Interferon Gamma Inducible protein (IFI)16 transcriptionally regulates type I interferons and other interferon stimulated genes and controls the interferon response to both DNA and RNA viruses [Immunology]

July 7th, 2014 by Thompson, M. R., Sharma, S., Atianand, M., Jensen, S. B., Carpenter, S., Knipe, D. M., Fitzgerald, K. A., Kurt-Jones, E. A.

The Interferon Gamma Inducible protein 16 (IFI16) has recently been linked to the detection of nuclear and cytosolic DNA during infection with herpes simplex virus-1 and HIV. IFI16 binds dsDNA via HIN200 domains and activates Stimulator of Interferon genes (STING) leading to TANK binding kinase-1 (TBK1) dependent phosphorylation of interferon regulatory factor 3 (IRF3) and transcription of type I interferons (IFN) and related genes. To better understand the role of IFI16 in coordinating type I IFN gene regulation, we generated cell lines with stable knockdown of IFI16 and examined responses to DNA and RNA viruses as well as cyclic-di-nucleotides. As expected, stable knockdown of IFI16 led to a severely attenuated type I IFN response to DNA ligands and viruses. In contrast, expression of the NF-κB regulated cytokines, IL-6 and IL-1β were unaffected in IFI16 knockdown cells, suggesting that the role of IFI16 in sensing these triggers was unique to the type I IFN pathway. Surprisingly, we also found that knockdown of IFI16 led to a severe attenuation of IFN-α and the IFN stimulated gene RIG-I in response to cyclic GMP-AMP (cGAMP), a second messenger produced in response to cGAS as well as RNA ligands and viruses. Analysis of IFI16 knockdown cells revealed compromised occupancy of RNA polymerase II on the IFN-α promoter in IFI16-knockdown cells, suggesting that transcription of ISGs is dependent on IFI16. These results indicate a broader role for IFI16 in the regulation of the type I IFN response to RNA and DNA viruses in anti-viral immunity.
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