id: Q16666
gene_symbol: IFI16
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: IFI16 (Gamma-interferon-inducible protein 16) is a PYHIN family 
  nuclear DNA sensor that plays a central role in innate immunity. It contains 
  an N-terminal pyrin domain (PYD) and two C-terminal HIN-200 domains that bind 
  double-stranded DNA via OB-fold structures. The primary functions of IFI16 
  include sensing cytosolic and nuclear viral DNA during herpesvirus infection, 
  activating STING-dependent type I interferon responses, and forming 
  ASC-dependent inflammasomes that activate caspase-1 and IL-1beta maturation. 
  IFI16 also functions as a transcriptional regulator, interacting with p53 and 
  Sp1 family transcription factors to modulate gene expression. It acts as a 
  restriction factor against herpesviruses (HSV-1, HCMV, KSHV) by binding viral 
  DNA and inhibiting viral gene expression. The protein is predominantly nuclear
  but can translocate to the cytoplasm depending on acetylation status and upon 
  viral infection.
existing_annotations:
  - term:
      id: GO:0003690
      label: double-stranded DNA binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:7536752
          supporting_text: "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."
        - reference_id: PMID:20890285
          supporting_text: "IFI16 directly associated with IFN-beta-inducing viral
            DNA motifs."
  - term:
      id: GO:0035458
      label: cellular response to interferon-beta
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:22046441
          supporting_text: "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."
  - term:
      id: GO:0002218
      label: activation of innate immune response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:20890285
          supporting_text: "Here we identify IFI16, a PYHIN protein, as an intracellular
            DNA sensor that mediates the induction of interferon-β (IFN-β)"
        - reference_id: PMID:21575908
          supporting_text: "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"
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:7536752
          supporting_text: "The nuclear localization of IFI 16 antigen was confirmed
            by immunohistochemical staining of HL-60 cells treated with IFN-gamma,
            dimethylsulfoxide, and retinoic acid."
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      reason: Cytosolic localization is functionally important for IFI16's role 
        in sensing cytoplasmic DNA and activating STING-dependent signaling. 
        Subcellular distribution is dynamically regulated.
      supported_by:
        - reference_id: PMID:22046441
          supporting_text: "The induced levels of IFI16 and AIM2 proteins were detected
            primarily in the cytoplasm."
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      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.
  - term:
      id: GO:0002218
      label: activation of innate immune response
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      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.
      action: ACCEPT
      reason: This IEA annotation is consistent with the IBA annotation and 
        extensive experimental evidence supporting IFI16's role in innate immune
        activation.
  - term:
      id: GO:0002376
      label: immune system process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: ACCEPT
      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.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      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).
      action: ACCEPT
      reason: Nuclear localization is well-supported. IFI16 functions primarily 
        in the nucleus for DNA sensing and transcriptional regulation.
      supported_by:
        - reference_id: PMID:7536752
          supporting_text: "The nuclear localization of IFI 16 antigen was confirmed
            by immunohistochemical staining of HL-60 cells treated with IFN-gamma,
            dimethylsulfoxide, and retinoic acid"
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      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.
      action: ACCEPT
      reason: Nucleolar localization is consistent with other evidence for 
        IFI16. This IEA from ARBA is supported by experimental data.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      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).
      action: ACCEPT
      reason: Cytoplasmic localization is well-documented and functionally 
        relevant for IFI16's role in cytosolic DNA sensing.
  - term:
      id: GO:0006914
      label: autophagy
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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).
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:21573174
          supporting_text: "IFI16 induction by glucose restriction in human fibroblasts
            contributes to autophagy through activation of the ATM/AMPK/p53 pathway."
        - reference_id: file:human/IFI16/IFI16-deep-research-falcon.md
          supporting_text: "IFI16's autophagy function is secondary, arising from
            p53 pathway activation during metabolic stress rather than an evolved
            autophagy function"
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
  - term:
      id: GO:0006954
      label: inflammatory response
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:21575908
          supporting_text: "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"
  - term:
      id: GO:0035458
      label: cellular response to interferon-beta
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      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.
      action: ACCEPT
      reason: This annotation is consistent with IFI16's role as an 
        interferon-inducible gene that mediates interferon-stimulated responses.
