IFI16

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003690 double-stranded DNA binding	IBA GO_REF:0000033	ACCEPT	Summary: IFI16 contains two HIN-200 domains that bind double-stranded DNA via electrostatic interactions with the DNA phosphate backbone. This is a well-established core function supported by structural studies (PMID:22483801) and functional assays (PMID:7536752, PMID:20890285). Reason: dsDNA binding is a fundamental molecular function of IFI16 that underlies its role as a DNA sensor. The HIN domains contain OB-folds that mediate sequence-independent dsDNA binding. This is supported by IBA phylogenetic inference and extensive experimental evidence. Supporting Evidence: PMID:7536752 Nuclear IFI 16 was able to bind double-stranded DNA in vitro and exhibited a similar elution profile from DNA-cellulose as previously observed for MNDA and 204. PMID:20890285 IFI16 directly associated with IFN-beta-inducing viral DNA motifs.
GO:0035458 cellular response to interferon-beta	IBA GO_REF:0000033	ACCEPT	Summary: IFI16 is an interferon-inducible gene whose expression is strongly induced by type I interferons including IFN-beta. The protein participates in interferon-mediated responses including antiviral immunity and inflammasome regulation (PMID:22046441). Reason: IFI16 expression is transcriptionally induced by interferons including IFN-beta, and IFI16 mediates downstream effects of interferon signaling. This represents a core aspect of IFI16 function in the interferon response pathway. Supporting Evidence: PMID:22046441 Treatment of THP-1 cells with type-I (IFN-alpha or beta) or type-II (IFN-gamma) IFN induced the expression levels of IFI16, AIM2, ASC and CASP1 proteins.
GO:0002218 activation of innate immune response	IBA GO_REF:0000033	ACCEPT	Summary: IFI16 is a key activator of innate immune responses by sensing cytosolic and nuclear DNA and triggering STING-dependent type I interferon production and inflammasome assembly (PMID:20890285, PMID:21575908). This is a core function of IFI16. Reason: Activation of innate immunity is a primary function of IFI16 as a DNA sensor. IFI16 recognizes viral DNA and activates both type I interferon responses via STING/TBK1/IRF3 and inflammasome-mediated IL-1beta production. Supporting Evidence: PMID:20890285 Here we identify IFI16, a PYHIN protein, as an intracellular DNA sensor that mediates the induction of interferon-β (IFN-β) PMID:21575908 We demonstrate that during KSHV infection of endothelial cells, interferon gamma-inducible protein 16 (IFI16) interacts with the adaptor molecule ASC and procaspase-1 to form a functional inflammasome
GO:0005654 nucleoplasm	IBA GO_REF:0000033	ACCEPT	Summary: IFI16 is predominantly localized to the nucleus under basal conditions. Nuclear localization is regulated by a multipartite nuclear localization signal (NLS) whose acetylation status determines subcellular distribution (PMID:7536752, UniProt Q16666). Reason: Nucleoplasm localization is well-established for IFI16. The protein contains nuclear localization signals and functions primarily in the nucleus where it senses viral DNA and regulates transcription. Supporting Evidence: PMID:7536752 The nuclear localization of IFI 16 antigen was confirmed by immunohistochemical staining of HL-60 cells treated with IFN-gamma, dimethylsulfoxide, and retinoic acid.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: IFI16 can localize to the cytosol, particularly during viral infection or when NLS acetylation promotes cytoplasmic distribution. Cytosolic IFI16 senses dsDNA and recruits STING to activate interferon signaling (PMID:20890285, PMID:22046441). Reason: Cytosolic localization is functionally important for IFI16's role in sensing cytoplasmic DNA and activating STING-dependent signaling. Subcellular distribution is dynamically regulated. Supporting Evidence: PMID:22046441 The induced levels of IFI16 and AIM2 proteins were detected primarily in the cytoplasm.
