id: P52630
gene_symbol: STAT2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Signal transducer and activator of transcription 2 (STAT2; p113) is a
  latent cytoplasmic transcription factor dedicated to type I (IFN-alpha/beta) and
  type III interferon signaling. It has the canonical STAT architecture (N-terminal
  domain, coiled-coil domain, DNA-binding domain, linker, SH2 domain, and a long C-terminal
  transactivation domain). Following type I IFN binding to the IFNAR1/IFNAR2 receptor,
  the receptor-associated kinases TYK2 and JAK1 are activated and phosphorylate STAT2
  on Tyr690; phospho-STAT2 then heterodimerizes with phospho-STAT1 and, together with
  IRF9, assembles the ISGF3 transcription factor complex. ISGF3 translocates to the
  nucleus and binds the interferon-stimulated response element (ISRE) to drive transcription
  of interferon-stimulated genes that establish an antiviral state. Unlike STAT1,
  STAT2 does not bind a GAS element on its own and does not stably contact DNA by itself;
  within ISGF3 it contributes the strong C-terminal transactivation domain and the
  IRF9-interaction surface, while STAT1 makes the direct, stabilizing DNA contacts.
  STAT2 docks to the receptor through its SH2 domain (binding phospho-Tyr466 of IFNAR1
  and constitutively binding IFNAR2). Beyond its positive effector role, STAT2 is also
  an essential adaptor for USP18-mediated negative feedback, recruiting USP18 to IFNAR2
  to desensitize the receptor. Loss-of-function STAT2 deficiency (IMD44) causes susceptibility
  to viral illness with impaired type I IFN responses, whereas variants disrupting
  the USP18 feedback cause a type I interferonopathy (PTORCH3). STAT2 has additionally
  been implicated in regulation of mitochondrial fission via DRP1 (DNM1L) phosphorylation.
alternative_products:
- name: '1'
  id: P52630-3
- name: '2'
  id: P52630-4
  sequence_note: VSP_046705
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: STAT2 acts in the nucleus as part of the activated ISGF3 transcription
      factor complex after IFN-induced nuclear translocation. Correct, well-supported
      localization.
    action: ACCEPT
    reason: Nuclear localization of activated STAT2 (within ISGF3) is established and
      directly supported by experimental data (PMID:11150296, PMID:23139419).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Latent STAT2 resides in the cytoplasm where it docks to the IFN receptor
      and is phosphorylated before nuclear translocation. Correct localization.
    action: ACCEPT
    reason: Cytoplasmic residence of latent STAT2 is well established experimentally
      (UniProt SUBCELLULAR LOCATION; PMID:11150296, PMID:23139419).
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: STAT2 regulates RNA Pol II transcription of interferon-stimulated genes
      as part of ISGF3. Correct but general; the more specific positive regulation
      and type I IFN signaling terms better capture the core function.
    action: KEEP_AS_NON_CORE
    reason: True but generic; superseded for core-function purposes by GO:0045944 and
      GO:0060337.
- term:
    id: GO:0006952
    label: defense response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: STAT2 contributes to antiviral defense via the type I IFN response. Correct
      but very general; the specific defense response to virus term is more informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Overly general parent term; the specific child GO:0051607 (defense response
      to virus, IMP) captures this more precisely.
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Sequence-specific ISRE binding is a property of the assembled ISGF3 complex;
      STAT2 itself does not stably contact DNA but contributes to the complex that
      binds ISRE. Defensible when interpreted at the complex level.
    action: KEEP_AS_NON_CORE
    reason: STAT2 does not autonomously bind DNA (PMID:9020188); DNA binding is contributed
      via ISGF3. Acceptable as part-of-complex activity but not a standalone STAT2
      core MF.
