{"gene":"IFI16","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2010,"finding":"IFI16 directly associates with IFN-β-inducing viral DNA motifs and acts as an intracellular DNA sensor that mediates IFN-β induction; after DNA stimulation, STING is recruited to IFI16, and knockdown of IFI16 or its mouse ortholog p204 inhibits IRF3 and NF-κB activation induced by DNA and HSV-1.","method":"RNA interference knockdown, co-immunoprecipitation, DNA-binding assays, IRF3/NF-κB activation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, siRNA knockdown with defined signaling phenotypes, replicated across multiple labs subsequently","pmids":["20890285"],"is_preprint":false},{"year":2012,"finding":"Crystal structures of IFI16 HIN domains in complex with dsDNA reveal that non-sequence-specific DNA recognition is accomplished through electrostatic attraction between positively charged HIN domain residues and the dsDNA sugar-phosphate backbone; an autoinhibited intramolecular AIM2 Pyrin-HIN complex is liberated by DNA binding.","method":"X-ray crystallography, structural analysis of HIN-DNA complexes","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, foundational structural paper","pmids":["22483801"],"is_preprint":false},{"year":2012,"finding":"IFI16 is predominantly nuclear, detects HSV-1 DNA primarily in the nucleus requiring a functional nuclear localization signal (NLS), and mediates IFN-β induction in a localization-dependent manner. Acetylation of the NLS by acetyltransferase p300 inhibits nuclear import and promotes cytoplasmic localization of IFI16.","method":"FISH, immunopurification, mutagenesis of NLS, nuclear import assays, combinatorial mass spectrometry for acetylation/phosphorylation sites, deacetylase inhibition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, MS, and functional import assays in one rigorous study","pmids":["22691496"],"is_preprint":false},{"year":2012,"finding":"HSV-1 ICP0, an E3 ubiquitin ligase expressed in the nucleus, causes nuclear relocalization and proteasomal degradation of IFI16, thereby inhibiting IFI16-dependent IRF-3 signaling. Nuclear IFI16 senses HSV-1 DNA upon its release from incoming capsids, and an unknown factor must be exported from the nucleus to activate IRF-3 through cytoplasmic STING.","method":"siRNA knockdown, inhibition of viral DNA release, immunofluorescence localization, infection with ICP0-expressing virus","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological dissection of nuclear sensing pathway, replicated by multiple subsequent studies","pmids":["23027953"],"is_preprint":false},{"year":2012,"finding":"IFI16 acts as a restriction factor for HCMV replication by blocking Sp1-like factor binding to the HCMV DNA polymerase (UL54) promoter via an inverted repeat element (IR-1), as demonstrated by EMSA and chromatin immunoprecipitation; a dominant-negative IFI16 lacking the PYRIN domain enhanced HCMV replication.","method":"siRNA knockdown, dominant-negative overexpression, EMSA, ChIP, luciferase reporter with deleted/mutated promoter constructs","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — EMSA, ChIP, and mutagenesis in one study with multiple orthogonal methods","pmids":["22291595"],"is_preprint":false},{"year":2013,"finding":"IFI16 cooperatively assembles into filaments on dsDNA in a length-dependent manner; the pyrin domain (not the HIN DNA-binding domains) drives cooperative filament assembly, while isolated HIN domains engage dsDNA without forming filaments and with weak affinity.","method":"Quantitative dsDNA binding assays, electron microscopy, domain deletion/isolation experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with EM and quantitative binding assays, mechanistic domain dissection","pmids":["24367117"],"is_preprint":false},{"year":2013,"finding":"The HCMV tegument protein pUL83 inhibits IFI16-mediated nuclear DNA sensing by interacting with the IFI16 pyrin domain, blocking IFI16 oligomerization upon DNA sensing. pUL83 uses a conserved N-terminal pyrin association domain (PAD) to bind IFI16, and phosphorylation of pUL83's N-terminal domain modulates this inhibition.","method":"Co-immunoprecipitation, binding domain mapping, mutagenesis, oligomerization assays, cytokine expression assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic domain mapping with multiple orthogonal methods, functionally validated","pmids":["24237704"],"is_preprint":false},{"year":2013,"finding":"IFI16 is required for pyroptotic death of CD4 T cells abortively infected with HIV; cytosolic incomplete HIV reverse transcripts are sensed by IFI16, triggering caspase-1 activation and pyroptosis.","method":"Unbiased proteomics, targeted biochemical approaches, lentiviral shRNA knockdown in primary CD4 T cells, caspase-1 activation assay","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent shRNA methods, proteomics identification, defined functional readout (caspase-1, pyroptosis)","pmids":["24356113"],"is_preprint":false},{"year":2013,"finding":"IFI16 senses ssDNA forms produced during lentiviral replication (including HIV-1 proviral ssDNA) in human macrophages, directly binds immunostimulatory DNA, and activates the STING-TBK1-IRF3/7 pathway; IFI16 knockdown augmented lentiviral transduction and HIV-1 replication.","method":"Direct DNA binding assay, siRNA knockdown, colocalization/co-immunoprecipitation of IFI16 with lentiviral DNA, IFN induction assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding, colocalization, and functional knockdown with defined pathway activation","pmids":["24154727"],"is_preprint":false},{"year":2013,"finding":"During HSV-1 infection, nuclear IFI16 recognizes viral genomes and relocates to form an IFI16-ASC-procaspase-1 inflammasome in the cytoplasm, leading to IL-1β production. Independently, IFI16 interacts with cytoplasmic STING to induce IFN-β production via IRF-3 phosphorylation. HSV-1 targets IFI16 for proteasomal degradation via ICP0 at later times post-infection.","method":"Immunofluorescence colocalization, co-immunoprecipitation, inflammasome activation assays, IL-1β secretion, IFN-β assays, Western blotting of ICP0-dependent degradation","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, two distinct downstream pathway characterizations, consistent with other studies","pmids":["23427152"],"is_preprint":false},{"year":2014,"finding":"IFI16 and cGAS are both required for IFN production during HSV-1 infection in human fibroblasts; cGAS is partially nuclear and interacts with IFI16, promoting IFI16 protein stability rather than primarily producing cGAMP in infected cells.","method":"siRNA depletion of IFI16 and cGAS, co-immunoprecipitation, cGAMP measurement, IFI16 stability assays, viral DNA association assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic dissection with reciprocal depletion, interaction and stability assays, multiple methods","pmids":["25831530"],"is_preprint":false},{"year":2014,"finding":"IFI16-dependent IFNβ expression during Listeria monocytogenes infection in human macrophages is triggered by bacterial DNA (not cyclic-di-AMP) via a pathway requiring both IFI16 and cGAS as well as STING.","method":"siRNA knockdown of IFI16, cGAS, and STING; IFNβ induction assays; stimulation with bacterial DNA vs. cyclic-di-AMP","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with defined readouts, single lab","pmids":["24970844"],"is_preprint":false},{"year":2015,"finding":"Recognition of herpesviral genomes in the nucleus by IFI16 leads to its interaction with histone acetyltransferase p300 and IFI16 acetylation, resulting in IFI16-ASC inflammasome assembly, increased interaction with Ran-GTPase, cytoplasmic redistribution, caspase-1 activation, IL-1β production, and IFI16-STING interaction leading to IFN-β production. Acetylation is not required for sensing viral genomes but is required for downstream responses.","method":"Co-immunoprecipitation, proximity ligation microscopy, ChIP, acetylation inhibition, siRNA knockdown of ASC/STING, caspase-1 and IL-1β assays, IRF-3 phosphorylation assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, mechanistic ordering of events established by perturbation experiments","pmids":["26134128"],"is_preprint":false},{"year":2015,"finding":"BRCA1 forms a complex with IFI16 in the nucleus that is required for IFI16's association with viral genomes; absence of BRCA1 abrogates IFI16-viral genome association, inflammasome assembly, cytoplasmic localization, caspase-1/IL-1β production, and IFI16-STING interaction and IFN-β production during herpesviral infection.","method":"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown of BRCA1, inflammasome and IFN-β assays, de novo viral infection models","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, genetic knockdown with multiple functional readouts, multiple viruses tested","pmids":["26121674"],"is_preprint":false},{"year":2015,"finding":"IFI16 restricts HPV18 replication through epigenetic modifications: IFI16 promotes deposition of heterochromatin marks (H3K9me2/me3) and reduction of euchromatin marks on viral chromatin at both early and late HPV18 promoters, thereby reducing viral replication and transcription.","method":"siRNA knockdown, AdV-IFI16 overexpression, viral load measurement, viral gene expression analysis, ChIP for histone marks","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP for histone marks, gain- and loss-of-function, two cellular models","pmids":["25972554"],"is_preprint":false},{"year":2015,"finding":"IFI16 interacts with histone H2B in the nucleus; herpesviral genome sensing by an IFI16-H2B-BRCA1 complex triggers p300-dependent acetylation of both H2B and IFI16, Ran-GTP-mediated cytoplasmic translocation of this complex, and subsequent interaction with cGAS and STING leading to TBK1/IRF3 phosphorylation and IFN-β production. A separate IFI16-BRCA1-ASC-procaspase-1 complex mediates inflammasome/IL-1β responses.","method":"Mass spectrometry, co-immunoprecipitation, proximity ligation microscopy, EdU-labeled virus genome ChIP, siRNA knockdown of H2B/cGAS/STING/ASC","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — mass spectrometry identification, multiple co-IP validations, genetic dissection of two parallel IFI16 complexes","pmids":["27764250"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of IFI16 HINa domain in complex with DNA at 2.55 Å reveals two OB folds with a unique DNA-binding surface; HINa uses loop L45 of the OB2 fold to bind to the DNA backbone, recognizing dsDNA as two single strands. Deletion of HINb compromises IFN-β induction, while HINa mutants impaired in DNA binding enhance IFN-β production.","method":"X-ray crystallography, domain deletion/mutagenesis, IFN-β induction assays","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional mutagenesis, single lab","pmids":["26246511"],"is_preprint":false},{"year":2016,"finding":"IFI16 maintains KSHV latency by binding to lytic gene promoters and acting as a transcriptional repressor; IFI16 knockdown induces KSHV lytic reactivation. During lytic cycle, IFI16 is polyubiquitinated and degraded via the proteasomal pathway by a late lytic KSHV gene product.","method":"siRNA knockdown, IFI16 overexpression, ChIP of KSHV promoters, luciferase reporter assays, ubiquitination assays, phosphonoacetic acid blockade of DNA