GO:0005730 nucleolus	IBA GO_REF:0000033	ACCEPT	Summary: IFI16 has been detected in the nucleolus in addition to the nucleoplasm. Nucleolar localization is supported by immunofluorescence studies and proteomics data (UniProt Q16666, HPA data). Reason: Nucleolar localization of IFI16 is supported by multiple lines of evidence including immunofluorescence and proteomics. This is consistent with its nuclear DNA-binding functions.
GO:0002218 activation of innate immune response	IEA GO_REF:0000002	ACCEPT	Summary: IFI16 activates innate immune responses through DNA sensing and downstream signaling via STING/IRF3 and inflammasome pathways. This IEA annotation based on InterPro mapping is consistent with experimental evidence. Reason: This IEA annotation is consistent with the IBA annotation and extensive experimental evidence supporting IFI16's role in innate immune activation.
GO:0002376 immune system process	IEA GO_REF:0000043	ACCEPT	Summary: IFI16 is involved in immune system processes, primarily innate immunity. This broad term is appropriate as IFI16 participates in DNA sensing, interferon induction, and inflammasome activation. Reason: This general term is accurate but less informative than more specific immune terms. IFI16 is clearly involved in immune processes, specifically innate immunity and antiviral defense.
GO:0003677 DNA binding	IEA GO_REF:0000043	ACCEPT	Summary: IFI16 binds DNA through its HIN-200 domains. The more specific term GO:0003690 (double-stranded DNA binding) is preferred as IFI16 specifically binds dsDNA via its OB-fold containing HIN domains. Reason: While accurate, this is a parent term of the more specific GO:0003690 (double-stranded DNA binding) which better describes IFI16 function. Acceptable as a broader IEA annotation.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: IFI16 is predominantly nuclear under basal conditions. Nuclear localization is well-established through immunofluorescence, subcellular fractionation, and its characterized nuclear localization signals (PMID:7536752). Reason: Nuclear localization is well-supported. IFI16 functions primarily in the nucleus for DNA sensing and transcriptional regulation. Supporting Evidence: PMID:7536752 The nuclear localization of IFI 16 antigen was confirmed by immunohistochemical staining of HL-60 cells treated with IFN-gamma, dimethylsulfoxide, and retinoic acid
GO:0005730 nucleolus	IEA GO_REF:0000117	ACCEPT	Summary: Nucleolar localization of IFI16 is supported by ARBA machine learning models and consistent with experimental observations. IFI16 has been detected in nucleolus by immunofluorescence. Reason: Nucleolar localization is consistent with other evidence for IFI16. This IEA from ARBA is supported by experimental data.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: IFI16 localizes to the cytoplasm particularly upon acetylation of its NLS or during viral infection. Cytoplasmic IFI16 senses foreign DNA and activates STING signaling (PMID:20890285, PMID:22046441). Reason: Cytoplasmic localization is well-documented and functionally relevant for IFI16's role in cytosolic DNA sensing.
GO:0006914 autophagy	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: This annotation is based on UniProtKB keyword mapping. PMID:21573174 shows IFI16 contributes to autophagy under glucose restriction via the ATM/AMPK/p53 pathway. However, autophagy is not a core function of IFI16 - it is a secondary effect of IFI16-mediated p53 activation under metabolic stress conditions (file:human/IFI16/IFI16-deep-research-falcon.md). Reason: IFI16's primary functions are DNA sensing, innate immunity, and transcriptional regulation. The connection to autophagy in PMID:21573174 is through activation of the ATM/AMPK/p53 pathway under glucose restriction - a secondary metabolic stress response rather than an evolved autophagy function. The annotation derives from keyword mapping but overstates IFI16's role in autophagy. Supporting Evidence: PMID:21573174 IFI16 induction by glucose restriction in human fibroblasts contributes to autophagy through activation of the ATM/AMPK/p53 pathway. file:human/IFI16/IFI16-deep-research-falcon.md IFI16's autophagy function is secondary, arising from p53 pathway activation during metabolic stress rather than an evolved autophagy function
GO:0006915 apoptotic process	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: IFI16 can modulate apoptosis through interactions with p53 and BRCA1, and through inflammasome-mediated pyroptosis. However, apoptosis regulation is a secondary consequence of IFI16's transcriptional regulatory and inflammasome functions. Reason: IFI16 can influence apoptosis through p53 interaction and inflammasome activation, but this is not its primary evolved function. The core functions are DNA sensing and innate immune activation.