- term:
    id: GO:0042127
    label: regulation of cell population proliferation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Type I IFN signaling, in which STAT2 participates, can modulate cell proliferation
      (e.g., IFN antiproliferative/growth-inhibitory effects), but this is a downstream
      pleiotropic consequence rather than a core STAT2 function.
    action: KEEP_AS_NON_CORE
    reason: Plausible downstream effect of IFN signaling; pleiotropic and non-core
      for STAT2.
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: STAT2 is a defining component of the JAK-STAT signaling pathway downstream
      of the type I IFN receptor. Core process annotation.
    action: ACCEPT
    reason: STAT2 is centrally and experimentally established as a JAK-STAT pathway
      effector (UniProt FUNCTION; PMID:28165510).
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: As part of ISGF3, STAT2 functions as a sequence-specific Pol II transcription
      activator. The activity is best understood at the complex level (STAT2 supplies
      the transactivation domain; STAT1 contacts DNA), but the term is appropriate.
    action: ACCEPT
    reason: Supported by IDA evidence (PMID:9020188, PMID:31127039) that STAT2 acts
      as a transcription activator within the IFN-responsive complex.
- term:
    id: GO:0070721
    label: ISGF3 complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: STAT2 is an obligate subunit of the ISGF3 complex (STAT1:STAT2:IRF9),
      the central type I IFN-responsive transcription factor. Core localization/complex
      annotation.
    action: ACCEPT
    reason: Definitive and central; STAT2 is a defining ISGF3 component (PMID:28165510,
      PMID:24065129).
- term:
    id: GO:0043434
    label: response to peptide hormone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: STAT2 responds to interferons (cytokines), not peptide hormones. This
      IBA-propagated term is a misleading generalization from the broader STAT family.
    action: REMOVE
    reason: Type I/III interferons are cytokines, not peptide hormones; this is an
      over-propagated IBA term not supported for STAT2 (electronic inference, not curator
      experimental call).
- term:
    id: GO:0060337
    label: type I interferon-mediated signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: The defining biological process of STAT2 - it is a dedicated and non-redundant
      component of type I interferon-mediated signaling.
    action: ACCEPT
    reason: Core function, abundantly supported experimentally (PMID:23391734, PMID:28165510,
      PMID:9020188).
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Generic DNA binding from InterPro. STAT2 alone does not stably contact
      DNA; any DNA association is contributed within the ISGF3 complex via STAT1. The
      generic term is uninformative and slightly misleading for STAT2.
    action: MARK_AS_OVER_ANNOTATED
    reason: STAT2 does not autonomously bind DNA (PMID:9020188); generic IEA DNA-binding
      over-annotates the standalone protein.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Generic DNA-binding transcription factor activity from automated pipelines.
      STAT2's transcriptional activator role is real but exerted within ISGF3; the
      Pol II-specific child term is preferred.
    action: MODIFY
    reason: Generalize/refine to GO:0000981 (Pol II-specific), which is the experimentally
      supported activity within ISGF3.
    proposed_replacement_terms:
    - id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Nuclear localization of activated STAT2. Correct.
    action: ACCEPT
    reason: Consistent with experimental localization data (PMID:11150296, PMID:23139419).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Cytoplasmic localization of latent STAT2. Correct.
    action: ACCEPT
    reason: Consistent with experimental localization data (PMID:11150296, PMID:23139419).
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Generic transcription regulation. Correct in essence but superseded by
      more specific RNA Pol II positive-regulation terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Overly general; the specific GO:0045944 and GO:0060337 better capture STAT2's
      role.
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Generic signal transduction. STAT2 is a signal transducer, but the specific
      JAK-STAT and type I IFN signaling terms are far more informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Root-level generic term superseded by GO:0007259 and GO:0060337.
- term:
    id: GO:0060337
    label: type I interferon-mediated signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Core type I IFN signaling process (electronic). Redundant with experimentally
      supported instances but correct.
    action: ACCEPT
    reason: Core function; corroborated by IMP and IBA annotations of the same term.