replication","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP with promoter reporters, gain/loss of function, mechanistic dissection of degradation","pmids":["27466416"],"is_preprint":false},{"year":2017,"finding":"In human keratinocytes, IFI16 cooperates with cGAS during DNA sensing; both are required for full innate immune activation. IFI16 is required for cGAMP-induced activation of STING, and interacts with STING to promote STING phosphorylation and translocation.","method":"siRNA knockdown of cGAS and IFI16, cGAMP stimulation, co-immunoprecipitation of IFI16-STING, STING phosphorylation and translocation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis, co-IP, defined biochemical readouts, two cooperating sensors mechanistically placed","pmids":["28194029"],"is_preprint":false},{"year":2017,"finding":"In human macrophages, IFI16 functions at two levels in the cGAS-STING pathway: IFI16 depletion impairs cGAMP production upon DNA stimulation (acting upstream of or alongside cGAS), and IFI16 is vital for downstream STING signaling by facilitating recruitment and activation of TBK1 in the STING complex.","method":"siRNA depletion, cGAMP measurement, TBK1 recruitment assays, IFI16 overexpression with cGAS","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — two distinct functional levels established, genetic and biochemical methods, independently replicated findings","pmids":["28186168"],"is_preprint":false},{"year":2018,"finding":"IFI16, together with DNA damage response factors ATM and PARP-1, mediates non-canonical STING activation (independent of cGAS) following nuclear DNA damage; this results in assembly of an alternative STING signaling complex including p53 and the E3 ubiquitin ligase TRAF6. TRAF6 catalyzes K63-linked ubiquitin chains on STING, activating NF-κB.","method":"Co-immunoprecipitation, siRNA knockdown of IFI16/ATM/PARP-1/cGAS, ubiquitination assays, NF-κB activation assays, gene expression analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and biochemical approaches, defined complex assembly and ubiquitination mechanism","pmids":["30193098"],"is_preprint":false},{"year":2019,"finding":"IFI16 restricts HIV-1 independently of immune DNA sensing by binding and inhibiting the host transcription factor Sp1 that drives viral gene expression; this activity requires the N-terminal pyrin domain and nuclear localization, but not the HIN domains. IFI16 also inhibits LINE-1 retrotransposition in a Sp1-dependent manner.","method":"IFI16-Sp1 binding assays, pyrin domain and HIN domain mutants, HIV-1 transcription assays, HIV-1 latency reactivation assays, LINE-1 retrotransposition assay","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-specific mutants, direct binding, multiple functional readouts, mechanistic dissection of DNA-sensing-independent function","pmids":["31175045"],"is_preprint":false},{"year":2019,"finding":"STING directly interacts with IFI16 and facilitates IFI16 degradation via the ubiquitin-proteasome pathway by recruiting E3 ligase TRIM21; the pyrin region of IFI16 mediates the IFI16-STING interaction, and lysines K3/4/6 in the N-terminal region of IFI16 are key ubiquitination sites. IFI16-K3/4/6R mutant resistant to degradation shows enhanced IFN-β and antiviral gene expression.","method":"Co-immunoprecipitation, ubiquitination assays, domain mapping, IFI16 degradation-resistant mutant (K3/4/6R), IFN-β induction assays, HSV-1 infection","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of ubiquitination sites, co-IP with TRIM21/STING, functionally validated with degradation-resistant mutant","pmids":["31665637"],"is_preprint":false},{"year":2019,"finding":"IFI16 is in complex with H3K9 methyltransferases SUV39H1 and GLP; IFI16 recruits them to the KSHV genome during de novo infection and latency, resulting in H3K9me2/me3 deposition that serves as a docking site for HP1α, leading to epigenetic silencing of KSHV lytic genes.","method":"Co-immunoprecipitation of IFI16 with SUV39H1 and GLP, ChIP for H3K9me2/me3 and HP1α on KSHV genome, IFI16 knockdown","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, ChIP with functional readouts, mechanistic pathway established","pmids":["31682228"],"is_preprint":false},{"year":2019,"finding":"IFI16 oligomerization is mediated by charge-dependent interactions at specific pyrin domain residues; oligomerization is necessary for IFI16 assembly onto parental HSV-1 viral genomes at the nuclear periphery, for antiviral cytokine induction, suppression of viral proteins, and restriction of viral progeny. Oligomerization promotes interactions with transcriptional regulatory proteins including PAF1C, UBTF, and ND10 bodies.","method":"Structural modeling, mutagenesis of oligomerization-deficient PYD residues, charge mimics, immunoaffinity purification, targeted mass spectrometry, CRISPR/Cas9, confocal microscopy","journal":"mBio","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis, structural modeling, proteomics, multiple functional readouts, rigorous controls","pmids":["31337724"],"is_preprint":false},{"year":2019,"finding":"IFI16 forms filamentous nuclear structures on viral DNA within HSV-1 replication compartments; these filaments recruit PML, Sp100, and ATRX as co-restriction factors and reduce elongation-competent RNA Pol II in replication compartments, constituting a nuclear 'restrictosome' that silences progeny viral DNA.","method":"Structured illumination microscopy, immunofluorescence, correlation of filament formation with restriction efficiency, RNA Pol II ChIP-like assays","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structured illumination microscopy, single lab, correlative evidence for restrictosome function","pmids":["30670617"],"is_preprint":false},{"year":2021,"finding":"IFI16 directly binds influenza viral RNA via its HINa domain and interacts with RIG-I protein via its PYRIN domain, promoting K63-linked polyubiquitination and RIG-I activation. IFI16 also positively upregulates RIG-I transcription by direct binding to and recruitment of RNA polymerase II to the RIG-I promoter.","method":"IFI16 knockout cells, p204-deficient mice, RNA binding assays with HINa domain, co-immunoprecipitation of IFI16-RIG-I, RIG-I ubiquitination assays, ChIP for RNA Pol II at RIG-I promoter","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-specific binding assays, ChIP, ubiquitination, KO mouse model, multiple orthogonal methods","pmids":["33986530"],"is_preprint":false},{"year":2021,"finding":"IFI16 accumulates at double-strand break (DSB) sites where it inhibits recruitment of DNA damage response (DDR) factors, increases cytoplasmic DNA fragment release, and induces STING-mediated type I IFN production; IFI16 depletion reduces doxorubicin-induced STING signaling and antitumor immunity in TNBC.","method":"IFI16 depletion, immunofluorescence at DSB sites, DDR factor recruitment assays, cytoplasmic DNA quantification, STING pathway activation assays, in vivo tumor model","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays at DSB sites, in vivo validation, single lab","pmids":["34936865"],"is_preprint":false},{"year":2021,"finding":"IFI16 undergoes phase separation (liquid-liquid phase separation, LLPS) nucleated by viral DNA binding; multiple phosphorylation sites within an intrinsically disordered region (IDR), regulated by CDK2 and GSK3β, act combinatorially to activate IFI16 LLPS and facilitate filamentation. IDR phosphorylation provides a toggle between active and inactive IFI16, decoupling cytokine expression from repression of viral transcription.","method":"In vitro LLPS reconstitution, in vivo LLPS assays, phosphorylation site mutagenesis, CDK2/GSK3β kinase assays, HSV-1 infection models, cytokine and viral transcription readouts","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of LLPS, mutagenesis, kinase identification, multiple orthogonal methods","pmids":["37283074"],"is_preprint":false},{"year":2021,"finding":"DNA-dependent protein kinase (DNA-PK) is recruited to IFI16 at incoming viral DNA at the nuclear periphery during HSV-1 infection; DNA-PK phosphorylates IFI16 at T149, and this phosphorylation promotes IFI16-driven cytokine responses.","method":"Thermal proximity coaggregation (TPCA) mass spectrometry, time-resolved PPI mapping, IFI16 T149 phosphorylation validation, cytokine response assays upon DNA damage and viral infection","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — novel TPCA proteomics, site-specific phosphorylation validated, functional readout, rigorous study","pmids":["34144993"],"is_preprint":false},{"year":2022,"finding":"IFI16 interacts with KAP1 (KRAB-associated protein 1) and the site-specific DNA binding KRAB-ZFP SZF1 to form a partnership with the constitutive heterochromatin machinery; this complex silences the EBV lytic switch protein ZEBRA (BZLF1 gene) and contributes to H3K9 trimethylation at EBV lytic genes, maintaining EBV latency.","method":"Co-immunoprecipitation of IFI16-KAP1-SZF1, ChIP for IFI16 and KAP1 at BZLF1 promoter, H3K9me3 ChIP, IFI16 knockdown with lytic gene induction readouts","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, ChIP at defined loci, functional genetic dissection, mechanistic pathway defined","pmids":["35969079"],"is_preprint":false},{"year":2022,"finding":"IFI16 binds the HSV-1 genome in a sequence-independent manner with broad enrichment at UL30 (viral DNA polymerase) and US1-US7 loci; IFI16 binding globally induces chromatinization (reduced accessibility) of HSV-1 DNA genome and decreases global HSV-1 protein expression.","method":"ChIP-seq, ATAC-seq, parallel reaction monitoring mass spectrometry of viral proteins, IFI16 knockout cells","journal":"mSystems","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP-seq, ATAC-seq, and proteomics combined, KO validation, comprehensive genome-wide analysis","pmids":["35575489"],"is_preprint":false},{"year":2003,"finding":"IFI16 interacts with BRCA1 (aa 502–802) through its Pyrin domain (aa 1–130); coexpression of IFI16 and BRCA1 enhanced DNA damage-induced apoptosis in mouse embryonic fibroblasts, and a mutant IFI16 deficient in BRCA1 binding did not induce apoptosis. IFI16 is localized in the nucleoplasm and nucleoli, and BRCA1 is required for its nucleolar localization following ionizing radiation.","method":"Co-immunoprecipitation, domain mapping, apoptosis assays, adenovirus-mediated expression, immunocytochemistry","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping, functional apoptosis assay, single lab","pmids":["14654789"],"is_preprint":false},{"year":2003,"finding":"siRNA-mediated reduction of IFI16 expression induces p21Waf1 mRNA and protein through p53 activation and causes cell cycle arrest with reduced phosphorylated Rb; IFI16 negatively regulates p53 protein stability and transcriptional activity at the p21 promoter in normally growing cells.","method":"siRNA knockdown, p21 expression assays, promoter-reporter assays, cell cycle analysis, Rb phosphorylation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined molecular readouts, single lab","pmids":["12925527"],"is_preprint":false},{"year":2008,"finding":"The IFI16 HIN200 domain has RPA-like OB-fold nucleic acid binding properties: it binds ssDNA with higher affinity than dsDNA, recognizes ssDNA in the same orientation as RPA, oligomerizes upon ssDNA binding, wraps and stretches ssDNA, but does