IFI16 explained

Gamma-interferon-inducible protein Ifi-16 (Ifi-16) also known as interferon-inducible myeloid differentiation transcriptional activator is a protein that in humans is encoded by the IFI16 gene.^{[1] [2] [3]}

Function

This gene encodes a member of the HIN-200 (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats) family of cytokines. The encoded protein contains domains involved in DNA binding, transcriptional regulation, and protein-protein interactions. The protein localizes to the nucleoplasm and nucleoli, and interacts with p53.^[4] It modulates p53 function, and inhibits cell growth in the Ras/Raf signaling pathway.^[3] IFI16 has been shown to play a role in the sensing of intracellular DNA^[5] - a hallmark of virally infected cells - and has also been linked to the death of HIV-infected helper CD4 T cells by pyroptosis, a highly inflammatory form of programmed cell death.^{[6] [7]} Recently, it has been shown how IFI16, once extracellularly released, can induce inflammation upon TLR4 binding, acting as a DAMP.^[8]

Further reading

• Dawson MJ, Trapani JA . IFI 16 gene encodes a nuclear protein whose expression is induced by interferons in human myeloid leukaemia cell lines . Journal of Cellular Biochemistry . 57 . 1 . 39–51 . January 1995 . 7536752 . 10.1002/jcb.240570106 . 3007802 .
• Dawson MJ, Trapani JA, Briggs RC, Nicholl JK, Sutherland GR, Baker E . The closely linked genes encoding the myeloid nuclear differentiation antigen (MNDA) and IFI16 exhibit contrasting haemopoietic expression . Immunogenetics . 41 . 1 . 40–43 . 1995 . 7806273 . 10.1007/BF00188431 . 12788123 .
• Johnstone RW, Kerry JA, Trapani JA . The human interferon-inducible protein, IFI 16, is a repressor of transcription . The Journal of Biological Chemistry . 273 . 27 . 17172–17177 . July 1998 . 9642285 . 10.1074/jbc.273.27.17172 . free .
• Johnstone RW, Kershaw MH, Trapani JA . Isotypic variants of the interferon-inducible transcriptional repressor IFI 16 arise through differential mRNA splicing . Biochemistry . 37 . 34 . 11924–11931 . August 1998 . 9718316 . 10.1021/bi981069a .
• Dawson MJ, Elwood NJ, Johnstone RW, Trapani JA . The IFN-inducible nucleoprotein IFI 16 is expressed in cells of the monocyte lineage, but is rapidly and markedly down-regulated in other myeloid precursor populations . Journal of Leukocyte Biology . 64 . 4 . 546–554 . October 1998 . 9766636 . 10.1002/jlb.64.4.546 . 40241172 .
• Briggs LJ, Johnstone RW, Elliot RM, Xiao CY, Dawson M, Trapani JA, Jans DA . Novel properties of the protein kinase CK2-site-regulated nuclear- localization sequence of the interferon-induced nuclear factor IFI 16 . The Biochemical Journal . 353 . Pt 1 . 69–77 . January 2001 . 11115400 . 1221544 . 10.1042/0264-6021:3530069 .
• Johnstone RW, Wei W, Greenway A, Trapani JA . Functional interaction between p53 and the interferon-inducible nucleoprotein IFI 16 . Oncogene . 19 . 52 . 6033–6042 . December 2000 . 11146555 . 10.1038/sj.onc.1204005 . 13273815 .
• Gariglio M, Azzimonti B, Pagano M, Palestro G, De Andrea M, Valente G, Voglino G, Navino L, Landolfo S . Immunohistochemical expression analysis of the human interferon-inducible gene IFI16, a member of the HIN200 family, not restricted to hematopoietic cells . Journal of Interferon & Cytokine Research . 22 . 7 . 815–821 . July 2002 . 12184920 . 10.1089/107999002320271413 . free . 2318/39497 .
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16899–16903 . December 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . free . 2002PNAS...9916899M .
• Izmailova E, Bertley FM, Huang Q, Makori N, Miller CJ, Young RA, Aldovini A . HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages . Nature Medicine . 9 . 2 . 191–197 . February 2003 . 12539042 . 10.1038/nm822 . 26145639 .
• Clarke CJ, Apostolidis V, Hii LL, Gough DJ, Trapani JA, Johnstone RW . Critical role of the transcription factor AP-1 for the constitutive and interferon-induced expression of IFI 16 . Journal of Cellular Biochemistry . 89 . 1 . 80–93 . May 2003 . 12682910 . 10.1002/jcb.10475 . 32678644 .
• Xin H, Curry J, Johnstone RW, Nickoloff BJ, Choubey D . Role of IFI 16, a member of the interferon-inducible p200-protein family, in prostate epithelial cellular senescence . Oncogene . 22 . 31 . 4831–4840 . July 2003 . 12894224 . 10.1038/sj.onc.1206754 . 21949316 .
• Kwak JC, Ongusaha PP, Ouchi T, Lee SW . IFI16 as a negative regulator in the regulation of p53 and p21(Waf1) . The Journal of Biological Chemistry . 278 . 42 . 40899–40904 . October 2003 . 12925527 . 10.1074/jbc.M308012200 . free .
• Aglipay JA, Lee SW, Okada S, Fujiuchi N, Ohtsuka T, Kwak JC, Wang Y, Johnstone RW, Deng C, Qin J, Ouchi T . A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway . Oncogene . 22 . 55 . 8931–8938 . December 2003 . 14654789 . 10.1038/sj.onc.1207057 . free .
• Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nature Genetics . 36 . 1 . 40–45 . January 2004 . 14702039 . 10.1038/ng1285 . free .
• Raffaella R, Gioia D, De Andrea M, Cappello P, Giovarelli M, Marconi P, Manservigi R, Gariglio M, Landolfo S . The interferon-inducible IFI16 gene inhibits tube morphogenesis and proliferation of primary, but not HPV16 E6/E7-immortalized human endothelial cells . Experimental Cell Research . 293 . 2 . 331–345 . February 2004 . 14729471 . 10.1016/j.yexcr.2003.10.014 . free . 2318/42932 .
• Fujiuchi N, Aglipay JA, Ohtsuka T, Maehara N, Sahin F, Su GH, Lee SW, Ouchi T . Requirement of IFI16 for the maximal activation of p53 induced by ionizing radiation . The Journal of Biological Chemistry . 279 . 19 . 20339–20344 . May 2004 . 14990579 . 10.1074/jbc.M400344200 . free .
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proceedings of the National Academy of Sciences of the United States of America . 101 . 33 . 12130–12135 . August 2004 . 15302935 . 514446 . 10.1073/pnas.0404720101 . free . 2004PNAS..10112130B .