GO:0006954 inflammatory response	IEA GO_REF:0000043	ACCEPT	Summary: IFI16 participates in inflammatory responses through inflammasome activation and cytokine production (IL-1beta). It can also have anti-inflammatory effects by suppressing AIM2 inflammasome activation (PMID:22046441). Reason: Inflammatory response involvement is a core function of IFI16 through its role in inflammasome assembly and IL-1beta maturation. The protein has context-dependent pro- and anti-inflammatory roles. Supporting Evidence: PMID:21575908 We demonstrate that during KSHV infection of endothelial cells, interferon gamma-inducible protein 16 (IFI16) interacts with the adaptor molecule ASC and procaspase-1 to form a functional inflammasome
GO:0035458 cellular response to interferon-beta	IEA GO_REF:0000002	ACCEPT	Summary: IFI16 expression is induced by type I interferons including IFN-beta, and the protein mediates downstream effects of interferon signaling. This IEA is consistent with the IBA annotation. Reason: This annotation is consistent with IFI16's role as an interferon-inducible gene that mediates interferon-stimulated responses.
GO:0045087 innate immune response	IEA GO_REF:0000043	ACCEPT	Summary: IFI16 is a key component of the innate immune system, functioning as a DNA sensor that activates type I interferon and inflammasome responses to detect intracellular pathogens (PMID:20890285, PMID:21575908). Reason: Innate immune response is a core function of IFI16. The protein senses foreign DNA and activates both interferon and inflammasome pathways. Supporting Evidence: PMID:20890285 Here we identify IFI16, a PYHIN protein, as an intracellular DNA sensor that mediates the induction of interferon-β (IFN-β)
GO:0005515 protein binding	IPI PMID:14654789 A member of the Pyrin family, IFI16, is a novel BRCA1-associ...	ACCEPT	Summary: IFI16 interacts with BRCA1 as demonstrated in PMID:14654789. While protein binding is general, the IPI evidence documents a specific interaction relevant to DNA damage response. Reason: While protein binding is general, this IPI annotation documents the specific IFI16-BRCA1 interaction which is functionally relevant. IPI annotations appropriately capture specific protein-protein interactions. Supporting Evidence: PMID:14654789 A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway.
GO:0005515 protein binding	IPI PMID:16494870 Androgen receptor auto-regulates its expression by a negativ...	ACCEPT	Summary: This annotation reflects IFI16 protein interactions in the context of androgen receptor signaling. IPI evidence documents specific interactions. Reason: IPI annotations document specific protein-protein interactions. While protein binding is general, the evidence type indicates a specific demonstrated interaction. Supporting Evidence: PMID:16494870 2006 Feb 17. Androgen receptor auto-regulates its expression by a negative feedback loop through upregulation of IFI16 protein.
GO:0005515 protein binding	IPI PMID:20890285 IFI16 is an innate immune sensor for intracellular DNA.	ACCEPT	Summary: This annotation reflects IFI16 interaction with STING (TMEM173) during DNA sensing. The IFI16-STING interaction is crucial for type I interferon induction. Reason: The IFI16-STING interaction is a key functional interaction for DNA sensing. While protein binding is general, IPI evidence documents this specific and important interaction. Supporting Evidence: PMID:20890285 IFI16 is an innate immune sensor for intracellular DNA.
GO:0005515 protein binding	IPI PMID:30833792 A protein-interaction network of interferon-stimulated genes...	UNDECIDED	Summary: This annotation from a protein interaction network study of interferon-stimulated genes. Protein binding is accurate but uninformative. Reason: Cannot access PMID:30833792 to determine the specific protein interactions identified. Protein binding is too general but may be acceptable for high-throughput interaction data. Supporting Evidence: PMID:30833792 Mar 4. A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: IFI16 nucleoplasm localization is supported by immunofluorescence data curated by HPA. This is consistent with IFI16's nuclear functions. Reason: Nucleoplasm localization is well-established for IFI16 and consistent with its role in nuclear DNA sensing and transcriptional regulation.