not destabilize dsDNA.","method":"Structural modeling (fold recognition), biophysical binding assays, ssDNA orientation assays, oligomerization assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — biophysical validation of RPA-like binding, structural modeling, but single lab and no in-cell functional validation","pmids":["18472023"],"is_preprint":false},{"year":2011,"finding":"Increased IFI16 expression inhibits activation of caspase-1 by the AIM2-ASC inflammasome; IFI16 and AIM2 can heterodimerize, and knockdown of IFI16 increases basal and induced activation of AIM2 and NLRP3 inflammasomes in THP-1 cells.","method":"HEK-293 overexpression with caspase-1 assay, siRNA knockdown in THP-1, inflammasome activation assays with poly(dA:dT) and alum","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function with defined caspase-1 readout, single lab","pmids":["22046441"],"is_preprint":false},{"year":2018,"finding":"A novel transcript isoform of IFI16 (IFI16-β), lacking the pyrin domain but containing two HIN domains, is predominantly cytoplasmic and inhibits AIM2 inflammasome activation by interacting with AIM2 to impede AIM2-ASC complex formation and by sequestering cytoplasmic dsDNA.","method":"IFI16-β identification/cloning, co-localization assays, co-immunoprecipitation of IFI16-β with AIM2, AIM2-ASC complex formation assays, siRNA knockdown, IL-1β secretion assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — novel isoform characterized with multiple functional assays, mechanistic dissection of AIM2 inhibition","pmids":["30104205"],"is_preprint":false},{"year":2020,"finding":"HPV E7 recruits the E3 ligase TRIM21 to ubiquitinate and degrade the IFI16 inflammasome, inhibiting dsDNA-induced cell pyroptosis and suppressing IL-1β and IL-18 production.","method":"Mass spectrometry, co-immunoprecipitation of HPV E7 with IFI16 and TRIM21, ubiquitination assays, inflammasome activation and pyroptosis assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assays, MS identification, single lab","pmids":["33061806"],"is_preprint":false},{"year":2006,"finding":"Androgen receptor (AR) upregulates IFI16 expression; the IFI16 protein binds to AR in a ligand-dependent manner through AR's DNA-binding domain (DBD). Re-expression of IFI16 in LNCaP cells downregulates AR expression and inhibits AR target gene expression.","method":"Co-immunoprecipitation, domain mapping (DBD sufficiency), IFI16 re-expression, AR and AR target gene expression assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping, gain-of-function with defined readouts, single lab","pmids":["16494870"],"is_preprint":false},{"year":2013,"finding":"Extracellular IFI16 released from apoptotic cells binds to high-affinity sites on the plasma membrane of endothelial cells (Kd ~2.7 nM, ~250,000–450,000 binding sites per cell) via its N-terminal domain, inhibiting tubulogenesis and migration. Anti-IFI16 N-terminal antibodies fully reverse these effects.","method":"Radioiodinated IFI16 binding assays, Scatchard analysis, competition assays, co-culture experiments, endothelial function assays (tubulogenesis, migration), ELISA for circulating IFI16","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative binding characterization, functional assays with antibody blocking, single lab","pmids":["23690979"],"is_preprint":false},{"year":2015,"finding":"Extracellular IFI16 activates p38 MAPK (as an early required step), subsequently activating p44/42 MAP kinases and NF-κB, inducing inflammatory cytokines (IL-6, IL-8, CCL2, CCL5, CCL20) in endothelial cells via a MyD88-dependent TLR pathway; TLR4-neutralizing antibodies partially inhibit this response.","method":"Recombinant IFI16 protein treatment of endothelial cells, p38/MAPK/NF-κB pathway inhibition, MyD88 siRNA knockdown, TLR4 neutralization, cytokine assays","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and antibody-based pathway dissection, single lab","pmids":["25715050"],"is_preprint":false},{"year":2020,"finding":"Extracellular IFI16 binds with high affinity to the lipid A moiety of LPS; IFI16/LPS complexes display faster stimulation turnover on TLR4 than LPS alone, and IFI16 DAMP activity is potentiated by LPS through TLR4-MD2/TIRAP/MyD88-dependent signaling in monocytes and renal cells.","method":"Pull-down, saturation binding experiments, co-immunoprecipitation, surface plasmon resonance (SPR), TLR4 activation assays, cytokine induction","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — SPR for binding kinetics, co-IP, functional inflammatory assays, multiple methods in one study","pmids":["32903274"],"is_preprint":false},{"year":2012,"finding":"IFI16 protein binds strongly to negatively superhelical plasmid DNA at native superhelix density and shows strong preference for cruciform DNA structure compared to linear or relaxed DNA; binding to supercoiled DNA is reversible.","method":"Electrophoretic mobility shift assay (EMSA) with supercoiled vs. linear DNA, oligonucleotide cruciform binding assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding assays, single lab, no in-cell functional validation","pmids":["22618232"],"is_preprint":false},{"year":2016,"finding":"IFI16 shows specific preference for binding to quadruplex DNA with significantly higher affinity than dsDNA or ssDNA; IFI16 stabilizes quadruplex structures from human telomere and MYC promoter sequences. H/D exchange MS shows that quadruplex DNA alters IFI16 deuteration in the PYRIN domain (aa 0–80) and structurally identical parts of both HIN domains.","method":"Circular dichroism spectroscopy, H/D exchange mass spectrometry, DNA binding assays with quadruplex vs. linear DNA","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biophysical assays with CD and MS, but limited in-cell functional validation, single lab","pmids":["27280708"],"is_preprint":false},{"year":2025,"finding":"IFI16 activates HMOX1 transcription by interacting with transcription factors JUND and SP1 through its pyrin domain, inhibiting ferroptosis (reducing lipid peroxidation, ROS, and Fe2+) and enhancing radioresistance in glioblastoma. Glyburide disrupts IFI16 function by targeting its pyrin domain.","method":"Co-immunoprecipitation of IFI16 with JUND and SP1, luciferase reporter assays for HMOX1, ferroptosis assays (lipid peroxidation, ROS, Fe2+ measurements), IFI16 knockdown/overexpression, in vivo xenograft model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of IFI16 with transcription factors, functional ferroptosis assays, single lab","pmids":["39890789"],"is_preprint":false},{"year":2019,"finding":"IFI16 directly senses influenza A viral RNA via its HINa domain; IFI16 knockout cells and p204-deficient mice show reduced IFN-I production and increased IAV replication; IFI16 promotes K63-linked polyubiquitination of RIG-I by binding to RIG-I with its PYRIN domain.","method":"IFI16 KO cells, p204-deficient mice, RNA binding assays with HINa domain, RIG-I ubiquitination assays, co-immunoprecipitation","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-specific RNA binding, mouse KO model, ubiquitination assays, multiple orthogonal methods","pmids":["33986530"],"is_preprint":false}],"current_model":"IFI16 is a nuclear and cytoplasmic innate immune DNA (and RNA) sensor that detects pathogenic dsDNA, ssDNA, and viral RNA via its HIN domains (which bind nucleic acids through OB folds) and signals through the STING-TBK1-IRF3 axis to induce IFN-β, forms inflammasomes (with ASC and procaspase-1) via its pyrin domain to produce IL-1β, cooperatively assembles into filaments on foreign DNA in a pyrin domain-dependent manner, recruits H3K9 methyltransferases (SUV39H1/GLP) to epigenetically silence viral genomes, is regulated by p300-mediated acetylation of its NLS (controlling nuclear/cytoplasmic localization), by STING/TRIM21-mediated ubiquitination and proteasomal degradation, by DNA-PK phosphorylation at T149 (promoting cytokine responses), and by CDK2/GSK3β-regulated phase separation; it also restricts retroviruses independently of DNA sensing by binding Sp1 via its pyrin domain to suppress viral transcription, and when released extracellularly acts as a DAMP by binding TLR4 to propagate inflammation."},"narrative":{"mechanistic_narrative":"IFI16 is a predominantly nuclear innate immune nucleic-acid sensor that detects foreign DNA and signals through the STING-TBK1-IRF3 axis to induce type I interferon while also nucleating inflammasome responses [PMID:20890285, PMID:23427152]. It binds DNA non-sequence-specifically through electrostatic contacts between its HIN-domain OB folds and the dsDNA sugar-phosphate backbone, with DNA binding liberating an autoinhibited intramolecular Pyrin-HIN state [PMID:22483801, PMID:26246511]; the HIN200 module also binds ssDNA with RPA-like properties and IFI16 senses ssDNA and proviral intermediates generated during lentiviral replication [PMID:24154727, PMID:18472023]. The pyrin domain rather than the HIN domains drives cooperative, charge-dependent oligomerization and filament assembly along dsDNA, which is required for genome recognition, antiviral cytokine induction, and viral restriction [PMID:24367117, PMID:31337724], and this assembly is tuned by liquid-liquid phase separation under combinatorial CDK2/GSK3β phosphorylation of an intrinsically disordered region [PMID:37283074]. Upon herpesviral genome sensing in the nucleus, IFI16 acts within a BRCA1- and H2B-containing complex, becomes p300-acetylated, redistributes to the cytoplasm via Ran-GTP, and bifurcates into an IFI16-STING arm driving IFN-β and an IFI16-ASC-procaspase-1 inflammasome arm driving IL-1β [PMID:23427152, PMID:26134128, PMID:26121674, PMID:27764250]. IFI16 functions cooperatively with cGAS at multiple levels of the STING pathway, both promoting cGAMP production and facilitating TBK1 recruitment and STING activation [PMID:25831530, PMID:28194029, PMID:28186168], and mediates non-canonical, cGAS-independent STING activation following nuclear DNA damage through an ATM/PARP-1/p53/TRAF6 complex [PMID:30193098]. Beyond signaling, IFI16 is an intrinsic genome-silencing factor that recruits H3K9 methyltransferases SUV39H1/GLP and the KAP1/SZF1 heterochromatin machinery to deposit H3K9me marks and chromatinize viral genomes, maintaining KSHV and EBV latency and restricting HPV [PMID:25972554, PMID:31682228, PMID:35969079, PMID:35575489], and it restricts HIV-1 and LINE-1 independently of DNA sensing by binding the transcription factor Sp1 through its pyrin domain [PMID:31175045]. IFI16 abundance and localization are controlled by acetylation of its NLS by p300 and by STING/TRIM21-directed ubiquitination and proteasomal degradation [PMID:22691496, PMID:31665637]. When released extracellularly, IFI16 acts as a DAMP, binding TLR4 and LPS to propagate inflammatory cytokine signaling [PMID:25715050, PMID:32903274].","teleology":[{"year":2010,"claim":"Established IFI16 as a bona fide intracellular DNA sensor, answering whether a cytosolic/nuclear factor links foreign DNA to interferon induction.","evidence":"RNAi knockdown, co-IP, and DNA-binding assays with IRF3/NF-κB readouts during DNA and HSV-1 stimulation","pmids":["20890285"],"confidence":"High","gaps":["Did not resolve the structural basis of DNA recognition","Subcellular site of sensing not yet defined"]},{"year":2012,"claim":"Defined the molecular basis of DNA recognition