HGNC Approved Gene Symbol: IFI16
Cytogenetic location: 1q23.1 Genomic coordinates (GRCh38): 1:158,999,976-159,055,151 (from NCBI)
The interferons are a family of vertebrate cytokines with pleiotropic activities including antiviral effects, the regulation of cell growth and differentiation, and modulation of immune function. Interferon-gamma (IFNG; 147570) causes an increase in the expression of major histocompatibility complex (MHC) class I and class II proteins on a variety of cells, serving to enhance antigen presentation and recognition of foreign cell surface antigens by MHC-restricted cytotoxic T lymphocytes. Trapani et al. (1992) described a human IFN-gamma-inducible gene, IFI16, which has nucleotide sequence similarity with portions of 2 mouse IFI genes. A full-length cDNA clone encodes a putative polypeptide of 729 amino acids. IFI16 mRNA was found to be constitutively expressed in lymphoid cells and in cell lines of both the T and B lineages. By contrast, the mRNA was not expressed in cell lines that represent early stages of myeloid development, although it was inducible in 2 of these lines with interferon-gamma.
Kerur et al. (2011) found that infection of endothelial cells with Kaposi sarcoma-associated herpesvirus (KSHV; see 148000) resulted in interaction of IFI16 with the adaptor molecule ASC (PYCARD; 606838) and procaspase-1 (CASP1; 147678) to form a functional inflammasome. This inflammasome localized initially to the nucleus and subsequently in the perinuclear area. KSHV colocalized with IFI16 in the nucleus. CASP1 activation by KSHV was reduced by IFI16 and ASC silencing. Kerur et al. (2011) concluded that IFI16 is a nuclear pathogen sensor and that the inflammasome functions in both the cytoplasm and nucleus.
Using unbiased proteomic and targeted biochemical approaches, as well as 2 independent methods of lentiviral short hairpin RNA-mediated gene knockdown in primary CD4 (186940) T cells, Monroe et al. (2014) identified IFI16 as a host DNA sensor required for CD4 T-cell death due to abortive HIV infection. These findings provided insights into a key host pathway that plays a central role in CD4 T-cell depletion during disease progression to AIDS.
At least 6 interferon-gamma-inducible genes located on mouse chromosome 1 were described by Choubey et al. (1989), Kingsmore et al. (1989), and others. In the mouse, the genes mapped to a 150-kb segment of DNA, and the serum amyloid P component gene (Sap; see 104770) mapped within approximately 450 kb of the IFN-inducible gene cluster. The erythrocyte alpha-spectrin gene (see 182860) was also closely linked.
Using a panel of interspecies somatic cell hybrid cell lines, Trapani et al. (1992) localized the human IFI16 gene to 1q12-qter. DNA blotting indicated that, in contrast to the mouse, human IFI16 is present in single copy.
Choubey, D., Snoddy, J., Chaturvedi, V., Toniato, E., Opdenakker, G., Thakur, A., Samanta, H., Engel, D. A., Lengyel, P. Interferons as gene activators: indications for repeated gene duplication during the evolution of a cluster of interferon-activatable genes on murine chromosome 1. J. Biol. Chem. 264: 17182-17189, 1989. [PubMed: 2477366]
Kerur, N., Veettil, M. V., Sharma-Walia, N., Bottero, V., Sadagopan, S., Otageri, P., Chandran, B. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi sarcoma-associated herpesvirus infection. Cell Host Microbe 9: 363-375, 2011. [PubMed: 21575908] [Full Text: https://doi.org/10.1016/j.chom.2011.04.008]
Kingsmore, S. F., Snoddy, J., Choubey, D., Lengyel, P., Seldin, M. F. Physical mapping of a family of interferon-activated genes, serum amyloid P-component, and alpha-spectrin on mouse chromosome 1. Immunogenetics 30: 169-174, 1989. [PubMed: 2476388] [Full Text: https://doi.org/10.1007/BF02421202]
Monroe, K. M., Yang, Z., Johnson, J. R., Geng, X., Doitsh, G., Krogan, N. J., Greene, W. C. IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV. Science 343: 428-432, 2014. [PubMed: 24356113] [Full Text: https://doi.org/10.1126/science.1243640]
Trapani, J. A., Browne, K. A., Dawson, M. J., Ramsay, R. G., Eddy, R. L., Shows, T. B., White, P. C., Dupont, B. A novel gene constitutively expressed in human lymphoid cells is inducible with interferon-gamma in myeloid cells. Immunogenetics 36: 369-376, 1992. [PubMed: 1526658] [Full Text: https://doi.org/10.1007/BF00218044]