GO:0005730 nucleolus	IDA GO_REF:0000052	ACCEPT	Summary: IFI16 nucleolar localization is supported by immunofluorescence data. This is consistent with multiple lines of evidence for nucleolar presence. Reason: Nucleolar localization of IFI16 is supported by immunofluorescence and proteomics data.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: IFI16 cytosolic localization is supported by immunofluorescence data. Cytosolic IFI16 functions in DNA sensing and STING activation. Reason: Cytosolic localization is well-documented and functionally important for IFI16's role in sensing cytoplasmic DNA.
GO:0050727 regulation of inflammatory response	IDA PMID:21575908 IFI16 acts as a nuclear pathogen sensor to induce the inflam...	ACCEPT	Summary: IFI16 regulates inflammatory responses through inflammasome formation during KSHV infection, leading to IL-1beta production (PMID:21575908). This is a core function. Reason: Regulation of inflammatory response is a core function of IFI16 through its role in inflammasome activation and cytokine maturation. Supporting Evidence: PMID:21575908 We demonstrate that during KSHV infection of endothelial cells, interferon gamma-inducible protein 16 (IFI16) interacts with the adaptor molecule ASC and procaspase-1 to form a functional inflammasome
GO:0045814 negative regulation of gene expression, epigenetic	IMP PMID:24413532 Differential regulation of estrogen receptor α expression in...	KEEP AS NON CORE	Summary: PMID:24413532 describes IFI16 involvement in MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. This represents a secondary function in transcriptional regulation. Reason: Epigenetic regulation is a secondary function of IFI16 related to its transcriptional regulatory activities, not its primary DNA sensing function. Supporting Evidence: PMID:24413532 2014 Jan 10. Differential regulation of estrogen receptor α expression in breast cancer cells by metastasis-associated protein 1.
GO:0003690 double-stranded DNA binding	IDA PMID:7536752 IFI 16 gene encodes a nuclear protein whose expression is in...	ACCEPT	Summary: PMID:7536752 directly demonstrates IFI16 binds dsDNA in vitro using DNA-cellulose binding assays. This is a core molecular function. Reason: dsDNA binding is a fundamental molecular function of IFI16 demonstrated by direct biochemical evidence. Supporting Evidence: PMID:7536752 Nuclear IFI 16 was able to bind double-stranded DNA in vitro and exhibited a similar elution profile from DNA-cellulose as previously observed for MNDA and 204
GO:0005515 protein binding	IPI PMID:24531343 The PYRIN domain-only protein POP3 inhibits ALR inflammasome...	ACCEPT	Summary: PMID:24531343 shows IFI16 interaction with PYDC5/POP3 which inhibits ALR inflammasomes. Protein binding is accurate but uninformative. Reason: While protein binding is general, the interaction with POP3 is relevant to IFI16's inflammasome regulatory function. Supporting Evidence: PMID:24531343 The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses.
GO:0005634 nucleus	IDA PMID:24531343 The PYRIN domain-only protein POP3 inhibits ALR inflammasome...	ACCEPT	Summary: PMID:24531343 demonstrates IFI16 nuclear localization in the context of inflammasome regulation studies. Reason: Nuclear localization is well-established for IFI16 and consistent with its functions. Supporting Evidence: PMID:24531343 The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses.
GO:0005829 cytosol	IPI PMID:24531343 The PYRIN domain-only protein POP3 inhibits ALR inflammasome...	ACCEPT	Summary: Cytosolic localization of IFI16 demonstrated in the context of interaction studies with POP3. Reason: Cytosolic localization is consistent with IFI16's role in cytoplasmic DNA sensing. Supporting Evidence: PMID:24531343 The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses.
GO:0051607 defense response to virus	IDA PMID:21478870 A diverse range of gene products are effectors of the type I...	ACCEPT	Summary: PMID:21478870 is a systematic screen identifying type I interferon antiviral effectors, including IFI16. Defense against viruses is a core function. Reason: Antiviral defense is a core function of IFI16 as a DNA sensor that detects viral DNA and activates interferon responses. Supporting Evidence: PMID:21478870 A diverse range of gene products are effectors of the type I interferon antiviral response.
