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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
The paraspeckle protein NONO potentiates the antiviral innate immune response through chromatin regulation
Adam Hage1,2, Mikhaila Janes1, Byron Shue1
1Innate Immunity and Pathogenesis Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
Abstract:
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.
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