The role of IFI16 in the innate immune response to cytosolic nucleic acids (P1395)

Abstract

Abstract Recently, the Interferon Gamma Inducible (IFI)16 was linked to cytoplasmic DNA induced type I interferon (IFN) responses. IFI16 was shown to associate with Stimulator of IFN genes (STING), leading to TANK binding kinase-1 (TBK1) dependent phosphorylation of interferon regulatory factor 3 (IRF3) and transcription of type I IFN genes. Here we created THP1 monocytic cell lines with stable knockdown of IFI16 by lentiviral transduction of shRNA and demonstrated that IFI16 knockdown leads to a severely attenuated type I IFN response following treatment of cells with either synthetic DNA ligands, or after infection with DNA viruses such as HSV-1. Surprisingly, these cells were also compromised in their ability to induce type I IFNs to other non-DNA ligands including synthetic 5’pppRNA and Sendai Virus, both of which signal via RIG-I. In contrast the NF-kB regulated cytokines IL-6 and IL-1β remain unaffected in IFI16 knockdown cells. Utilizing Nanostring technology, we also determined that IFI16 is capable of regulating DNA and RNA induced expression of a panel of Interferon Stimulated genes (ISGs), including RIG-I. We also monitored key steps in the type 1 IFN pathway and found that levels of total IRF3 were also reduced in IFI16 knockdown cells. These results suggest that IFI16 senses DNA viruses, eliciting a type I IFN response, but also acts more broadly in the regulation of ISGs in response to both DNA and RNA viruses.