GO:0005515 protein binding	IPI PMID:24413532 Differential regulation of estrogen receptor α expression in...	ACCEPT	Summary: PMID:24413532 shows IFI16 interaction with MTA1 in breast cancer epigenetic regulation. The IPI evidence documents this specific protein interaction. Reason: While protein binding is general, this IPI annotation documents the specific IFI16-MTA1 interaction relevant to transcriptional regulation. Supporting Evidence: PMID:24413532 2014 Jan 10. Differential regulation of estrogen receptor α expression in breast cancer cells by metastasis-associated protein 1.
GO:0005634 nucleus	IDA PMID:24413532 Differential regulation of estrogen receptor α expression in...	ACCEPT	Summary: Nuclear localization of IFI16 demonstrated in breast cancer cells in context of MTA1 interaction studies. Reason: Nuclear localization is well-established for IFI16. Supporting Evidence: PMID:24413532 2014 Jan 10. Differential regulation of estrogen receptor α expression in breast cancer cells by metastasis-associated protein 1.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	UNDECIDED	Summary: PMID:19946888 is a proteomics study of NK cell membrane proteins. Membrane association of IFI16 is not well-established as a core localization. Reason: Cannot access PMID:19946888 to evaluate the evidence. Membrane localization is not a well-characterized aspect of IFI16 function and may represent a minor or indirect association. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells.
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	UNDECIDED	Summary: PMID:22658674 is a large-scale atlas of mRNA-binding proteins. RNA binding by IFI16 is not well-characterized functionally and may represent incidental binding. Reason: Cannot access PMID:22658674. RNA binding is not a well-established function of IFI16 whose primary function is dsDNA binding. This may be over-annotation from high-throughput data. Supporting Evidence: PMID:22658674 May 31. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:22046441 IFI16 protein mediates the anti-inflammatory actions of the ...	KEEP AS NON CORE	Summary: PMID:22046441 shows IFI16 mediates anti-inflammatory effects of type I interferons through suppression of inflammasome activation. Transcriptional repression is a secondary function. Reason: Transcriptional repression is a secondary function of IFI16 related to its broader regulatory activities, not its primary DNA sensing function. Supporting Evidence: PMID:22046441 IFI16 protein mediates the anti-inflammatory actions of the type-I interferons through suppression of activation of caspase-1 by inflammasomes.
GO:0001819 positive regulation of cytokine production	TAS PMID:22046441 IFI16 protein mediates the anti-inflammatory actions of the ...	ACCEPT	Summary: IFI16 can both promote (via inflammasome) and inhibit cytokine production depending on context. PMID:22046441 shows IFI16 suppresses caspase-1 activation. Reason: IFI16 positively regulates cytokine production through inflammasome activation and IL-1beta maturation, though it also has anti-inflammatory roles in some contexts. Supporting Evidence: PMID:22046441 IFI16 protein mediates the anti-inflammatory actions of the type-I interferons through suppression of activation of caspase-1 by inflammasomes.
GO:0008134 transcription factor binding	IDA PMID:12894224 Role of IFI 16, a member of the interferon-inducible p200-pr...	ACCEPT	Summary: PMID:12894224 describes IFI16 role in prostate epithelial senescence and its interactions with transcription factors. This is a more specific and informative term than protein binding. Reason: Transcription factor binding is a well-documented molecular function of IFI16. The protein interacts with p53, Rb, E2F1, and Sp1 family members. Supporting Evidence: PMID:12894224 Role of IFI 16, a member of the interferon-inducible p200-protein family, in prostate epithelial cellular senescence.
