| 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
Interferon gamma-inducible protein 16 (IFI16) senses DNA in the cytoplasm and the nucleus by using two tandem hematopoietic interferon-inducible nuclear (HIN) domains, HINa and HINb, through the cooperative assembly of IFI16 filaments on double-stranded DNA (dsDNA). The role of HINa in sensing DNA is not clearly understood. Here, we describe the crystal structure of the HINa domain in complex with DNA at 2.55 A resolution and provide the first insight into the mode of DNA binding by the HINa domain. The structure reveals the presence of two oligosaccharide/nucleotide-binding (OB) folds with a unique DNA-binding surface. HINa uses loop L45 of the canonical OB2 fold to bind to the DNA backbone. The dsDNA is recognized as two single strands of DNA. Interestingly, deletion of HINb compromises the ability of IFI16 to induce IFN-beta, while HINa mutants impaired in DNA binding enhance the production of IFN-beta. These results shed light on the roles of IFI16 HIN domains in DNA recognition and innate immune responses.
New insights into the structural basis of DNA recognition by HINa and HINb domains of IFI16.,Ni X, Ru H, Ma F, Zhao L, Shaw N, Feng Y, Ding W, Gong W, Wang Q, Ouyang S, Cheng G, Liu ZJ J Mol Cell Biol. 2016 Feb;8(1):51-61. doi: 10.1093/jmcb/mjv053. Epub 2015 Aug 5. PMID:26246511[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
- ↑ Ni X, Ru H, Ma F, Zhao L, Shaw N, Feng Y, Ding W, Gong W, Wang Q, Ouyang S, Cheng G, Liu ZJ. New insights into the structural basis of DNA recognition by HINa and HINb domains of IFI16. J Mol Cell Biol. 2016 Feb;8(1):51-61. doi: 10.1093/jmcb/mjv053. Epub 2015 Aug 5. PMID:26246511 doi:http://dx.doi.org/10.1093/jmcb/mjv053
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