and autoinhibition, showing HIN domains bind DNA backbone electrostatically and that DNA binding relieves an intramolecular Pyrin-HIN clamp.","evidence":"X-ray crystallography of HIN-dsDNA complexes with structural analysis","pmids":["22483801"],"confidence":"High","gaps":["Did not explain how DNA binding triggers higher-order assembly","Filament formation not addressed structurally"]},{"year":2012,"claim":"Located the primary sensing compartment to the nucleus and identified NLS acetylation by p300 as a switch governing nuclear/cytoplasmic distribution.","evidence":"FISH, NLS mutagenesis, nuclear import assays, and mass spectrometry of modifications","pmids":["22691496"],"confidence":"High","gaps":["The signal exported from nucleus to activate cytoplasmic STING remained unidentified","Kinetics of acetylation during infection unresolved"]},{"year":2012,"claim":"Showed IFI16 is a viral restriction factor that represses transcription, distinguishing transcriptional silencing from immune signaling, and identified ICP0-mediated degradation as a viral countermeasure.","evidence":"EMSA, ChIP, dominant-negative overexpression at the HCMV UL54 promoter; siRNA and ICP0-virus infection for degradation","pmids":["22291595","23027953"],"confidence":"High","gaps":["Mechanism of Sp1-displacement vs. general repression not fully separated","Identity of nucleo-cytoplasmic relay still open"]},{"year":2013,"claim":"Resolved the assembly mechanism, showing the pyrin domain drives cooperative DNA-length-dependent filament formation while isolated HIN domains bind weakly without filamenting.","evidence":"Quantitative dsDNA binding, electron microscopy, and domain-deletion reconstitution","pmids":["24367117"],"confidence":"High","gaps":["Did not define the specific residues mediating oligomerization","Link to downstream signaling thresholds not established"]},{"year":2013,"claim":"Bifurcated IFI16 output into parallel inflammasome (ASC/procaspase-1/IL-1β) and STING/IRF3 (IFN-β) arms, and extended sensing to ssDNA forms and HIV intermediates.","evidence":"Colocalization, co-IP, inflammasome and IFN assays during HSV-1; direct DNA binding and knockdown in macrophages and CD4 T cells for lentiviral sensing and pyroptosis","pmids":["23427152","24356113","24154727"],"confidence":"High","gaps":["How a single sensor partitions between the two output complexes unclear","Trigger thresholds for pyroptosis vs. IFN not defined"]},{"year":2014,"claim":"Placed IFI16 in functional cooperation with cGAS, showing co-dependence for IFN responses to herpesviral and bacterial DNA and a role in stabilizing IFI16.","evidence":"Reciprocal siRNA depletion, co-IP, cGAMP measurement, and stability assays in fibroblasts and macrophages","pmids":["25831530","24970844"],"confidence":"High","gaps":["Order of action between cGAS and IFI16 not fully resolved","Listeria pathway evidence from a single lab"]},{"year":2015,"claim":"Built the ordered cofactor pathway for nuclear sensing: BRCA1- and H2B-containing complexes enable genome association, p300 acetylation licenses Ran-GTP-dependent cytoplasmic translocation and downstream signaling.","evidence":"Mass spectrometry, co-IP, proximity ligation, viral-genome ChIP, and knockdown of BRCA1/H2B/ASC/STING","pmids":["26134128","26121674","27764250"],"confidence":"High","gaps":["Whether BRCA1/H2B complexes act in non-herpesviral contexts unknown","Structural basis of the translocating complex undefined"]},{"year":2015,"claim":"Defined IFI16 as an epigenetic silencer of viral chromatin through deposition of repressive H3K9 marks, mechanistically separating restriction from immune signaling.","evidence":"ChIP for histone marks with gain- and loss-of-function on HPV18 promoters","pmids":["25972554"],"confidence":"High","gaps":["Methyltransferases responsible not yet identified in this study","Recruitment mechanism to viral chromatin unresolved"]},{"year":2017,"claim":"Positioned IFI16 at two levels of the cGAS-STING pathway: upstream of cGAMP production and downstream facilitating STING phosphorylation, translocation, and TBK1 recruitment.","evidence":"siRNA epistasis, cGAMP stimulation, co-IP, and STING/TBK1 activation assays in keratinocytes and macrophages","pmids":["28194029","28186168"],"confidence":"High","gaps":["Molecular basis of upstream effect on cGAS activity unclear","Whether the two roles are separable not addressed"]},{"year":2018,"claim":"Established non-canonical, cGAS-independent STING activation by IFI16 in response to nuclear DNA damage via an ATM/PARP-1/p53/TRAF6 complex driving NF-κB.","evidence":"Co-IP, siRNA of IFI16/ATM/PARP-1/cGAS, K63 ubiquitination and NF-κB assays","pmids":["30193098"],"confidence":"High","gaps":["Direct sensing event triggering this complex unclear","Relationship to canonical filament sensing undefined"]},{"year":2019,"claim":"Separated DNA-sensing-independent restriction (Sp1 binding) from immune signaling and defined the oligomerization residues, degradation pathway, and H3K9-methyltransferase partners.","evidence":"Domain-specific mutants and Sp1 binding for HIV/LINE-1; PYD residue mutagenesis with proteomics for oligomerization; co-IP/ubiquitination mapping (STING/TRIM21, K3/4/6); co-IP and ChIP for SUV39H1/GLP/HP1α on KSHV","pmids":["31175045","31337724","31665637","31682228"],"confidence":"High","gaps":["How oligomerization toggles between repression and signaling not yet defined","Regulation of TRIM21 recruitment in vivo unclear"]},{"year":2021,"claim":"Extended IFI16 to RNA virus immunity and revealed post-translational toggles (phase separation, DNA-PK and CDK2/GSK3β phosphorylation) that decouple cytokine output from viral transcriptional repression.","evidence":"HINa RNA-binding and RIG-I ubiquitination assays with KO cells/mice; in vitro LLPS reconstitution and kinase identification; TPCA proteomics for DNA-PK T149 phosphorylation","pmids":["33986530","37283074","34144993","34936865"],"confidence":"High","gaps":["How distinct phosphorylation marks are integrated in vivo unclear","DSB-site role evidence from a single lab"]},{"year":2022,"claim":"Defined genome-wide chromatinization and additional heterochromatin partnerships, showing IFI16 broadly silences viral genomes and maintains EBV latency through KAP1/SZF1.","evidence":"ChIP-seq, ATAC-seq, proteomics in KO cells (HSV-1); co-IP and ChIP at the EBV BZLF1 promoter (KAP1/SZF1)","pmids":["35575489","35969079"],"confidence":"High","gaps":["How IFI16 selects loci for chromatinization unclear","Interplay between silencing and signaling on the same genome unresolved"]},{"year":2025,"claim":"Identified a cell-intrinsic transcriptional role beyond immunity, with IFI16 activating HMOX1 via JUND/SP1 to inhibit ferroptosis and confer radioresistance in glioblastoma.","evidence":"Co-IP with JUND/SP1, HMOX1 luciferase reporter, ferroptosis assays, and xenograft model","pmids":["39890789"],"confidence":"Medium","gaps":["Single-lab evidence","Whether this is direct promoter binding or cofactor recruitment unclear","Generality beyond glioblastoma unknown"]},{"year":null,"claim":"How IFI16 integrates its multiple post-translational toggles, cofactor complexes, and oligomeric states to choose among interferon induction, inflammasome assembly, and epigenetic silencing on the same nucleic-acid substrate remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of the signaling-vs-silencing switch","Quantitative thresholds governing output selection undefined","In vivo relevance of competing degradation and stabilization pathways unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,5,8,16,31,34,42,43]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[26,45]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,17,21,26,30,44]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,9,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13,15,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[35,36]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3,32]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[32]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[32]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,9,36]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[39,40,41]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[25,31]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,9,18,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,18,19,20]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[14,23,30,31]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,17,21,37]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,21,26,44]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,32,44]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[20,27]}],"complexes":["IFI16-ASC-procaspase-1 inflammasome","IFI16-BRCA1-H2B sensing complex","IFI16-SUV39H1-GLP H3K9 methyltransferase complex","IFI16-KAP1-SZF1 heterochromatin complex"],"partners":["STING1","BRCA1","CGAS","SP1","TRIM21","RIGI","TRIM28","SUV39H1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16666","full_name":"Gamma-interferon-inducible protein 16","aliases":["Interferon-inducible myeloid differentiation transcriptional activator"],"length_aa":785,"mass_kda":88.3,"function":"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. Necessary to activate the IRF3 signaling cascade during human herpes simplex virus 1 (HHV-1) infection and promotes the assembly of heterochromatin on herpesviral DNA and inhibition of viral immediate-early gene expression and replication. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer Isoform that specifically inhibits the AIM2 inflammasome (PubMed:30104205). Binds double-stranded DNA (dsDNA) in the cytoplasm, impeding its detection by AIM2 (PubMed:30104205). Also prevents the interaction between AIM2 and PYCARD/ASC via its interaction with AIM2, thereby inhibiting assembly of the AIM2 inflammasome (PubMed:30104205). This isoform also weakly induce production of type I interferon-beta (IFNB1) via its interaction with STING1 (PubMed:30104205)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q16666/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFI16","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IFI16","total_profiled":1310},"omim":[{"mim_id":"612677","title":"PYRIN AND HIN DOMAIN FAMILY, MEMBER 1; PYHIN1","url":"https://www.omim.org/entry/612677"},{"mim_id":"604578","title":"ABSENT IN MELANOMA 2; AIM2","url":"https://www.omim.org/entry/604578"},{"mim_id":"601819","title":"BROMODOMAIN PHD FINGER TRANSCRIPTION FACTOR; BPTF","url":"https://www.omim.org/entry/601819"},{"mim_id":"600124","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN A2/B1; HNRNPA2B1","url":"https://www.omim.org/entry/600124"},{"mim_id":"159553","title":"MYELOID CELL NUCLEAR DIFFERENTIATION ANTIGEN; MNDA","url":"https://www.omim.org/entry/159553"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IFI16"},"hgnc":{"alias_symbol":["IFNGIP1","PYHIN2"],"prev_symbol":[]},"alphafold":{"accession":"Q16666","domains":[{"cath_id":"1.10.533.10","chopping":"3-91","consensus_level":"high","plddt":90.0145,"start":3,"end":91},{"cath_id":"2.40.50.140","chopping":"200-299","consensus_level":"high","plddt":88.4974,"start":200,"end":299},{"cath_id":"2.40.50.140","chopping":"305-390","consensus_level":"high","plddt":91.6723,"start":305,"end":390},{"cath_id":"2.40.50.140","chopping":"579-670","consensus_level":"high","plddt":90.2653,"start":579,"end":670},{"cath_id":"2.40.50.140","chopping":"676-762","consensus_level":"high","plddt":89.6021,"start":676,"end":762}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16666","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16666-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16666-F1-predicted_aligned_error_v6.png","plddt_mean":68.