- term:
    id: GO:0060339
    label: negative regulation of type I interferon-mediated signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: STAT2 has a non-redundant negative-feedback role by recruiting USP18 to
      IFNAR2 to desensitize the receptor. Correct; experimentally supported by IMP
      annotation (PMID:28165510).
    action: ACCEPT
    reason: Well established negative-feedback function (PMID:28165510, PMID:31836668,
      PMID:32092142).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12220192
  qualifier: enables
  review:
    summary: Documents STAT2 SH2-domain binding to the IFNAR receptor subunits (IFNAR1
      pTyr466 and constitutive IFNAR2). Informative interaction but captured by the
      uninformative protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Per curation guidelines the generic protein binding term is uninformative;
      the underlying receptor-docking interaction is real and functionally relevant
      but better modelled as part of receptor signaling.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15825084
  qualifier: enables
  review:
    summary: Interaction in the context of viral (HCV) antagonism of STAT signaling.
      Uninformative protein binding term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term is uninformative; host-virus interaction
      context does not define a core STAT2 molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16227264
  qualifier: enables
  review:
    summary: STAT2 interaction documented in the context of SV5 V protein linking DDB1
      to STAT2. Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term is uninformative; viral-adaptor context
      not a core function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17923090
  qualifier: enables
  review:
    summary: Interaction in the context of acetylation-dependent IFN receptor signaling.
      Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term is uninformative for defining function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18579593
  qualifier: enables
  review:
    summary: STAT2-measles V protein interaction (viral antagonism). Uninformative
      term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term is uninformative; host-virus interaction
      not a core MF.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20404187
  qualifier: enables
  review:
    summary: Interaction documented in a study of HHV-6 susceptibility to type I IFN.
      Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term is uninformative for function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21903422
  qualifier: enables
  review:
    summary: Interaction from an innate-immunity protein interaction network study.
      Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term is uninformative; network-screen interaction
      not a core MF.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24065129
  qualifier: enables
  review:
    summary: Interaction in the IFNbeta/U-ISGF3 (STAT1, STAT2, IRF9) resistance study.
      Uninformative term, though it underpins the functionally important ISGF3 associations.
    action: KEEP_AS_NON_CORE
    reason: The generic protein binding term is uninformative; the underlying STAT1/STAT2/IRF9
      association is biologically central but better captured by ISGF3 complex membership.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26966684
  qualifier: enables
  review:
    summary: Interaction from a methods/software (PIPINO AP-MS) paper. Uninformative
      and low-specificity.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term from a high-throughput methods paper is
      uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Interaction from a large-scale interactome study. Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term from a high-throughput interactome screen
      is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32953130
  qualifier: enables
  review:
    summary: STAT2 interaction in the context of SARS-CoV-2 N protein antagonism of
      IFN signaling. Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term is uninformative; host-virus interaction
      not a core MF.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Interaction from a large-scale dual proteome-scale interactome study.
      Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term from a high-throughput interactome screen
      is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34471099
  qualifier: enables
  review:
    summary: STAT2 interaction in the context of SARS-CoV-2 N protein innate-immune
      regulation. Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term is uninformative; host-virus interaction
      not a core MF.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34521819
  qualifier: enables
  review:
    summary: Interaction with an unverified cached reference (title not fetched). Uninformative
      protein binding term regardless.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term is uninformative; cannot verify the specific
      interaction and it would not define a core function in any case.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35140242
  qualifier: enables
  review:
    summary: Interaction from a human transcription factor interaction network study.
      Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term from a high-throughput interactome screen
      is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Interaction from a multimodal cell-map structural/functional genomics
      study. Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term from a high-throughput map is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8605876
  qualifier: enables
  review:
    summary: Documents SH2-dependent docking of latent STAT2 to phospho-IFNAR1 (Tyr466).