  - term:
      id: GO:0045087
      label: innate immune response
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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).
      action: ACCEPT
      reason: Innate immune response is a core function of IFI16. The protein 
        senses foreign DNA and activates both interferon and inflammasome 
        pathways.
      supported_by:
        - reference_id: PMID:20890285
          supporting_text: "Here we identify IFI16, a PYHIN protein, as an intracellular
            DNA sensor that mediates the induction of interferon-β (IFN-β)"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14654789
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:14654789
          supporting_text: A member of the Pyrin family, IFI16, is a novel 
            BRCA1-associated protein involved in the p53-mediated apoptosis 
            pathway.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16494870
    review:
      summary: This annotation reflects IFI16 protein interactions in the 
        context of androgen receptor signaling. IPI evidence documents specific 
        interactions.
      action: ACCEPT
      reason: IPI annotations document specific protein-protein interactions. 
        While protein binding is general, the evidence type indicates a specific
        demonstrated interaction.
      supported_by:
        - reference_id: PMID:16494870
          supporting_text: 2006 Feb 17. Androgen receptor auto-regulates its 
            expression by a negative feedback loop through upregulation of IFI16
            protein.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20890285
    review:
      summary: This annotation reflects IFI16 interaction with STING (TMEM173) 
        during DNA sensing. The IFI16-STING interaction is crucial for type I 
        interferon induction.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:20890285
          supporting_text: IFI16 is an innate immune sensor for intracellular 
            DNA.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30833792
    review:
      summary: This annotation from a protein interaction network study of 
        interferon-stimulated genes. Protein binding is accurate but 
        uninformative.
      action: UNDECIDED
      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.
      supported_by:
        - reference_id: PMID:30833792
          supporting_text: Mar 4. A protein-interaction network of 
            interferon-stimulated genes extends the innate immune system 
            landscape.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: IFI16 nucleoplasm localization is supported by immunofluorescence
        data curated by HPA. This is consistent with IFI16's nuclear functions.
      action: ACCEPT
      reason: Nucleoplasm localization is well-established for IFI16 and 
        consistent with its role in nuclear DNA sensing and transcriptional 
        regulation.
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: IFI16 nucleolar localization is supported by immunofluorescence 
        data. This is consistent with multiple lines of evidence for nucleolar 
        presence.
      action: ACCEPT
      reason: Nucleolar localization of IFI16 is supported by immunofluorescence
        and proteomics data.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: IFI16 cytosolic localization is supported by immunofluorescence 
        data. Cytosolic IFI16 functions in DNA sensing and STING activation.
      action: ACCEPT
      reason: Cytosolic localization is well-documented and functionally 
        important for IFI16's role in sensing cytoplasmic DNA.
  - term:
      id: GO:0050727
      label: regulation of inflammatory response
    evidence_type: IDA
    original_reference_id: PMID:21575908
    review:
      summary: IFI16 regulates inflammatory responses through inflammasome 
        formation during KSHV infection, leading to IL-1beta production 
        (PMID:21575908). This is a core function.
      action: ACCEPT
      reason: Regulation of inflammatory response is a core function of IFI16 
        through its role in inflammasome activation and cytokine maturation.
      supported_by:
        - reference_id: PMID:21575908
          supporting_text: "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"
  - term:
      id: GO:0045814
      label: negative regulation of gene expression, epigenetic
    evidence_type: IMP
    original_reference_id: PMID:24413532
    review:
      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.
      action: KEEP_AS_NON_CORE
      reason: Epigenetic regulation is a secondary function of IFI16 related to 
        its transcriptional regulatory activities, not its primary DNA sensing 
        function.
      supported_by:
        - reference_id: PMID:24413532
          supporting_text: 2014 Jan 10. Differential regulation of estrogen 
            receptor α expression in breast cancer cells by 
            metastasis-associated protein 1.