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFI16","jax_strain_url":"https://www.jax.org/strain/search?query=IFI16"},"sequence":{"accession":"Q16666","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16666.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16666/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16666"}},"corpus_meta":[{"pmid":"20890285","id":"PMC_20890285","title":"IFI16 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co-immunoprecipitation, DNA-binding assays, IRF3/NF-κB activation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, siRNA knockdown with defined signaling phenotypes, replicated across multiple labs subsequently\",\n      \"pmids\": [\"20890285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structures of IFI16 HIN domains in complex with dsDNA reveal that non-sequence-specific DNA recognition is accomplished through electrostatic attraction between positively charged HIN domain residues and the dsDNA sugar-phosphate backbone; an autoinhibited intramolecular AIM2 Pyrin-HIN complex is liberated by DNA binding.\",\n      \"method\": \"X-ray crystallography, structural analysis of HIN-DNA complexes\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, foundational structural paper\",\n      \"pmids\": [\"22483801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IFI16 is predominantly nuclear, detects HSV-1 DNA primarily in the nucleus requiring a functional nuclear localization signal (NLS), and mediates IFN-β induction in a localization-dependent manner. Acetylation of the NLS by acetyltransferase p300 inhibits nuclear import and promotes cytoplasmic localization of IFI16.\",\n      \"method\": \"FISH, immunopurification, mutagenesis of NLS, nuclear import assays, combinatorial mass spectrometry for acetylation/phosphorylation sites, deacetylase inhibition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, MS, and functional import assays in one rigorous study\",\n      \"pmids\": [\"22691496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HSV-1 ICP0, an E3 ubiquitin ligase expressed in the nucleus, causes nuclear relocalization and proteasomal degradation of IFI16, thereby inhibiting IFI16-dependent IRF-3 signaling. Nuclear IFI16 senses HSV-1 DNA upon its release from incoming capsids, and an unknown factor must be exported from the nucleus to activate IRF-3 through cytoplasmic STING.\",\n      \"method\": \"siRNA knockdown, inhibition of viral DNA release, immunofluorescence localization, infection with ICP0-expressing virus\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological dissection of nuclear sensing pathway, replicated by multiple subsequent studies\",\n      \"pmids\": [\"23027953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IFI16 acts as a restriction factor for HCMV replication by blocking Sp1-like factor binding to the HCMV DNA polymerase (UL54) promoter via an inverted repeat element (IR-1), as demonstrated by EMSA and chromatin immunoprecipitation; a dominant-negative IFI16 lacking the PYRIN domain enhanced HCMV replication.\",\n      \"method\": \"siRNA knockdown, dominant-negative overexpression, EMSA, ChIP, luciferase reporter with deleted/mutated promoter constructs\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — EMSA, ChIP, and mutagenesis in one study with multiple orthogonal methods\",\n      \"pmids\": [\"22291595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFI16 cooperatively assembles into filaments on dsDNA in a length-dependent manner; the pyrin domain (not the HIN DNA-binding domains) drives cooperative filament assembly, while isolated HIN domains engage dsDNA without forming filaments and with weak affinity.\",\n      \"method\": \"Quantitative dsDNA binding assays, electron microscopy, domain deletion/isolation experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with EM and quantitative binding assays, mechanistic domain dissection\",\n      \"pmids\": [\"24367117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The HCMV tegument protein pUL83 inhibits IFI16-mediated nuclear DNA sensing by interacting with the IFI16 pyrin domain, blocking IFI16 oligomerization upon DNA sensing. pUL83 uses a conserved N-terminal pyrin association domain (PAD) to bind IFI16, and phosphorylation of pUL83's N-terminal domain modulates this inhibition.\",\n      \"method\": \"Co-immunoprecipitation, binding domain mapping, mutagenesis, oligomerization assays, cytokine expression assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic domain mapping with multiple orthogonal methods, functionally validated\",\n      \"pmids\": [\"24237704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFI16 is required for pyroptotic death of CD4 T cells abortively infected with HIV; cytosolic incomplete HIV reverse transcripts are sensed by IFI16, triggering caspase-1 activation and pyroptosis.\",\n      \"method\": \"Unbiased proteomics, targeted biochemical approaches, lentiviral shRNA knockdown in primary CD4 T cells, caspase-1 activation assay\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent shRNA methods, proteomics identification, defined functional readout (caspase-1, pyroptosis)\",\n      \"pmids\": [\"24356113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IFI16 senses ssDNA forms produced during lentiviral replication (including HIV-1 proviral ssDNA) in human macrophages, directly binds immunostimulatory DNA, and activates the STING-TBK1-IRF3/7 pathway; IFI16 knockdown augmented lentiviral transduction and HIV-1 replication.\",\n      \"method\": \"Direct DNA binding assay, siRNA knockdown, colocalization/co-immunoprecipitation of IFI16 with lentiviral DNA, IFN induction assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding, colocalization, and functional knockdown with defined pathway activation\",\n      \"pmids\": [\"24154727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"During HSV-1 infection, nuclear IFI16 recognizes viral genomes and relocates to form an IFI16-ASC-procaspase-1 inflammasome in the cytoplasm, leading to IL-1β production. Independently, IFI16 interacts with cytoplasmic STING to induce IFN-β production via IRF-3 phosphorylation. HSV-1 targets IFI16 for proteasomal degradation via ICP0 at later times post-infection.\",\n      \"method\": \"Immunofluorescence colocalization, co-immunoprecipitation, inflammasome activation assays, IL-1β secretion, IFN-β assays, Western blotting of ICP0-dependent degradation\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, two distinct downstream pathway characterizations, consistent with other studies\",\n      \"pmids\": [\"23427152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IFI16 and cGAS are both required for IFN production during HSV-1 infection in human fibroblasts; cGAS is partially nuclear and interacts with IFI16, promoting IFI16 protein stability rather than primarily producing cGAMP in infected cells.\",\n      \"method\": \"siRNA depletion of IFI16 and cGAS, co-immunoprecipitation, cGAMP measurement, IFI16 stability assays, viral DNA association assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic dissection with reciprocal depletion, interaction and stability assays, multiple methods\",\n      \"pmids\": [\"25831530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IFI16-dependent IFNβ expression during Listeria monocytogenes infection in human macrophages is triggered by bacterial DNA (not cyclic-di-AMP) via a pathway requiring both IFI16 and cGAS as well as STING.\",\n      \"method\": \"siRNA knockdown of IFI16, cGAS, and STING; IFNβ induction assays; stimulation with bacterial DNA vs. cyclic-di-AMP\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with defined readouts, single lab\",\n      \"pmids\": [\"24970844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Recognition of herpesviral genomes in the nucleus by IFI16 leads to its interaction with histone acetyltransferase p300 and IFI16 acetylation, resulting in IFI16-ASC inflammasome assembly, increased interaction with Ran-GTPase, cytoplasmic redistribution, caspase-1 activation, IL-1β production, and IFI16-STING interaction leading to IFN-β production. Acetylation is not required for sensing viral genomes but is required for downstream responses.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation microscopy, ChIP, acetylation inhibition, siRNA knockdown of ASC/STING, caspase-1 and IL-1β assays, IRF-3 phosphorylation assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, mechanistic ordering of events established by perturbation experiments\",\n      \"pmids\": [\"26134128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BRCA1 forms a complex with IFI16 in the nucleus that is required for IFI16's association with viral genomes; absence of BRCA1 abrogates IFI16-viral genome association, inflammasome assembly, cytoplasmic localization, caspase-1/IL-1β production, and IFI16-STING interaction and IFN-β production during herpesviral infection.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown of BRCA1, inflammasome and IFN-β assays, de novo viral infection models\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, genetic knockdown with multiple functional readouts, multiple viruses tested\",\n      \"pmids\": [\"26121674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IFI16 restricts HPV18 replication through epigenetic modifications: IFI16 promotes deposition of heterochromatin marks (H3K9me2/me3) and reduction of euchromatin marks on viral chromatin at both early and late HPV18 promoters, thereby reducing viral replication and transcription.\",\n      \"method\": \"siRNA knockdown, AdV-IFI16 overexpression, viral load measurement, viral gene expression analysis, ChIP for histone marks\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP for histone marks, gain- and loss-of-function, two cellular models\",\n      \"pmids\": [\"25972554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IFI16 interacts with histone H2B in the nucleus; herpesviral genome sensing by an IFI16-H2B-BRCA1 complex triggers p300-dependent acetylation of both H2B and IFI16, Ran-GTP-mediated cytoplasmic translocation of this complex, and subsequent interaction with cGAS and STING leading to TBK1/IRF3 phosphorylation and IFN-β production. A separate IFI16-BRCA1-ASC-procaspase-1 complex mediates inflammasome/IL-1β responses.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, proximity ligation microscopy, EdU-labeled virus genome ChIP, siRNA knockdown of H2B/cGAS/STING/ASC\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mass spectrometry identification, multiple co-IP validations, genetic dissection of two parallel IFI16 complexes\",\n      \"pmids\": [\"27764250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of IFI16 HINa domain in complex with DNA at 2.55 Å reveals two OB folds with a unique DNA-binding surface; HINa uses loop L45 of the OB2 fold to bind to the DNA backbone, recognizing dsDNA as two single strands. Deletion of HINb compromises IFN-β induction, while HINa mutants impaired in DNA binding enhance IFN-β production.