      Functionally important receptor interaction, but the term itself is uninformative.
    action: KEEP_AS_NON_CORE
    reason: The generic protein binding term is uninformative; the IFNAR1 docking is
      real and relevant (PMID:8605876) but is part of receptor signaling rather than
      a standalone core MF.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8605877
  qualifier: enables
  review:
    summary: Documents SH2-mediated STAT1/STAT2 homo- and heterodimerization. Functionally
      important but the generic term is uninformative; identical protein binding (GO:0042802)
      from this paper captures homodimerization more specifically.
    action: KEEP_AS_NON_CORE
    reason: The generic protein binding term is uninformative; the dimerization activity
      is captured better by GO:0042802.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9121453
  qualifier: enables
  review:
    summary: Documents STAT2 subdomains required for IFNAR preassociation and signaling.
      Functionally relevant receptor interaction; uninformative term.
    action: KEEP_AS_NON_CORE
    reason: The generic protein binding term is uninformative; receptor preassociation
      interaction relevant but not a standalone core MF.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9677371
  qualifier: enables
  review:
    summary: Maps residues critical for SH2-dependent docking of STAT2 to IFNAR1. Functionally
      relevant; uninformative term.
    action: KEEP_AS_NON_CORE
    reason: The generic protein binding term is uninformative; receptor-docking interaction
      relevant but not a standalone core MF.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Homodimerization captured in a large-scale cell-map study. STAT2 can homodimerize,
      but this is a low-specificity assignment from a high-throughput dataset.
    action: KEEP_AS_NON_CORE
    reason: STAT2 homodimerization is documented (PMID:9020188); identical protein
      binding is non-core relative to the heterodimeric ISGF3 function.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:8605877
  qualifier: enables
  review:
    summary: SH2-mediated STAT2 homodimerization documented experimentally. Real but
      non-core; the functionally dominant species is the STAT1:STAT2 heterodimer within
      ISGF3.
    action: KEEP_AS_NON_CORE
    reason: STAT2 can self-associate (PMID:9020188, PMID:8605877); non-core relative
      to its heterodimeric ISGF3 role.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT2 by immunofluorescence (HPA). Correct.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but non-core; consistent with cytoplasmic residence
      of latent STAT2 and with the redundant Reactome cytosol annotations.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:11150296
  qualifier: located_in
  review:
    summary: Experimental demonstration of IFN-induced nuclear import of STAT2 via
      an arginine/lysine-rich element. Correct.
    action: ACCEPT
    reason: Directly demonstrated experimentally (PMID:11150296).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:11150296
  qualifier: located_in
  review:
    summary: Experimental cytoplasmic localization of latent STAT2 prior to nuclear
      import. Correct.
    action: ACCEPT
    reason: Directly demonstrated experimentally (PMID:11150296).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:23139419
  qualifier: located_in
  review:
    summary: Cytoplasmic localization of STAT2 demonstrated in the Ser287 phosphoregulation
      study. Correct.
    action: ACCEPT
    reason: Directly supported experimentally (PMID:23139419).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:27782195
  qualifier: located_in
  review:
    summary: Cytoplasmic localization documented in the DCST1 ubiquitination/degradation
      study. Correct.
    action: ACCEPT
    reason: Directly supported experimentally (PMID:27782195).
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: NAS
  original_reference_id: PMID:24058793
  qualifier: involved_in
  review:
    summary: STAT2 as a JAK-STAT pathway component (asserted in a STAT heterodimer
      review). Correct core process, though NAS evidence; corroborated by IDA/IBA.
    action: ACCEPT
    reason: Core process annotation, corroborated by experimental annotations of the
      same term.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: NAS
  original_reference_id: PMID:24058793
  qualifier: involved_in
  review:
    summary: STAT2 positively regulates Pol II transcription of ISGs via its transactivation
      domain in ISGF3. Correct; corroborated by IDA (PMID:24065129).
    action: ACCEPT
    reason: Core transcriptional-activation function; corroborated by IDA annotation.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:24065129
  qualifier: involved_in
  review:
    summary: Direct evidence that increased STAT1/STAT2/IRF9 (ISGF3 and U-ISGF3) drives
      antiviral ISG transcription, mediating resistance to viruses and DNA damage.