  - term:
      id: GO:0003690
      label: double-stranded DNA binding
    evidence_type: IDA
    original_reference_id: PMID:7536752
    review:
      summary: PMID:7536752 directly demonstrates IFI16 binds dsDNA in vitro 
        using DNA-cellulose binding assays. This is a core molecular function.
      action: ACCEPT
      reason: dsDNA binding is a fundamental molecular function of IFI16 
        demonstrated by direct biochemical evidence.
      supported_by:
        - reference_id: PMID:7536752
          supporting_text: "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"
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24531343
    review:
      summary: PMID:24531343 shows IFI16 interaction with PYDC5/POP3 which 
        inhibits ALR inflammasomes. Protein binding is accurate but 
        uninformative.
      action: ACCEPT
      reason: While protein binding is general, the interaction with POP3 is 
        relevant to IFI16's inflammasome regulatory function.
      supported_by:
        - reference_id: PMID:24531343
          supporting_text: The PYRIN domain-only protein POP3 inhibits ALR 
            inflammasomes and regulates responses to infection with DNA viruses.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:24531343
    review:
      summary: PMID:24531343 demonstrates IFI16 nuclear localization in the 
        context of inflammasome regulation studies.
      action: ACCEPT
      reason: Nuclear localization is well-established for IFI16 and consistent 
        with its functions.
      supported_by:
        - reference_id: PMID:24531343
          supporting_text: The PYRIN domain-only protein POP3 inhibits ALR 
            inflammasomes and regulates responses to infection with DNA viruses.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IPI
    original_reference_id: PMID:24531343
    review:
      summary: Cytosolic localization of IFI16 demonstrated in the context of 
        interaction studies with POP3.
      action: ACCEPT
      reason: Cytosolic localization is consistent with IFI16's role in 
        cytoplasmic DNA sensing.
      supported_by:
        - reference_id: PMID:24531343
          supporting_text: The PYRIN domain-only protein POP3 inhibits ALR 
            inflammasomes and regulates responses to infection with DNA viruses.
  - term:
      id: GO:0051607
      label: defense response to virus
    evidence_type: IDA
    original_reference_id: PMID:21478870
    review:
      summary: PMID:21478870 is a systematic screen identifying type I 
        interferon antiviral effectors, including IFI16. Defense against viruses
        is a core function.
      action: ACCEPT
      reason: Antiviral defense is a core function of IFI16 as a DNA sensor that
        detects viral DNA and activates interferon responses.
      supported_by:
        - reference_id: PMID:21478870
          supporting_text: A diverse range of gene products are effectors of the
            type I interferon antiviral response.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24413532
    review:
      summary: PMID:24413532 shows IFI16 interaction with MTA1 in breast cancer 
        epigenetic regulation. The IPI evidence documents this specific protein 
        interaction.
      action: ACCEPT
      reason: While protein binding is general, this IPI annotation documents 
        the specific IFI16-MTA1 interaction relevant to transcriptional 
        regulation.
      supported_by:
        - reference_id: PMID:24413532
          supporting_text: 2014 Jan 10. Differential regulation of estrogen 
            receptor α expression in breast cancer cells by 
            metastasis-associated protein 1.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:24413532
    review:
      summary: Nuclear localization of IFI16 demonstrated in breast cancer cells
        in context of MTA1 interaction studies.
      action: ACCEPT
      reason: Nuclear localization is well-established for IFI16.
      supported_by:
        - reference_id: PMID:24413532
          supporting_text: 2014 Jan 10. Differential regulation of estrogen 
            receptor α expression in breast cancer cells by 
            metastasis-associated protein 1.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: HDA
    original_reference_id: PMID:19946888
    review:
      summary: PMID:19946888 is a proteomics study of NK cell membrane proteins.
        Membrane association of IFI16 is not well-established as a core 
        localization.
      action: UNDECIDED
      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.
      supported_by:
        - reference_id: PMID:19946888
          supporting_text: Defining the membrane proteome of NK cells.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22658674
    review:
      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.
      action: UNDECIDED
      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.
      supported_by:
        - reference_id: PMID:22658674
          supporting_text: May 31. Insights into RNA biology from an atlas of 
            mammalian mRNA-binding proteins.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:22046441
    review:
      summary: PMID:22046441 shows IFI16 mediates anti-inflammatory effects of 
        type I interferons through suppression of inflammasome activation. 
        Transcriptional repression is a secondary function.
      action: KEEP_AS_NON_CORE
      reason: Transcriptional repression is a secondary function of IFI16 
        related to its broader regulatory activities, not its primary DNA 
        sensing function.
      supported_by:
        - reference_id: PMID:22046441
          supporting_text: IFI16 protein mediates the anti-inflammatory actions 
            of the type-I interferons through suppression of activation of 
            caspase-1 by inflammasomes.