Notes and References

1. Trapani JA, Browne KA, Dawson MJ, Ramsay RG, Eddy RL, Show TB, White PC, Dupont B . A novel gene constitutively expressed in human lymphoid cells is inducible with interferon-gamma in myeloid cells . Immunogenetics . 36 . 6 . 369–376 . Oct 1992 . 1526658 . 10.1007/bf00218044 . 1196925 .
2. Trapani JA, Dawson M, Apostolidis VA, Browne KA . Genomic organization of IFI16, an interferon-inducible gene whose expression is associated with human myeloid cell differentiation: correlation of predicted protein domains with exon organization . Immunogenetics . 40 . 6 . 415–424 . Dec 1994 . 7959953 . 10.1007/bf00177824 . 2602156 .
3. Web site: Entrez Gene: IFI16 interferon, gamma-inducible protein 16.
4. Ouchi M, Ouchi T . Role of IFI16 in DNA damage and checkpoint . Frontiers in Bioscience . 13 . 13 . 236–239 . January 2008 . 17981541 . 10.2741/2673 . free .
5. Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB, Sharma S, Sirois CM, Jin T, Latz E, Xiao TS, Fitzgerald KA, Paludan SR, Bowie AG . IFI16 is an innate immune sensor for intracellular DNA . Nature Immunology . 11 . 11 . 997–1004 . November 2010 . 20890285 . 3142795 . 10.1038/ni.1932 .
6. Monroe KM, Yang Z, Johnson JR, Geng X, Doitsh G, Krogan NJ, Greene WC . IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV . Science . 343 . 6169 . 428–432 . January 2014 . 24356113 . 3976200 . 10.1126/science.1243640 . 2014Sci...343..428M .
7. Doitsh G, Galloway NL, Geng X, Yang Z, Monroe KM, Zepeda O, Hunt PW, Hatano H, Sowinski S, Muñoz-Arias I, Greene WC . Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection . Nature . 505 . 7484 . 509–514 . January 2014 . 24356306 . 4047036 . 10.1038/nature12940 . 2014Natur.505..509D .
8. Iannucci A, Caneparo V, Raviola S, Debernardi I, Colangelo D, et al. (2020) Toll-like receptor 4-mediated inflammation triggered by extracellular IFI16 is enhanced by lipopolysaccharide binding. PLOS Pathogens 16(9): e1008811. https://doi.org/10.1371/journal.ppat.1008811