufficiency leads to R-loop accumulation and subsequent increased dsDNA breaks that trigger a cGAS-STING–mediated type I IFN response. Cytoplasmically localized DDX41 can bind to infection-derived or damaged endogenous dsDNA and then promote STING activation and type I IFN response. In addition, DDX41 can modulate cGAS activity via its dsDNA unwinding capabilities by altering the relative amounts of dsDNA-to-ssDNA. For example, the R525H DDX41 mutant, which has intact dsDNA binding activity but diminished unwinding activity, can overstimulate cGAS leading to a heightened type I IFN response. Created with BioRender.com. DDX41, DEAD-box helicase 41; ssDNA, single-stranded DNA.