The paraspeckle protein NONO potentiates the antiviral innate immune response through chromatin regulation

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Summary Type-I interferons (IFN-I) and IFN-stimulated genes (ISGs) are central to antiviral defense, while dysregulation can drive autoimmunity. IFNB1 expression is controlled by a highly ordered multiprotein complex composed of IRF3/7, NFκB, and ATF2/c-Jun (AP-1) that recruit coactivators and chromatin-remodeling proteins to expose the IFNB1 promoter for the RNA polymerase II (RNA Pol II) transcriptional machinery. Here, we identified the paraspeckle protein non-POU domain-containing octamer-binding protein (NONO) as a critical facilitator of innate immune activation. Loss of NONO enhanced replication of multiple orthoflaviviruses including West Nile virus due to impaired induction of IFN-I and ISGs. NONO did not affect upstream signaling but instead promoted chromatin accessibility and promoter access for RNA Pol II to drive expression of IFNB1 , ISGs, and proinflammatory cytokines. These findings position NONO as a key regulator of antiviral gene expression and reveal chromatin-levels of control that determine effective antiviral immunity.