GO:0008134 transcription factor binding	IDA PMID:22291595 The intracellular DNA sensor IFI16 gene acts as restriction ...	ACCEPT	Summary: PMID:22291595 shows IFI16 inhibits HCMV replication by blocking Sp1 binding to viral promoters. Transcription factor binding is a key mechanism. Reason: Transcription factor binding, specifically to Sp1, is directly demonstrated in PMID:22291595 as a mechanism for IFI16's antiviral activity. Supporting Evidence: PMID:22291595 suppression of the UL54 promoter is mediated by IFI16-induced blocking of Sp1-like factors
GO:0010506 regulation of autophagy	IEP PMID:21573174 IFI16 induction by glucose restriction in human fibroblasts ...	MARK AS OVER ANNOTATED	Summary: PMID:21573174 shows IFI16 induction correlates with autophagy during glucose restriction via ATM/AMPK/p53 pathway. This is a secondary effect, not a primary autophagy function. Reason: IFI16's connection to autophagy is indirect, via p53 pathway activation during metabolic stress. This is not an evolved autophagy function but a secondary consequence of its p53 interaction. Supporting Evidence: PMID:21573174 IFI16 induction by glucose restriction in human fibroblasts contributes to autophagy through activation of the ATM/AMPK/p53 pathway
GO:0032731 positive regulation of interleukin-1 beta production	IDA PMID:21575908 IFI16 acts as a nuclear pathogen sensor to induce the inflam...	ACCEPT	Summary: IFI16 promotes IL-1beta production through inflammasome activation during KSHV infection (PMID:21575908). This is a core function. Reason: Positive regulation of IL-1beta production through inflammasome activation is a core innate immune function of IFI16. Supporting Evidence: PMID:21575908 We demonstrate that during KSHV infection of endothelial cells, interferon gamma-inducible protein 16 (IFI16) interacts with the adaptor molecule ASC and procaspase-1 to form a functional inflammasome
GO:0042149 cellular response to glucose starvation	IDA PMID:21573174 IFI16 induction by glucose restriction in human fibroblasts ...	KEEP AS NON CORE	Summary: PMID:21573174 shows IFI16 is induced by glucose restriction and participates in the cellular stress response. This is a secondary function. Reason: Response to glucose starvation is not a core function of IFI16. The protein is induced under metabolic stress but its primary functions are DNA sensing and innate immunity. Supporting Evidence: PMID:21573174 glucose restriction or treatment of human diploid fibroblasts (HDFs) with the activators of the AMPK/p53 pathway induced the expression of IFI16 protein
GO:0043392 negative regulation of DNA binding	IDA PMID:22291595 The intracellular DNA sensor IFI16 gene acts as restriction ...	ACCEPT	Summary: PMID:22291595 shows IFI16 negatively regulates Sp1 DNA binding to viral promoters, inhibiting HCMV replication. This is part of its antiviral mechanism. Reason: Negative regulation of DNA binding (specifically Sp1 binding to viral promoters) is a mechanism by which IFI16 restricts herpesvirus replication. Supporting Evidence: PMID:22291595 suppression of the UL54 promoter is mediated by IFI16-induced blocking of Sp1-like factors
GO:0045071 negative regulation of viral genome replication	IDA PMID:22291595 The intracellular DNA sensor IFI16 gene acts as restriction ...	ACCEPT	Summary: PMID:22291595 demonstrates IFI16 acts as a restriction factor against HCMV replication by inhibiting viral early gene expression. This is a core antiviral function. Reason: Negative regulation of viral genome replication is a core function of IFI16 as an antiviral restriction factor. Supporting Evidence: PMID:22291595 IFI16 overexpression decreased both virus yield and viral DNA copy number
GO:0045824 negative regulation of innate immune response	IDA PMID:22046441 IFI16 protein mediates the anti-inflammatory actions of the ...	ACCEPT	Summary: PMID:22046441 shows IFI16 suppresses AIM2 and NLRP3 inflammasome activation, having anti-inflammatory effects. This reflects IFI16's dual role in immune regulation. Reason: IFI16 has both pro- and anti-inflammatory functions. Its ability to suppress AIM2 inflammasome is well-documented and represents negative regulation of innate immunity. Supporting Evidence: PMID:22046441 the expression of IFI16 protein in THP-1 cells suppresses the activation of caspase-1 by the AIM2 and NLRP3 inflammasomes