      Core function.
    action: ACCEPT
    reason: Experimentally supported positive transcriptional regulation by STAT2-containing
      complexes (PMID:24065129).
- term:
    id: GO:0070721
    label: ISGF3 complex
  evidence_type: IPI
  original_reference_id: PMID:24065129
  qualifier: part_of
  review:
    summary: Direct evidence (IPI) for STAT2 membership in the ISGF3 complex (with
      STAT1 and IRF9). Core complex annotation.
    action: ACCEPT
    reason: STAT2 is an obligate ISGF3 subunit, experimentally demonstrated (PMID:24065129).
- term:
    id: GO:0090575
    label: RNA polymerase II transcription regulator complex
  evidence_type: NAS
  original_reference_id: PMID:24058793
  qualifier: part_of
  review:
    summary: ISGF3 is an RNA Pol II transcription regulator complex; this is a correct
      parent of the ISGF3 complex annotation. Redundant with GO:0070721.
    action: KEEP_AS_NON_CORE
    reason: Correct but a more general parent of the specific ISGF3 complex term (GO:0070721).
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IDA
  original_reference_id: PMID:31127039
  qualifier: enables
  review:
    summary: Experimental data show STAT2 (via its transactivation domain) is recruited
      to ISRE-containing ISG promoters with HDAC4. Supports a transcription-activator
      role; the Pol II-specific term is preferred for specificity.
    action: MODIFY
    reason: Refine to GO:0000981 (Pol II-specific); STAT2's documented activity is
      promoter recruitment/transactivation within an RNA Pol II complex (PMID:31127039).
    proposed_replacement_terms:
    - id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IDA
  original_reference_id: PMID:9020188
  qualifier: enables
  review:
    summary: Demonstrates STAT2 is a potent transactivator that, within a homodimer/p48
      or ISGF3 complex, can be recruited to DNA and activate transcription, although
      STAT2 alone does not stably contact DNA. Supports transcription-activator activity.
    action: MODIFY
    reason: Refine to GO:0000981 (Pol II-specific); STAT2's transactivation requires
      the complex and is Pol II-directed (PMID:9020188).
    proposed_replacement_terms:
    - id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:23139419
  qualifier: is_active_in
  review:
    summary: STAT2 is active in the nucleus following IFN-induced phosphorylation and
      translocation. Correct.
    action: ACCEPT
    reason: Directly supported experimentally (PMID:23139419).
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IDA
  original_reference_id: PMID:9020188
  qualifier: enables
  review:
    summary: STAT2 functions as a Pol II-specific transcription activator within the
      IFN-responsive complex (contributing the transactivation domain). Core molecular
      function (at the complex level).
    action: ACCEPT
    reason: Experimentally supported transactivator role (PMID:9020188); the most specific
      and appropriate MF term for STAT2.
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: IDA
  original_reference_id: PMID:23139419
  qualifier: involved_in
  review:
    summary: Direct evidence for STAT2 in JAK-STAT signaling downstream of the type
      I IFN receptor. Core process.
    action: ACCEPT
    reason: Experimentally supported core JAK-STAT involvement (PMID:23139419).
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IC
  original_reference_id: PMID:31127039
  qualifier: is_active_in
  review:
    summary: STAT2 is recruited to ISRE-containing chromatin (ISG promoters) upon IFN
      stimulation, consistent with its transcription-activator role within ISGF3.
    action: ACCEPT
    reason: Supported by ChIP evidence of STAT2 promoter recruitment (PMID:31127039);
      consistent with active transcription factor localization.