  - term:
      id: GO:0001819
      label: positive regulation of cytokine production
    evidence_type: TAS
    original_reference_id: PMID:22046441
    review:
      summary: IFI16 can both promote (via inflammasome) and inhibit cytokine 
        production depending on context. PMID:22046441 shows IFI16 suppresses 
        caspase-1 activation.
      action: ACCEPT
      reason: IFI16 positively regulates cytokine production through 
        inflammasome activation and IL-1beta maturation, though it also has 
        anti-inflammatory roles in some contexts.
      supported_by:
        - reference_id: PMID:22046441
          supporting_text: IFI16 protein mediates the anti-inflammatory actions 
            of the type-I interferons through suppression of activation of 
            caspase-1 by inflammasomes.
  - term:
      id: GO:0008134
      label: transcription factor binding
    evidence_type: IDA
    original_reference_id: PMID:12894224
    review:
      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.
      action: ACCEPT
      reason: Transcription factor binding is a well-documented molecular 
        function of IFI16. The protein interacts with p53, Rb, E2F1, and Sp1 
        family members.
      supported_by:
        - reference_id: PMID:12894224
          supporting_text: Role of IFI 16, a member of the interferon-inducible 
            p200-protein family, in prostate epithelial cellular senescence.
  - term:
      id: GO:0008134
      label: transcription factor binding
    evidence_type: IDA
    original_reference_id: PMID:22291595
    review:
      summary: PMID:22291595 shows IFI16 inhibits HCMV replication by blocking 
        Sp1 binding to viral promoters. Transcription factor binding is a key 
        mechanism.
      action: ACCEPT
      reason: Transcription factor binding, specifically to Sp1, is directly 
        demonstrated in PMID:22291595 as a mechanism for IFI16's antiviral 
        activity.
      supported_by:
        - reference_id: PMID:22291595
          supporting_text: "suppression of the UL54 promoter is mediated by IFI16-induced
            blocking of Sp1-like factors"
  - term:
      id: GO:0010506
      label: regulation of autophagy
    evidence_type: IEP
    original_reference_id: PMID:21573174
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:21573174
          supporting_text: "IFI16 induction by glucose restriction in human fibroblasts
            contributes to autophagy through activation of the ATM/AMPK/p53 pathway"
  - term:
      id: GO:0032731
      label: positive regulation of interleukin-1 beta production
    evidence_type: IDA
    original_reference_id: PMID:21575908
    review:
      summary: IFI16 promotes IL-1beta production through inflammasome 
        activation during KSHV infection (PMID:21575908). This is a core 
        function.
      action: ACCEPT
      reason: Positive regulation of IL-1beta production through inflammasome 
        activation is a core innate immune function of IFI16.
      supported_by:
        - reference_id: PMID:21575908
          supporting_text: "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"
  - term:
      id: GO:0042149
      label: cellular response to glucose starvation
    evidence_type: IDA
    original_reference_id: PMID:21573174
    review:
      summary: PMID:21573174 shows IFI16 is induced by glucose restriction and 
        participates in the cellular stress response. This is a secondary 
        function.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:21573174
          supporting_text: "glucose restriction or treatment of human diploid fibroblasts
            (HDFs) with the activators of the AMPK/p53 pathway induced the expression
            of IFI16 protein"
  - term:
      id: GO:0043392
      label: negative regulation of DNA binding
    evidence_type: IDA
    original_reference_id: PMID:22291595
    review:
      summary: PMID:22291595 shows IFI16 negatively regulates Sp1 DNA binding to
        viral promoters, inhibiting HCMV replication. This is part of its 
        antiviral mechanism.
      action: ACCEPT
      reason: Negative regulation of DNA binding (specifically Sp1 binding to 
        viral promoters) is a mechanism by which IFI16 restricts herpesvirus 
        replication.
      supported_by:
        - reference_id: PMID:22291595
          supporting_text: "suppression of the UL54 promoter is mediated by IFI16-induced
            blocking of Sp1-like factors"
  - term:
      id: GO:0045071
      label: negative regulation of viral genome replication
    evidence_type: IDA
    original_reference_id: PMID:22291595
    review:
      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.