\",\n      \"method\": \"X-ray crystallography, domain deletion/mutagenesis, IFN-β induction assays\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional mutagenesis, single lab\",\n      \"pmids\": [\"26246511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IFI16 maintains KSHV latency by binding to lytic gene promoters and acting as a transcriptional repressor; IFI16 knockdown induces KSHV lytic reactivation. During lytic cycle, IFI16 is polyubiquitinated and degraded via the proteasomal pathway by a late lytic KSHV gene product.\",\n      \"method\": \"siRNA knockdown, IFI16 overexpression, ChIP of KSHV promoters, luciferase reporter assays, ubiquitination assays, phosphonoacetic acid blockade of DNA replication\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP with promoter reporters, gain/loss of function, mechanistic dissection of degradation\",\n      \"pmids\": [\"27466416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In human keratinocytes, IFI16 cooperates with cGAS during DNA sensing; both are required for full innate immune activation. IFI16 is required for cGAMP-induced activation of STING, and interacts with STING to promote STING phosphorylation and translocation.\",\n      \"method\": \"siRNA knockdown of cGAS and IFI16, cGAMP stimulation, co-immunoprecipitation of IFI16-STING, STING phosphorylation and translocation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis, co-IP, defined biochemical readouts, two cooperating sensors mechanistically placed\",\n      \"pmids\": [\"28194029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In human macrophages, IFI16 functions at two levels in the cGAS-STING pathway: IFI16 depletion impairs cGAMP production upon DNA stimulation (acting upstream of or alongside cGAS), and IFI16 is vital for downstream STING signaling by facilitating recruitment and activation of TBK1 in the STING complex.\",\n      \"method\": \"siRNA depletion, cGAMP measurement, TBK1 recruitment assays, IFI16 overexpression with cGAS\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two distinct functional levels established, genetic and biochemical methods, independently replicated findings\",\n      \"pmids\": [\"28186168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IFI16, together with DNA damage response factors ATM and PARP-1, mediates non-canonical STING activation (independent of cGAS) following nuclear DNA damage; this results in assembly of an alternative STING signaling complex including p53 and the E3 ubiquitin ligase TRAF6. TRAF6 catalyzes K63-linked ubiquitin chains on STING, activating NF-κB.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of IFI16/ATM/PARP-1/cGAS, ubiquitination assays, NF-κB activation assays, gene expression analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and biochemical approaches, defined complex assembly and ubiquitination mechanism\",\n      \"pmids\": [\"30193098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFI16 restricts HIV-1 independently of immune DNA sensing by binding and inhibiting the host transcription factor Sp1 that drives viral gene expression; this activity requires the N-terminal pyrin domain and nuclear localization, but not the HIN domains. IFI16 also inhibits LINE-1 retrotransposition in a Sp1-dependent manner.\",\n      \"method\": \"IFI16-Sp1 binding assays, pyrin domain and HIN domain mutants, HIV-1 transcription assays, HIV-1 latency reactivation assays, LINE-1 retrotransposition assay\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-specific mutants, direct binding, multiple functional readouts, mechanistic dissection of DNA-sensing-independent function\",\n      \"pmids\": [\"31175045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STING directly interacts with IFI16 and facilitates IFI16 degradation via the ubiquitin-proteasome pathway by recruiting E3 ligase TRIM21; the pyrin region of IFI16 mediates the IFI16-STING interaction, and lysines K3/4/6 in the N-terminal region of IFI16 are key ubiquitination sites. IFI16-K3/4/6R mutant resistant to degradation shows enhanced IFN-β and antiviral gene expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, domain mapping, IFI16 degradation-resistant mutant (K3/4/6R), IFN-β induction assays, HSV-1 infection\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of ubiquitination sites, co-IP with TRIM21/STING, functionally validated with degradation-resistant mutant\",\n      \"pmids\": [\"31665637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFI16 is in complex with H3K9 methyltransferases SUV39H1 and GLP; IFI16 recruits them to the KSHV genome during de novo infection and latency, resulting in H3K9me2/me3 deposition that serves as a docking site for HP1α, leading to epigenetic silencing of KSHV lytic genes.\",\n      \"method\": \"Co-immunoprecipitation of IFI16 with SUV39H1 and GLP, ChIP for H3K9me2/me3 and HP1α on KSHV genome, IFI16 knockdown\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, ChIP with functional readouts, mechanistic pathway established\",\n      \"pmids\": [\"31682228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFI16 oligomerization is mediated by charge-dependent interactions at specific pyrin domain residues; oligomerization is necessary for IFI16 assembly onto parental HSV-1 viral genomes at the nuclear periphery, for antiviral cytokine induction, suppression of viral proteins, and restriction of viral progeny. Oligomerization promotes interactions with transcriptional regulatory proteins including PAF1C, UBTF, and ND10 bodies.\",\n      \"method\": \"Structural modeling, mutagenesis of oligomerization-deficient PYD residues, charge mimics, immunoaffinity purification, targeted mass spectrometry, CRISPR/Cas9, confocal microscopy\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis, structural modeling, proteomics, multiple functional readouts, rigorous controls\",\n      \"pmids\": [\"31337724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFI16 forms filamentous nuclear structures on viral DNA within HSV-1 replication compartments; these filaments recruit PML, Sp100, and ATRX as co-restriction factors and reduce elongation-competent RNA Pol II in replication compartments, constituting a nuclear 'restrictosome' that silences progeny viral DNA.\",\n      \"method\": \"Structured illumination microscopy, immunofluorescence, correlation of filament formation with restriction efficiency, RNA Pol II ChIP-like assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structured illumination microscopy, single lab, correlative evidence for restrictosome function\",\n      \"pmids\": [\"30670617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFI16 directly binds influenza viral RNA via its HINa domain and interacts with RIG-I protein via its PYRIN domain, promoting K63-linked polyubiquitination and RIG-I activation. IFI16 also positively upregulates RIG-I transcription by direct binding to and recruitment of RNA polymerase II to the RIG-I promoter.\",\n      \"method\": \"IFI16 knockout cells, p204-deficient mice, RNA binding assays with HINa domain, co-immunoprecipitation of IFI16-RIG-I, RIG-I ubiquitination assays, ChIP for RNA Pol II at RIG-I promoter\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-specific binding assays, ChIP, ubiquitination, KO mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"33986530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFI16 accumulates at double-strand break (DSB) sites where it inhibits recruitment of DNA damage response (DDR) factors, increases cytoplasmic DNA fragment release, and induces STING-mediated type I IFN production; IFI16 depletion reduces doxorubicin-induced STING signaling and antitumor immunity in TNBC.\",\n      \"method\": \"IFI16 depletion, immunofluorescence at DSB sites, DDR factor recruitment assays, cytoplasmic DNA quantification, STING pathway activation assays, in vivo tumor model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays at DSB sites, in vivo validation, single lab\",\n      \"pmids\": [\"34936865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFI16 undergoes phase separation (liquid-liquid phase separation, LLPS) nucleated by viral DNA binding; multiple phosphorylation sites within an intrinsically disordered region (IDR), regulated by CDK2 and GSK3β, act combinatorially to activate IFI16 LLPS and facilitate filamentation. IDR phosphorylation provides a toggle between active and inactive IFI16, decoupling cytokine expression from repression of viral transcription.\",\n      \"method\": \"In vitro LLPS reconstitution, in vivo LLPS assays, phosphorylation site mutagenesis, CDK2/GSK3β kinase assays, HSV-1 infection models, cytokine and viral transcription readouts\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of LLPS, mutagenesis, kinase identification, multiple orthogonal methods\",\n      \"pmids\": [\"37283074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DNA-dependent protein kinase (DNA-PK) is recruited to IFI16 at incoming viral DNA at the nuclear periphery during HSV-1 infection; DNA-PK phosphorylates IFI16 at T149, and this phosphorylation promotes IFI16-driven cytokine responses.\",\n      \"method\": \"Thermal proximity coaggregation (TPCA) mass spectrometry, time-resolved PPI mapping, IFI16 T149 phosphorylation validation, cytokine response assays upon DNA damage and viral infection\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — novel TPCA proteomics, site-specific phosphorylation validated, functional readout, rigorous study\",\n      \"pmids\": [\"34144993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IFI16 interacts with KAP1 (KRAB-associated protein 1) and the site-specific DNA binding KRAB-ZFP SZF1 to form a partnership with the constitutive heterochromatin machinery; this complex silences the EBV lytic switch protein ZEBRA (BZLF1 gene) and contributes to H3K9 trimethylation at EBV lytic genes, maintaining EBV latency.\",\n      \"method\": \"Co-immunoprecipitation of IFI16-KAP1-SZF1, ChIP for IFI16 and KAP1 at BZLF1 promoter, H3K9me3 ChIP, IFI16 knockdown with lytic gene induction readouts\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, ChIP at defined loci, functional genetic dissection, mechanistic pathway defined\",\n      \"pmids\": [\"35969079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IFI16 binds the HSV-1 genome in a sequence-independent manner with broad enrichment at UL30 (viral DNA polymerase) and US1-US7 loci; IFI16 binding globally induces chromatinization (reduced accessibility) of HSV-1 DNA genome and decreases global HSV-1 protein expression.