GO:0051607 defense response to virus	IMP PMID:21575908 IFI16 acts as a nuclear pathogen sensor to induce the inflam...	ACCEPT	Summary: PMID:21575908 shows IFI16 senses KSHV DNA and activates inflammasome, contributing to antiviral defense. Defense response to virus is a core function. Reason: Defense response to virus is a core function of IFI16 as a DNA sensor that detects herpesvirus genomes and activates innate immune responses. Supporting Evidence: PMID:21575908 IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection
GO:0072332 intrinsic apoptotic signaling pathway by p53 class mediator	IMP PMID:21573174 IFI16 induction by glucose restriction in human fibroblasts ...	KEEP AS NON CORE	Summary: PMID:21573174 shows IFI16 participates in p53-dependent apoptotic signaling under glucose restriction. This is a secondary function related to p53 interaction. Reason: p53-mediated apoptotic signaling is a secondary function of IFI16 arising from its interaction with p53, not its primary DNA sensing function. Supporting Evidence: PMID:21573174 The induced levels of IFI16 protein were associated with the induction of autophagy and reduced cell survival
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:12894224 Role of IFI 16, a member of the interferon-inducible p200-pr...	KEEP AS NON CORE	Summary: PMID:12894224 describes IFI16 role in transcriptional repression in prostate epithelial senescence. Transcriptional repression is a secondary function. Reason: Transcriptional repression is a secondary function related to IFI16's broader role as a transcriptional regulator, not its primary DNA sensing function. Supporting Evidence: PMID:12894224 Role of IFI 16, a member of the interferon-inducible p200-protein family, in prostate epithelial cellular senescence.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:11146555 Functional interaction between p53 and the interferon-induci...	KEEP AS NON CORE	Summary: PMID:11146555 shows IFI16 enhances p53-mediated transcriptional activation. IFI16 can both activate and repress transcription depending on context. Reason: Positive regulation of transcription is a secondary function related to IFI16's interaction with p53, not its primary DNA sensing function. Supporting Evidence: PMID:11146555 Functional interaction between p53 and the interferon-inducible nucleoprotein IFI 16.
GO:0071479 cellular response to ionizing radiation	IDA PMID:14654789 A member of the Pyrin family, IFI16, is a novel BRCA1-associ...	KEEP AS NON CORE	Summary: PMID:14654789 describes IFI16 involvement in the DNA damage response pathway through BRCA1 and p53 interactions. This is a secondary function. Reason: Response to ionizing radiation is a secondary function related to IFI16's interactions with DNA damage response proteins BRCA1 and p53, not its primary innate immune function. Supporting Evidence: PMID:14654789 A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway.
GO:0005829 cytosol	TAS Reactome:R-HSA-1834951	ACCEPT	Summary: Reactome pathway R-HSA-1834951 describes IFI16 binding cytosolic dsDNA, supporting cytosolic localization. This is functionally relevant for DNA sensing. Reason: Cytosolic localization is well-established and functionally important for IFI16's role in sensing cytoplasmic DNA and activating STING signaling.
GO:0005634 nucleus	IDA PMID:19158679 An orthogonal proteomic-genomic screen identifies AIM2 as a ...	ACCEPT	Summary: PMID:19158679 identified AIM2 as a cytoplasmic DNA sensor and discusses PYHIN family nuclear localization including IFI16. Reason: Nuclear localization is well-established for IFI16. Supporting Evidence: PMID:19158679 An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome.
GO:0016607 nuclear speck	IDA PMID:19158679 An orthogonal proteomic-genomic screen identifies AIM2 as a ...	ACCEPT	Summary: Nuclear speck localization of IFI16 suggested by PMID:19158679 data. Nuclear specks are sites of splicing factor concentration. Reason: Nuclear speck localization is consistent with IFI16's nuclear functions and its role in transcriptional regulation. Supporting Evidence: PMID:19158679 An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome.