      action: ACCEPT
      reason: Negative regulation of viral genome replication is a core function
        of IFI16 as an antiviral restriction factor.
      supported_by:
        - reference_id: PMID:22291595
          supporting_text: "IFI16 overexpression decreased both virus yield and viral
            DNA copy number"
  - term:
      id: GO:0045824
      label: negative regulation of innate immune response
    evidence_type: IDA
    original_reference_id: PMID:22046441
    review:
      summary: PMID:22046441 shows IFI16 suppresses AIM2 and NLRP3 inflammasome 
        activation, having anti-inflammatory effects. This reflects IFI16's dual
        role in immune regulation.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:22046441
          supporting_text: "the expression of IFI16 protein in THP-1 cells suppresses
            the activation of caspase-1 by the AIM2 and NLRP3 inflammasomes"
  - term:
      id: GO:0051607
      label: defense response to virus
    evidence_type: IMP
    original_reference_id: PMID:21575908
    review:
      summary: PMID:21575908 shows IFI16 senses KSHV DNA and activates 
        inflammasome, contributing to antiviral defense. Defense response to 
        virus is a core function.
      action: ACCEPT
      reason: Defense response to virus is a core function of IFI16 as a DNA 
        sensor that detects herpesvirus genomes and activates innate immune 
        responses.
      supported_by:
        - reference_id: PMID:21575908
          supporting_text: "IFI16 acts as a nuclear pathogen sensor to induce the
            inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection"
  - term:
      id: GO:0072332
      label: intrinsic apoptotic signaling pathway by p53 class mediator
    evidence_type: IMP
    original_reference_id: PMID:21573174
    review:
      summary: PMID:21573174 shows IFI16 participates in p53-dependent apoptotic
        signaling under glucose restriction. This is a secondary function 
        related to p53 interaction.
      action: KEEP_AS_NON_CORE
      reason: p53-mediated apoptotic signaling is a secondary function of IFI16 
        arising from its interaction with p53, not its primary DNA sensing 
        function.
      supported_by:
        - reference_id: PMID:21573174
          supporting_text: "The induced levels of IFI16 protein were associated with
            the induction of autophagy and reduced cell survival"
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:12894224
    review:
      summary: PMID:12894224 describes IFI16 role in transcriptional repression 
        in prostate epithelial senescence. Transcriptional repression is a 
        secondary function.
      action: KEEP_AS_NON_CORE
      reason: Transcriptional repression is a secondary function related to 
        IFI16's broader role as a transcriptional regulator, not its primary DNA
        sensing function.
      supported_by:
        - reference_id: PMID:12894224
          supporting_text: Role of IFI 16, a member of the interferon-inducible 
            p200-protein family, in prostate epithelial cellular senescence.
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:11146555
    review:
      summary: PMID:11146555 shows IFI16 enhances p53-mediated transcriptional 
        activation. IFI16 can both activate and repress transcription depending 
        on context.
      action: KEEP_AS_NON_CORE
      reason: Positive regulation of transcription is a secondary function 
        related to IFI16's interaction with p53, not its primary DNA sensing 
        function.
      supported_by:
        - reference_id: PMID:11146555
          supporting_text: Functional interaction between p53 and the 
            interferon-inducible nucleoprotein IFI 16.
  - term:
      id: GO:0071479
      label: cellular response to ionizing radiation
    evidence_type: IDA
    original_reference_id: PMID:14654789
    review:
      summary: PMID:14654789 describes IFI16 involvement in the DNA damage 
        response pathway through BRCA1 and p53 interactions. This is a secondary
        function.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:14654789
          supporting_text: A member of the Pyrin family, IFI16, is a novel 
            BRCA1-associated protein involved in the p53-mediated apoptosis 
            pathway.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1834951
    review:
      summary: Reactome pathway R-HSA-1834951 describes IFI16 binding cytosolic 
        dsDNA, supporting cytosolic localization. This is functionally relevant 
        for DNA sensing.
      action: ACCEPT
      reason: Cytosolic localization is well-established and functionally 
        important for IFI16's role in sensing cytoplasmic DNA and activating 
        STING signaling.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:19158679
    review:
      summary: PMID:19158679 identified AIM2 as a cytoplasmic DNA sensor and 
        discusses PYHIN family nuclear localization including IFI16.
      action: ACCEPT
      reason: Nuclear localization is well-established for IFI16.
      supported_by:
        - reference_id: PMID:19158679
          supporting_text: An orthogonal proteomic-genomic screen identifies 
            AIM2 as a cytoplasmic DNA sensor for the inflammasome.
