Interleukin-12 induces rapid STAT4/DDX5-dependent remodeling of RNA polymerase II occupancy in NK cells

Natural killer (NK) cells are innate lymphocytes that rapidly respond to inflammatory cytokines during infection, but the mechanisms underlying such swift responses remain incompletely understood. Here, we investigated the RNA polymerase II (Pol II) dynamics during rapid cytokine-induced activation in NK cells. Brief exposure to the proinflammatory cytokine interleukin-12 (IL-12) elicited rapid, genome-wide redistribution of Pol II within minutes, with increased promoter-proximal Pol II pausing at effector loci including Ifng. This IL-12–induced Pol II reorganization was mediated by the transcription factor STAT4. We further identified the RNA helicase DDX5 as a STAT4 interaction partner required for optimal IFN-γ production and appropriate modulation of Pol II occupancy following IL-12 stimulation. Together, these findings identify STAT4/DDX5-mediated regulation of Pol II as a critical mechanism enabling the rapid responsiveness of NK cells to proinflammatory cytokines.