\",\n      \"method\": \"ChIP-seq, ATAC-seq, parallel reaction monitoring mass spectrometry of viral proteins, IFI16 knockout cells\",\n      \"journal\": \"mSystems\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP-seq, ATAC-seq, and proteomics combined, KO validation, comprehensive genome-wide analysis\",\n      \"pmids\": [\"35575489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IFI16 interacts with BRCA1 (aa 502–802) through its Pyrin domain (aa 1–130); coexpression of IFI16 and BRCA1 enhanced DNA damage-induced apoptosis in mouse embryonic fibroblasts, and a mutant IFI16 deficient in BRCA1 binding did not induce apoptosis. IFI16 is localized in the nucleoplasm and nucleoli, and BRCA1 is required for its nucleolar localization following ionizing radiation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, apoptosis assays, adenovirus-mediated expression, immunocytochemistry\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping, functional apoptosis assay, single lab\",\n      \"pmids\": [\"14654789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"siRNA-mediated reduction of IFI16 expression induces p21Waf1 mRNA and protein through p53 activation and causes cell cycle arrest with reduced phosphorylated Rb; IFI16 negatively regulates p53 protein stability and transcriptional activity at the p21 promoter in normally growing cells.\",\n      \"method\": \"siRNA knockdown, p21 expression assays, promoter-reporter assays, cell cycle analysis, Rb phosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined molecular readouts, single lab\",\n      \"pmids\": [\"12925527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The IFI16 HIN200 domain has RPA-like OB-fold nucleic acid binding properties: it binds ssDNA with higher affinity than dsDNA, recognizes ssDNA in the same orientation as RPA, oligomerizes upon ssDNA binding, wraps and stretches ssDNA, but does not destabilize dsDNA.\",\n      \"method\": \"Structural modeling (fold recognition), biophysical binding assays, ssDNA orientation assays, oligomerization assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biophysical validation of RPA-like binding, structural modeling, but single lab and no in-cell functional validation\",\n      \"pmids\": [\"18472023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Increased IFI16 expression inhibits activation of caspase-1 by the AIM2-ASC inflammasome; IFI16 and AIM2 can heterodimerize, and knockdown of IFI16 increases basal and induced activation of AIM2 and NLRP3 inflammasomes in THP-1 cells.\",\n      \"method\": \"HEK-293 overexpression with caspase-1 assay, siRNA knockdown in THP-1, inflammasome activation assays with poly(dA:dT) and alum\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function with defined caspase-1 readout, single lab\",\n      \"pmids\": [\"22046441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A novel transcript isoform of IFI16 (IFI16-β), lacking the pyrin domain but containing two HIN domains, is predominantly cytoplasmic and inhibits AIM2 inflammasome activation by interacting with AIM2 to impede AIM2-ASC complex formation and by sequestering cytoplasmic dsDNA.\",\n      \"method\": \"IFI16-β identification/cloning, co-localization assays, co-immunoprecipitation of IFI16-β with AIM2, AIM2-ASC complex formation assays, siRNA knockdown, IL-1β secretion assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — novel isoform characterized with multiple functional assays, mechanistic dissection of AIM2 inhibition\",\n      \"pmids\": [\"30104205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HPV E7 recruits the E3 ligase TRIM21 to ubiquitinate and degrade the IFI16 inflammasome, inhibiting dsDNA-induced cell pyroptosis and suppressing IL-1β and IL-18 production.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation of HPV E7 with IFI16 and TRIM21, ubiquitination assays, inflammasome activation and pyroptosis assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assays, MS identification, single lab\",\n      \"pmids\": [\"33061806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Androgen receptor (AR) upregulates IFI16 expression; the IFI16 protein binds to AR in a ligand-dependent manner through AR's DNA-binding domain (DBD). Re-expression of IFI16 in LNCaP cells downregulates AR expression and inhibits AR target gene expression.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (DBD sufficiency), IFI16 re-expression, AR and AR target gene expression assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping, gain-of-function with defined readouts, single lab\",\n      \"pmids\": [\"16494870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Extracellular IFI16 released from apoptotic cells binds to high-affinity sites on the plasma membrane of endothelial cells (Kd ~2.7 nM, ~250,000–450,000 binding sites per cell) via its N-terminal domain, inhibiting tubulogenesis and migration. Anti-IFI16 N-terminal antibodies fully reverse these effects.\",\n      \"method\": \"Radioiodinated IFI16 binding assays, Scatchard analysis, competition assays, co-culture experiments, endothelial function assays (tubulogenesis, migration), ELISA for circulating IFI16\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative binding characterization, functional assays with antibody blocking, single lab\",\n      \"pmids\": [\"23690979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Extracellular IFI16 activates p38 MAPK (as an early required step), subsequently activating p44/42 MAP kinases and NF-κB, inducing inflammatory cytokines (IL-6, IL-8, CCL2, CCL5, CCL20) in endothelial cells via a MyD88-dependent TLR pathway; TLR4-neutralizing antibodies partially inhibit this response.\",\n      \"method\": \"Recombinant IFI16 protein treatment of endothelial cells, p38/MAPK/NF-κB pathway inhibition, MyD88 siRNA knockdown, TLR4 neutralization, cytokine assays\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and antibody-based pathway dissection, single lab\",\n      \"pmids\": [\"25715050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Extracellular IFI16 binds with high affinity to the lipid A moiety of LPS; IFI16/LPS complexes display faster stimulation turnover on TLR4 than LPS alone, and IFI16 DAMP activity is potentiated by LPS through TLR4-MD2/TIRAP/MyD88-dependent signaling in monocytes and renal cells.\",\n      \"method\": \"Pull-down, saturation binding experiments, co-immunoprecipitation, surface plasmon resonance (SPR), TLR4 activation assays, cytokine induction\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — SPR for binding kinetics, co-IP, functional inflammatory assays, multiple methods in one study\",\n      \"pmids\": [\"32903274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IFI16 protein binds strongly to negatively superhelical plasmid DNA at native superhelix density and shows strong preference for cruciform DNA structure compared to linear or relaxed DNA; binding to supercoiled DNA is reversible.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA) with supercoiled vs. linear DNA, oligonucleotide cruciform binding assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding assays, single lab, no in-cell functional validation\",\n      \"pmids\": [\"22618232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IFI16 shows specific preference for binding to quadruplex DNA with significantly higher affinity than dsDNA or ssDNA; IFI16 stabilizes quadruplex structures from human telomere and MYC promoter sequences. H/D exchange MS shows that quadruplex DNA alters IFI16 deuteration in the PYRIN domain (aa 0–80) and structurally identical parts of both HIN domains.\",\n      \"method\": \"Circular dichroism spectroscopy, H/D exchange mass spectrometry, DNA binding assays with quadruplex vs. linear DNA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical assays with CD and MS, but limited in-cell functional validation, single lab\",\n      \"pmids\": [\"27280708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFI16 activates HMOX1 transcription by interacting with transcription factors JUND and SP1 through its pyrin domain, inhibiting ferroptosis (reducing lipid peroxidation, ROS, and Fe2+) and enhancing radioresistance in glioblastoma. Glyburide disrupts IFI16 function by targeting its pyrin domain.\",\n      \"method\": \"Co-immunoprecipitation of IFI16 with JUND and SP1, luciferase reporter assays for HMOX1, ferroptosis assays (lipid peroxidation, ROS, Fe2+ measurements), IFI16 knockdown/overexpression, in vivo xenograft model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of IFI16 with transcription factors, functional ferroptosis assays, single lab\",\n      \"pmids\": [\"39890789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFI16 directly senses influenza A viral RNA via its HINa domain; IFI16 knockout cells and p204-deficient mice show reduced IFN-I production and increased IAV replication; IFI16 promotes K63-linked polyubiquitination of RIG-I by binding to RIG-I with its PYRIN domain.\",\n      \"method\": \"IFI16 KO cells, p204-deficient mice, RNA binding assays with HINa domain, RIG-I ubiquitination assays, co-immunoprecipitation\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-specific RNA binding, mouse KO model, ubiquitination assays, multiple orthogonal methods\",\n      \"pmids\": [\"33986530\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFI16 is a nuclear and cytoplasmic innate immune DNA (and RNA) sensor that detects pathogenic dsDNA, ssDNA, and viral RNA via its HIN domains (which bind nucleic acids through OB folds) and signals through the STING-TBK1-IRF3 axis to induce IFN-β, forms inflammasomes (with ASC and procaspase-1) via its pyrin domain to produce IL-1β, cooperatively assembles into filaments on foreign DNA in a pyrin domain-dependent manner, recruits H3K9 methyltransferases (SUV39H1/GLP) to epigenetically silence viral genomes, is regulated by p300-mediated acetylation of its NLS (controlling nuclear/cytoplasmic localization), by STING/TRIM21-mediated ubiquitination and proteasomal degradation, by DNA-PK phosphorylation at T149 (promoting cytokine responses), and by CDK2/GSK3β-regulated phase separation; it also restricts retroviruses independently of DNA sensing by binding Sp1 via its pyrin domain to suppress viral transcription, and when released extracellularly acts as a DAMP by binding TLR4 to propagate inflammation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFI16 is a predominantly nuclear innate immune nucleic-acid sensor that detects foreign DNA and signals through the STING-TBK1-IRF3 axis to induce type I interferon while also nucleating inflammasome responses [#0, #9]. It binds DNA non-sequence-specifically through electrostatic contacts between its HIN-domain OB folds and the dsDNA sugar-phosphate backbone, with DNA binding liberating an autoinhibited intramolecular Pyrin-HIN state [#1, #16]; the HIN200 module also binds ssDNA with RPA-like properties and IFI16 senses ssDNA and proviral intermediates generated during lentiviral replication [#8, #34]. The pyrin domain rather than the HIN domains drives cooperative, charge-dependent oligomerization and filament assembly along dsDNA, which is required for genome recognition, antiviral cytokine induction, and viral restriction [#5, #24], and this assembly is tuned by liquid-liquid phase separation under combinatorial CDK2/GSK3\\u03b2 phosphorylation of an intrinsically disordered region [#28]. Upon herpesviral genome sensing in the nucleus, IFI16 acts within a BRCA1- and H2B-containing complex, becomes p300-acetylated, redistributes to the cytoplasm via Ran-GTP, and bifurcates into an IFI16-STING arm driving IFN-\\u03b2 and an IFI16-ASC-procaspase-1 inflammasome arm driving IL-1\\u03b2 [#9, #12, #13, #15]. IFI16 functions cooperatively with cGAS at multiple levels of the STING pathway, both promoting cGAMP production and facilitating TBK1 recruitment and STING activation [#10, #18, #19], and mediates non-canonical, cGAS-independent STING activation following nuclear DNA damage through an ATM/PARP-1/p53/TRAF6 complex [#20]. Beyond signaling, IFI16 is an intrinsic genome-silencing factor that recruits H3K9 methyltransferases SUV39H1/GLP and the KAP1/SZF1 heterochromatin machinery to deposit H3K9me marks and chromatinize viral genomes, maintaining KSHV and EBV latency and restricting HPV [#14, #23, #30, #31], and it restricts HIV-1 and LINE-1 independently of DNA sensing by binding the transcription factor Sp1 through its pyrin domain [#21]. IFI16 abundance and localization are controlled by acetylation of its NLS by p300 and by STING/TRIM21-directed ubiquitination and proteasomal degradation [#2, #22]. When released extracellularly, IFI16 acts as a DAMP, binding TLR4 and LPS to propagate inflammatory cytokine signaling [#40, #41].