  - term:
      id: GO:0016607
      label: nuclear speck
    evidence_type: IDA
    original_reference_id: PMID:19158679
    review:
      summary: Nuclear speck localization of IFI16 suggested by PMID:19158679 
        data. Nuclear specks are sites of splicing factor concentration.
      action: ACCEPT
      reason: Nuclear speck localization is consistent with IFI16's nuclear 
        functions and its role in transcriptional regulation.
      supported_by:
        - reference_id: PMID:19158679
          supporting_text: An orthogonal proteomic-genomic screen identifies 
            AIM2 as a cytoplasmic DNA sensor for the inflammasome.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: PMID:14654789
    review:
      summary: PMID:14654789 demonstrates IFI16 nucleoplasm localization in the 
        context of BRCA1 and p53 interaction studies.
      action: ACCEPT
      reason: Nucleoplasm localization is well-established for IFI16.
      supported_by:
        - reference_id: PMID:14654789
          supporting_text: A member of the Pyrin family, IFI16, is a novel 
            BRCA1-associated protein involved in the p53-mediated apoptosis 
            pathway.
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IDA
    original_reference_id: PMID:14654789
    review:
      summary: >-
        PMID:14654789 demonstrates IFI16 nucleolar localization using immunofluorescence
        microscopy in the context of BRCA1 interaction studies.
      action: ACCEPT
      reason: >-
        Nucleolar localization is well-established for IFI16. The protein localizes
        to both
        nucleoplasm and nucleoli as demonstrated by multiple immunofluorescence studies.
      supported_by:
        - reference_id: PMID:14654789
          supporting_text: "We found that IFI16 was localized in the nucleoplasm and
            nucleoli."
  - term:
      id: GO:0042771
      label: intrinsic apoptotic signaling pathway in response to DNA damage by 
        p53 class mediator
    evidence_type: IDA
    original_reference_id: PMID:14654789
    review:
      summary: >-
        PMID:14654789 demonstrates IFI16 participates in p53-mediated apoptosis in
        response
        to DNA damage through its interaction with BRCA1.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:14654789
          supporting_text: "Coexpression of IFI16 and BRCA1 enhanced DNA damage-induced
            apoptosis in mouse embryonic fibroblasts from BRCA1 mutant mice expressing
            wild-type p53"
  - term:
      id: GO:0030224
      label: monocyte differentiation
    evidence_type: IDA
    original_reference_id: PMID:9766636
    review:
      summary: PMID:9766636 describes IFI16 expression during monocyte 
        differentiation. IFI16 may play a role in myeloid cell differentiation 
        as part of interferon responses.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:9766636
          supporting_text: 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.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:7536752
    review:
      summary: PMID:7536752 directly demonstrates nuclear localization of IFI16 
        by immunohistochemistry and biochemical fractionation.
      action: ACCEPT
      reason: Nuclear localization is a well-established core feature of IFI16.
      supported_by:
        - reference_id: PMID:7536752
          supporting_text: "The nuclear localization of IFI 16 antigen was confirmed
            by immunohistochemical staining of HL-60 cells treated with IFN-gamma,
            dimethylsulfoxide, and retinoic acid"
  - term:
      id: GO:0030099
      label: myeloid cell differentiation
    evidence_type: NAS
    original_reference_id: PMID:7536752
    review:
      summary: PMID:7536752 describes IFI16 expression during myeloid cell 
        differentiation in HL-60 cells. This is a secondary function.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:7536752
          supporting_text: "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"
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:9642285
    review:
      summary: IFI16 negatively regulates transcription through interactions 
        with E2F transcription factors and other mechanisms. This is a secondary
        transcriptional regulatory function.
      action: KEEP_AS_NON_CORE
      reason: Negative regulation of transcription is a secondary function of 
        IFI16 related to its interactions with transcription factors, not its 
        primary DNA sensing function.