GO:0005654 nucleoplasm	IDA PMID:14654789 A member of the Pyrin family, IFI16, is a novel BRCA1-associ...	ACCEPT	Summary: PMID:14654789 demonstrates IFI16 nucleoplasm localization in the context of BRCA1 and p53 interaction studies. Reason: Nucleoplasm localization is well-established for IFI16. Supporting Evidence: PMID:14654789 A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway.
GO:0005730 nucleolus	IDA PMID:14654789 A member of the Pyrin family, IFI16, is a novel BRCA1-associ...	ACCEPT	Summary: PMID:14654789 demonstrates IFI16 nucleolar localization using immunofluorescence microscopy in the context of BRCA1 interaction studies. Reason: Nucleolar localization is well-established for IFI16. The protein localizes to both nucleoplasm and nucleoli as demonstrated by multiple immunofluorescence studies. Supporting Evidence: PMID:14654789 We found that IFI16 was localized in the nucleoplasm and nucleoli.
GO:0042771 intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	IDA PMID:14654789 A member of the Pyrin family, IFI16, is a novel BRCA1-associ...	KEEP AS NON CORE	Summary: PMID:14654789 demonstrates IFI16 participates in p53-mediated apoptosis in response to DNA damage through its interaction with BRCA1. Reason: This is a secondary function of IFI16 related to DNA damage response and cell death. The core function of IFI16 is innate immune DNA sensing. The p53-mediated apoptotic signaling represents a specialized function in genotoxic stress contexts. Supporting Evidence: PMID:14654789 Coexpression of IFI16 and BRCA1 enhanced DNA damage-induced apoptosis in mouse embryonic fibroblasts from BRCA1 mutant mice expressing wild-type p53
GO:0030224 monocyte differentiation	IDA PMID:9766636 The IFN-inducible nucleoprotein IFI 16 is expressed in cells...	KEEP AS NON CORE	Summary: PMID:9766636 describes IFI16 expression during monocyte differentiation. IFI16 may play a role in myeloid cell differentiation as part of interferon responses. Reason: Monocyte differentiation is a secondary function of IFI16. While the protein is expressed during myeloid differentiation, its primary evolved functions are DNA sensing and innate immunity. Supporting Evidence: PMID:9766636 The IFN-inducible nucleoprotein IFI 16 is expressed in cells of the monocyte lineage, but is rapidly and markedly down-regulated in other myeloid precursor populations.
GO:0005634 nucleus	IDA PMID:7536752 IFI 16 gene encodes a nuclear protein whose expression is in...	ACCEPT	Summary: PMID:7536752 directly demonstrates nuclear localization of IFI16 by immunohistochemistry and biochemical fractionation. Reason: Nuclear localization is a well-established core feature of IFI16. Supporting Evidence: PMID:7536752 The nuclear localization of IFI 16 antigen was confirmed by immunohistochemical staining of HL-60 cells treated with IFN-gamma, dimethylsulfoxide, and retinoic acid
GO:0030099 myeloid cell differentiation	NAS PMID:7536752 IFI 16 gene encodes a nuclear protein whose expression is in...	KEEP AS NON CORE	Summary: PMID:7536752 describes IFI16 expression during myeloid cell differentiation in HL-60 cells. This is a secondary function. Reason: Myeloid cell differentiation is a secondary function of IFI16. The protein is expressed during differentiation but its primary functions are DNA sensing and innate immunity. Supporting Evidence: PMID:7536752 Culture of HL-60 cells in medium containing dimethylsulfoxide, retinoic acid, and 1,25 dihydroxyvitamin D3, agents that stimulate the differentiation of HL-60 along myeloid pathways, also caused the induction of IFI 16 mRNA
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:9642285 The human interferon-inducible protein, IFI 16, is a repress...	KEEP AS NON CORE	Summary: IFI16 negatively regulates transcription through interactions with E2F transcription factors and other mechanisms. This is a secondary transcriptional regulatory function. Reason: Negative regulation of transcription is a secondary function of IFI16 related to its interactions with transcription factors, not its primary DNA sensing function. Supporting Evidence: PMID:9642285 The human interferon-inducible protein, IFI 16, is a repressor of transcription.

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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