| IFI16 is a PYHIN family interferon‑inducible protein that functions as a nuclear and cytoplasmic DNA sensor and transcriptional regulator, linking recognition of double‑stranded DNA to type I interferon production, inflammasome modulation, and control of cell growth and death pathways. The protein contains an N‑terminal pyrin domain that mediates homotypic protein–protein interactions and assembly of signaling complexes, and two C‑terminal HIN‑200 domains that bind double‑stranded DNA with preference for supercoiled and cruciform structures, allowing IFI16 to associate with viral and endogenous DNA in the nucleus and cytoplasm. IFI16 binding to viral or foreign DNA in the cytoplasm or nucleus leads to engagement of the adaptor STING and activation of IRF3 and NF‑κB signaling cascades, which results in transcriptional induction of type I interferons and a broad panel of interferon‑stimulated genes that establish an antiviral state against DNA and some RNA viruses. IFI16 also exerts direct transcriptional regulatory functions by interacting with p53, retinoblastoma protein, and chromatin, enhancing p53 sequence‑specific DNA binding, modulating p53 phosphorylation, and influencing transcription of genes that control cell‑cycle arrest, senescence, autophagy, and BRCA1‑linked DNA damage responses. Nuclear IFI16 senses herpesviral episomal DNA and promotes epigenetic silencing of viral genomes by supporting heterochromatin assembly on herpesviral promoters, reducing immediate‑early gene expression and replication, and contributing to intrinsic restriction of herpesviruses such as HSV‑1 and HCMV. IFI16 also regulates inflammasome activity in a context‑dependent manner; certain isoforms inhibit the AIM2 inflammasome by sequestering cytosolic dsDNA and interfering with AIM2–ASC interactions, while nuclear IFI16 can form an ASC‑ and caspase‑1‑containing inflammasome on viral DNA, supporting IL‑1 family cytokine maturation during specific herpesvirus infections. Phase separation of IFI16 driven by multi‑site phosphorylation promotes formation of nuclear biomolecular condensates on pathogenic DNA, which facilitates assembly of signaling platforms that amplify innate immune responses and reinforce transcriptional silencing of foreign genomes. Within innate immune pathways, IFI16 participates in the cytosolic sensors of pathogen‑associated DNA network and coordinates with cGAS–STING signaling, providing transcriptional reinforcement of interferon and ISG expression in response to both DNA ligands and cGAMP and adjusting the magnitude and duration of antiviral programs. Dysregulated IFI16 expression or mislocalization associates with autoimmune phenomena such as anti‑IFI16 autoantibodies in systemic autoimmune diseases, and with altered growth control, hormone‑responsive transcription, and epigenetic regulation in cancers including breast cancer, where IFI16 participates in MTA1‑mediated control of ESR1 expression. |