      supported_by:
        - reference_id: PMID:9642285
          supporting_text: The human interferon-inducible protein, IFI 16, is a 
            repressor of transcription.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: PMID:11146555
    title: Functional interaction between p53 and the interferon-inducible 
      nucleoprotein IFI 16.
    findings: []
  - id: PMID:12894224
    title: Role of IFI 16, a member of the interferon-inducible p200-protein 
      family, in prostate epithelial cellular senescence.
    findings: []
  - id: PMID:14654789
    title: A member of the Pyrin family, IFI16, is a novel BRCA1-associated 
      protein involved in the p53-mediated apoptosis pathway.
    findings: []
  - id: PMID:16494870
    title: Androgen receptor auto-regulates its expression by a negative 
      feedback loop through upregulation of IFI16 protein.
    findings: []
  - id: PMID:19158679
    title: An orthogonal proteomic-genomic screen identifies AIM2 as a 
      cytoplasmic DNA sensor for the inflammasome.
    findings: []
  - id: PMID:19946888
    title: Defining the membrane proteome of NK cells.
    findings: []
  - id: PMID:20890285
    title: IFI16 is an innate immune sensor for intracellular DNA.
    findings: []
  - id: PMID:21478870
    title: A diverse range of gene products are effectors of the type I 
      interferon antiviral response.
    findings: []
  - id: PMID:21573174
    title: IFI16 induction by glucose restriction in human fibroblasts 
      contributes to autophagy through activation of the ATM/AMPK/p53 pathway.
    findings: []
  - id: PMID:21575908
    title: IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in
      response to Kaposi Sarcoma-associated herpesvirus infection.
    findings: []
  - id: PMID:22046441
    title: IFI16 protein mediates the anti-inflammatory actions of the type-I 
      interferons through suppression of activation of caspase-1 by 
      inflammasomes.
    findings: []
  - id: PMID:22291595
    title: The intracellular DNA sensor IFI16 gene acts as restriction factor 
      for human cytomegalovirus replication.
    findings: []
  - id: PMID:22658674
    title: Insights into RNA biology from an atlas of mammalian mRNA-binding 
      proteins.
    findings: []
  - id: PMID:24413532
    title: Differential regulation of estrogen receptor α expression in breast 
      cancer cells by metastasis-associated protein 1.
    findings: []
  - id: PMID:24531343
    title: The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and 
      regulates responses to infection with DNA viruses.
    findings: []
  - id: PMID:30833792
    title: A protein-interaction network of interferon-stimulated genes extends 
      the innate immune system landscape.
    findings: []
  - id: PMID:7536752
    title: IFI 16 gene encodes a nuclear protein whose expression is induced by 
      interferons in human myeloid leukaemia cell lines.
    findings: []
  - id: PMID:9642285
    title: The human interferon-inducible protein, IFI 16, is a repressor of 
      transcription.
    findings: []
  - id: PMID:9766636
    title: 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.
    findings: []
  - id: Reactome:R-HSA-1834951
    title: IFI16 binds cytosolic dsDNA
    findings: []
core_functions:
  - molecular_function:
      id: GO:0003690
      label: double-stranded DNA binding
    description: >-
      IFI16 is a cytosolic and nuclear DNA sensor that binds double-stranded DNA through
      its two HIN-200 domains (HIN-A and HIN-B). The HIN domains contain OB-fold motifs
      that recognize DNA through electrostatic interactions with the phosphate backbone.
      Upon DNA binding, IFI16 recruits STING to activate type I interferon signaling
      and/or assembles with ASC to form an inflammasome complex for IL-1beta maturation.
    directly_involved_in:
      - id: GO:0002218
        label: activation of innate immune response
      - id: GO:0051607
        label: defense response to virus
      - id: GO:0032731
        label: positive regulation of interleukin-1 beta production
    locations:
      - id: GO:0005634
        label: nucleus
      - id: GO:0005829
        label: cytosol
    supported_by:
      - reference_id: PMID:20890285
        supporting_text: "Here we identify IFI16, a PYHIN protein, as an intracellular
          DNA sensor that mediates the induction of interferon-beta (IFN-beta)"
      - reference_id: PMID:21575908
        supporting_text: "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"
      - reference_id: PMID:7536752
        supporting_text: "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"