| Structural highlights
Function
[IF16_HUMAN] Binds double-stranded DNA. Binds preferentially to supercoiled DNA and cruciform DNA structures. Seems to be involved in transcriptional regulation. May function as a transcriptional repressor. Could have a role in the regulation of hematopoietic differentiation through activation of unknown target genes. Controls cellular proliferation by modulating the functions of cell cycle regulatory factors including p53/TP53 and the retinoblastoma protein. May be involved in TP53-mediated transcriptional activation by enhancing TP53 sequence-specific DNA binding and modulating TP53 phosphorylation status. Seems to be involved in energy-level-dependent activation of the ATM/ AMPK/TP53 pathway coupled to regulation of autophagy. May be involved in regulation of TP53-mediated cell death also involving BRCA1. May be involved in the senescence of prostate epithelial cells. Involved in innate immune response by recognizing viral dsDNA in the cytosol and probably in the nucleus. After binding to viral DNA in the cytoplasm recruits TMEM173/STING and mediates the induction of IFN-beta. Has anti-inflammatory activity and inhibits the activation of the AIM2 inflammasome, probably via association with AIM2. Proposed to bind viral DNA in the nucleus, such as of Kaposi's sarcoma-associated herpesvirus, and to induce the formation of nuclear caspase-1-activating inflammasome formation via association with PYCARD. Inhibits replication of herpesviruses such as human cytomegalovirus (HCMV) probably by interfering with promoter recruitment of members of the Sp1 family of transcription factors.[1] [2] [3] [4] [5] [6] [7] [8] [9]
Publication Abstract from PubMed
Recognition of DNA by the innate immune system is central to antiviral and antibacterial defenses, as well as an important contributor to autoimmune diseases involving self DNA. AIM2 (absent in melanoma 2) and IFI16 (interferon-inducible protein 16) have been identified as DNA receptors that induce inflammasome formation and interferon production, respectively. Here we present the crystal structures of their HIN domains in complex with double-stranded (ds) DNA. Non-sequence-specific DNA recognition is accomplished through electrostatic attraction between the positively charged HIN domain residues and the dsDNA sugar-phosphate backbone. An intramolecular complex of the AIM2 Pyrin and HIN domains in an autoinhibited state is liberated by DNA binding, which may facilitate the assembly of inflammasomes along the DNA staircase. These findings provide mechanistic insights into dsDNA as the activation trigger and oligomerization platform for the assembly of large innate signaling complexes such as the inflammasomes.
Structures of the HIN Domain:DNA Complexes Reveal Ligand Binding and Activation Mechanisms of the AIM2 Inflammasome and IFI16 Receptor.,Jin T, Perry A, Jiang J, Smith P, Curry JA, Unterholzner L, Jiang Z, Horvath G, Rathinam VA, Johnstone RW, Hornung V, Latz E, Bowie AG, Fitzgerald KA, Xiao TS Immunity. 2012 Apr 20;36(4):561-71. Epub 2012 Apr 5. PMID:22483801[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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. 2003 Jul 31;22(31):4831-40. PMID:12894224 doi:http://dx.doi.org/10.1038/sj.onc.1206754
- ↑ Johnstone RW, Kerry JA, Trapani JA. The human interferon-inducible protein, IFI 16, is a repressor of transcription. J Biol Chem. 1998 Jul 3;273(27):17172-7. PMID:9642285
- ↑ Johnstone RW, Wei W, Greenway A, Trapani JA. Functional interaction between p53 and the interferon-inducible nucleoprotein IFI 16. Oncogene. 2000 Dec 7;19(52):6033-42. PMID:11146555 doi:http://dx.doi.org/10.1038/sj.onc.1204005
- ↑ 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. 2003 Dec 4;22(55):8931-8. PMID:14654789 doi:http://dx.doi.org/10.1038/sj.onc.1207057
- ↑ 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. Nat Immunol. 2010 Nov;11(11):997-1004. doi: 10.1038/ni.1932. Epub 2010 Oct 3. PMID:20890285 doi:http://dx.doi.org/10.1038/ni.1932
- ↑ Kerur N, Veettil MV, 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. 2011 May 19;9(5):363-75. doi: 10.1016/j.chom.2011.04.008. PMID:21575908 doi:http://dx.doi.org/10.1016/j.chom.2011.04.008
- ↑ Duan X, Ponomareva L, Veeranki S, Choubey D. IFI16 induction by glucose restriction in human fibroblasts contributes to autophagy through activation of the ATM/AMPK/p53 pathway. PLoS One. 2011 May 5;6(5):e19532. doi: 10.1371/journal.pone.0019532. PMID:21573174 doi:http://dx.doi.org/10.1371/journal.pone.0019532
- ↑ Veeranki S, Duan X, Panchanathan R, Liu H, Choubey D. IFI16 protein mediates the anti-inflammatory actions of the type-I interferons through suppression of activation of caspase-1 by inflammasomes. PLoS One. 2011;6(10):e27040. doi: 10.1371/journal.pone.0027040. Epub 2011 Oct 28. PMID:22046441 doi:http://dx.doi.org/10.1371/journal.pone.0027040
- ↑ Gariano GR, Dell'Oste V, Bronzini M, Gatti D, Luganini A, De Andrea M, Gribaudo G, Gariglio M, Landolfo S. The intracellular DNA sensor IFI16 gene acts as restriction factor for human cytomegalovirus replication. PLoS Pathog. 2012 Jan;8(1):e1002498. doi: 10.1371/journal.ppat.1002498. Epub 2012, Jan 26. PMID:22291595 doi:http://dx.doi.org/10.1371/journal.ppat.1002498
- ↑ Jin T, Perry A, Jiang J, Smith P, Curry JA, Unterholzner L, Jiang Z, Horvath G, Rathinam VA, Johnstone RW, Hornung V, Latz E, Bowie AG, Fitzgerald KA, Xiao TS. Structures of the HIN Domain:DNA Complexes Reveal Ligand Binding and Activation Mechanisms of the AIM2 Inflammasome and IFI16 Receptor. Immunity. 2012 Apr 20;36(4):561-71. Epub 2012 Apr 5. PMID:22483801 doi:10.1016/j.immuni.2012.02.014
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