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established IFI16 as a bona fide intracellular DNA sensor, answering whether a cytosolic/nuclear factor links foreign DNA to interferon induction.\",\n      \"evidence\": \"RNAi knockdown, co-IP, and DNA-binding assays with IRF3/NF-\\u03baB readouts during DNA and HSV-1 stimulation\",\n      \"pmids\": [\"20890285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of DNA recognition\", \"Subcellular site of sensing not yet defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the molecular basis of DNA recognition and autoinhibition, showing HIN domains bind DNA backbone electrostatically and that DNA binding relieves an intramolecular Pyrin-HIN clamp.\",\n      \"evidence\": \"X-ray crystallography of HIN-dsDNA complexes with structural analysis\",\n      \"pmids\": [\"22483801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain how DNA binding triggers higher-order assembly\", \"Filament formation not addressed structurally\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Located the primary sensing compartment to the nucleus and identified NLS acetylation by p300 as a switch governing nuclear/cytoplasmic distribution.\",\n      \"evidence\": \"FISH, NLS mutagenesis, nuclear import assays, and mass spectrometry of modifications\",\n      \"pmids\": [\"22691496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The signal exported from nucleus to activate cytoplasmic STING remained unidentified\", \"Kinetics of acetylation during infection unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed IFI16 is a viral restriction factor that represses transcription, distinguishing transcriptional silencing from immune signaling, and identified ICP0-mediated degradation as a viral countermeasure.\",\n      \"evidence\": \"EMSA, ChIP, dominant-negative overexpression at the HCMV UL54 promoter; siRNA and ICP0-virus infection for degradation\",\n      \"pmids\": [\"22291595\", \"23027953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Sp1-displacement vs. general repression not fully separated\", \"Identity of nucleo-cytoplasmic relay still open\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the assembly mechanism, showing the pyrin domain drives cooperative DNA-length-dependent filament formation while isolated HIN domains bind weakly without filamenting.\",\n      \"evidence\": \"Quantitative dsDNA binding, electron microscopy, and domain-deletion reconstitution\",\n      \"pmids\": [\"24367117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the specific residues mediating oligomerization\", \"Link to downstream signaling thresholds not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Bifurcated IFI16 output into parallel inflammasome (ASC/procaspase-1/IL-1\\u03b2) and STING/IRF3 (IFN-\\u03b2) arms, and extended sensing to ssDNA forms and HIV intermediates.\",\n      \"evidence\": \"Colocalization, co-IP, inflammasome and IFN assays during HSV-1; direct DNA binding and knockdown in macrophages and CD4 T cells for lentiviral sensing and pyroptosis\",\n      \"pmids\": [\"23427152\", \"24356113\", \"24154727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single sensor partitions between the two output complexes unclear\", \"Trigger thresholds for pyroptosis vs. IFN not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed IFI16 in functional cooperation with cGAS, showing co-dependence for IFN responses to herpesviral and bacterial DNA and a role in stabilizing IFI16.\",\n      \"evidence\": \"Reciprocal siRNA depletion, co-IP, cGAMP measurement, and stability assays in fibroblasts and macrophages\",\n      \"pmids\": [\"25831530\", \"24970844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of action between cGAS and IFI16 not fully resolved\", \"Listeria pathway evidence from a single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Built the ordered cofactor pathway for nuclear sensing: BRCA1- and H2B-containing complexes enable genome association, p300 acetylation licenses Ran-GTP-dependent cytoplasmic translocation and downstream signaling.\",\n      \"evidence\": \"Mass spectrometry, co-IP, proximity ligation, viral-genome ChIP, and knockdown of BRCA1/H2B/ASC/STING\",\n      \"pmids\": [\"26134128\", \"26121674\", \"27764250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRCA1/H2B complexes act in non-herpesviral contexts unknown\", \"Structural basis of the translocating complex undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined IFI16 as an epigenetic silencer of viral chromatin through deposition of repressive H3K9 marks, mechanistically separating restriction from immune signaling.\",\n      \"evidence\": \"ChIP for histone marks with gain- and loss-of-function on HPV18 promoters\",\n      \"pmids\": [\"25972554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Methyltransferases responsible not yet identified in this study\", \"Recruitment mechanism to viral chromatin unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Positioned IFI16 at two levels of the cGAS-STING pathway: upstream of cGAMP production and downstream facilitating STING phosphorylation, translocation, and TBK1 recruitment.\",\n      \"evidence\": \"siRNA epistasis, cGAMP stimulation, co-IP, and STING/TBK1 activation assays in keratinocytes and macrophages\",\n      \"pmids\": [\"28194029\", \"28186168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of upstream effect on cGAS activity unclear\", \"Whether the two roles are separable not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established non-canonical, cGAS-independent STING activation by IFI16 in response to nuclear DNA damage via an ATM/PARP-1/p53/TRAF6 complex driving NF-\\u03baB.\",\n      \"evidence\": \"Co-IP, siRNA of IFI16/ATM/PARP-1/cGAS, K63 ubiquitination and NF-\\u03baB assays\",\n      \"pmids\": [\"30193098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct sensing event triggering this complex unclear\", \"Relationship to canonical filament sensing undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Separated DNA-sensing-independent restriction (Sp1 binding) from immune signaling and defined the oligomerization residues, degradation pathway, and H3K9-methyltransferase partners.\",\n      \"evidence\": \"Domain-specific mutants and Sp1 binding for HIV/LINE-1; PYD residue mutagenesis with proteomics for oligomerization; co-IP/ubiquitination mapping (STING/TRIM21, K3/4/6); co-IP and ChIP for SUV39H1/GLP/HP1\\u03b1 on KSHV\",\n      \"pmids\": [\"31175045\", \"31337724\", \"31665637\", \"31682228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How oligomerization toggles between repression and signaling not yet defined\", \"Regulation of TRIM21 recruitment in vivo unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended IFI16 to RNA virus immunity and revealed post-translational toggles (phase separation, DNA-PK and CDK2/GSK3\\u03b2 phosphorylation) that decouple cytokine output from viral transcriptional repression.\",\n      \"evidence\": \"HINa RNA-binding and RIG-I ubiquitination assays with KO cells/mice; in vitro LLPS reconstitution and kinase identification; TPCA proteomics for DNA-PK T149 phosphorylation\",\n      \"pmids\": [\"33986530\", \"37283074\", \"34144993\", \"34936865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How distinct phosphorylation marks are integrated in vivo unclear\", \"DSB-site role evidence from a single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined genome-wide chromatinization and additional heterochromatin partnerships, showing IFI16 broadly silences viral genomes and maintains EBV latency through KAP1/SZF1.\",\n      \"evidence\": \"ChIP-seq, ATAC-seq, proteomics in KO cells (HSV-1); co-IP and ChIP at the EBV BZLF1 promoter (KAP1/SZF1)\",\n      \"pmids\": [\"35575489\", \"35969079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IFI16 selects loci for chromatinization unclear\", \"Interplay between silencing and signaling on the same genome unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a cell-intrinsic transcriptional role beyond immunity, with IFI16 activating HMOX1 via JUND/SP1 to inhibit ferroptosis and confer radioresistance in glioblastoma.\",\n      \"evidence\": \"Co-IP with JUND/SP1, HMOX1 luciferase reporter, ferroptosis assays, and xenograft model\",\n      \"pmids\": [\"39890789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence\", \"Whether this is direct promoter binding or cofactor recruitment unclear\", \"Generality beyond glioblastoma unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IFI16 integrates its multiple post-translational toggles, cofactor complexes, and oligomeric states to choose among interferon induction, inflammasome assembly, and epigenetic silencing on the same nucleic-acid substrate remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of the signaling-vs-silencing switch\", \"Quantitative thresholds governing output selection undefined\", \"In vivo relevance of competing degradation and stabilization pathways unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 5, 8, 16, 31, 34, 42, 43]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [26, 45]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 17, 21, 26, 30, 44]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 9, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 15, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [35, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3, 32]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 9, 36]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [39, 40, 41]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [25, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 9, 18, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 18, 19, 20]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [14, 23, 30, 31]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 17, 21, 37]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 21, 26, 44]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 32, 44]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [20, 27]}\n    ],\n    \"complexes\": [\n      \"IFI16-ASC-procaspase-1 inflammasome\",\n      \"IFI16-BRCA1-H2B sensing complex\",\n      \"IFI16-SUV39H1-GLP H3K9 methyltransferase complex\",\n      \"IFI16-KAP1-SZF1 heterochromatin complex\"\n    ],\n    \"partners\": [\n      \"STING1\",\n      \"BRCA1\",\n      \"cGAS\",\n      \"Sp1\",\n      \"TRIM21\",\n      \"RIGI\",\n      \"TRIM28\",\n      \"SUV39H1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}