IFI16

The IFI16 protein (IFI16 stands for "Interferon Gamma Inducible Protein 16") is encoded by the IFI16 gene, which is located on chromosome 1q23.1. IFI16 is a member of the HIN-200 family (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats) of cytokines. The protein contains domains involved in DNA binding, transcriptional regulation and protein-protein interactions. The protein is localized in the nucleoplasm and nucleoli and interacts with p53 and retinoblastoma-1. It modulates the function of p53 and inhibits cell growth via the Ras/Raf signaling pathway.

IFI16, binds double-stranded DNA. It binds preferentially to supercoiled DNA and cross-shaped DNA structures. It appears to be involved in transcription regulation. IFI16 can act as a transcriptional repressor and may play a role in the regulation of hematopoietic differentiation by activating unknown target genes.

IFI16 controls cellular proliferation by modulating the functions of cell cycle regulatory factors such as p53/TP53 and the retinoblastoma protein. Furthermore, it appears to be involved in the energy-dependent activation of the ATM/ AMPK/TP53 signaling pathway in conjunction with the regulation of autophagy. The IFI16 protein may be involved in the regulation of TP53-mediated cell death, in which BRCA1 is also involved.

IFI16 plays an important role in the innate immune response. It recognizes viral dsDNA in the cytosol and probably also in the nucleus. After binding to viral DNA in the cytoplasm, it recruits TMEM173/STING and mediates the induction of IFN-beta. Has an anti-inflammatory effect and inhibits the activation of the AIM2 inflammasome, probably by association with AIM2.

The IFI16 protein presumably binds viral DNA in the cell nucleus, e.g. of the Kaposi's sarcoma-associated herpes virus, and induces the formation of a caspase-1-activating inflammasome in the cell nucleus by association with PYCARD. It inhibits the replication of herpesviruses such as human cytomegalovirus (HCMV), probably by interfering with promoter recruitment of members of the Sp1 family of transcription factors.

The IFI16-beta isoform specifically inhibits the AIM2 inflammasome (Wang PH et al. 2018). It binds double-stranded DNA (dsDNA) in the cytoplasm and thus prevents its recognition by AIM2. Furthermore, it also prevents the interaction between AIM2 and PYCARD/ASC via its interaction with AIM2, thereby inhibiting the assembly of the AIM2 inflammasome (Wang PH et al. 2018).

1. Jiang Z et al. (2021) IFI16 directly senses viral RNA and enhances RIG-I transcription and activation to restrict influenza virus infection. Nat Microbiol 6:932-945.
2. Unterholzner L et al. (2010) IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol 11:997-1004.
3. Wang PH et al. (2018) Inhibition of AIM2 inflammasome activation by a novel transcript isoform of IFI16. EMBO Rep 19:e45737.