- term:
    id: GO:0060339
    label: negative regulation of type I interferon-mediated signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:28165510
  qualifier: involved_in
  review:
    summary: STAT2 is an essential adaptor recruiting USP18 to IFNAR2 to mediate negative-feedback
      desensitization of type I IFN signaling. Strong experimental support; core regulatory
      function.
    action: ACCEPT
    reason: Definitive IMP/mechanistic evidence (PMID:28165510); a non-redundant negative-feedback
      role.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28165510
  qualifier: enables
  review:
    summary: Documents the direct STAT2-USP18 interaction underlying negative feedback.
      Functionally important, but the generic term is uninformative; the ubiquitin-like
      protein ligase binding term (GO:0044389) is more specific.
    action: KEEP_AS_NON_CORE
    reason: The generic protein binding term is uninformative; the STAT2-USP18 interaction
      is captured better by GO:0044389 and the negative-regulation process term.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31836668
  qualifier: enables
  review:
    summary: Interaction (with USP18) documented in the PTORCH3 interferonopathy study.
      Uninformative term; the USP18 interaction is functionally important.
    action: KEEP_AS_NON_CORE
    reason: The generic protein binding term is uninformative; the underlying STAT2-USP18
      interaction is relevant but better captured by GO:0044389.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32092142
  qualifier: enables
  review:
    summary: Interaction (with USP18) documented in the gain-of-function interferonopathy
      study. Uninformative term.
    action: KEEP_AS_NON_CORE
    reason: The generic protein binding term is uninformative; the STAT2-USP18 interaction
      is relevant but better captured by GO:0044389.
- term:
    id: GO:0060337
    label: type I interferon-mediated signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:32092142
  qualifier: involved_in
  review:
    summary: A gain-of-function STAT2 variant (R148Q) alters the late type I IFN response,
      providing IMP evidence for STAT2's involvement in type I IFN signaling. Core
      function.
    action: ACCEPT
    reason: Human genetic IMP evidence for STAT2 in type I IFN signaling (PMID:32092142).
- term:
    id: GO:0060337
    label: type I interferon-mediated signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:31836668
  qualifier: involved_in
  review:
    summary: A homozygous STAT2 mutation causing unrestrained interferon signaling
      provides IMP evidence for STAT2's role in type I IFN signaling. Core function.
    action: ACCEPT
    reason: Human genetic IMP evidence for STAT2 in type I IFN signaling (PMID:31836668).
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  qualifier: located_in
  review:
    summary: Chromatin localization inferred from sequence analysis (DbTF classification).
      Consistent with STAT2's role within a chromatin-associated transcription complex.
    action: ACCEPT
    reason: Consistent with experimental ChIP evidence of STAT2 promoter recruitment
      (PMID:31127039).
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  qualifier: enables
  review:
    summary: Pol II-specific transcription factor activity inferred from sequence analysis.
      Consistent with the IDA-supported activity within ISGF3.
    action: ACCEPT
    reason: Consistent with experimental transactivator evidence (PMID:9020188, PMID:31127039).
- term:
    id: GO:0044389
    label: ubiquitin-like protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:27782195
  qualifier: enables
  review:
    summary: Documents STAT2 binding to the E3 ubiquitin ligase DCST1, leading to STAT2
      ubiquitination and degradation (negative regulation of IFN signaling). Specific
      and informative interaction term.
    action: KEEP_AS_NON_CORE
    reason: Real, specific interaction (PMID:27782195) relevant to STAT2 turnover/regulation,
      but not a defining core molecular function of STAT2 itself.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8986985
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome type III IFN (IFNL) phosphorylation
      reaction. Correct but redundant reaction-level localization.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant with experimental cytoplasm/cytosol annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8987033
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome IFNL dissociation reaction. Redundant
      reaction-level localization.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome reaction-level annotation.
- term:
    id: GO:0001932
    label: regulation of protein phosphorylation
  evidence_type: IMP
  original_reference_id: PMID:26122121
  qualifier: involved_in
  review:
    summary: STAT2 deficiency alters DRP1 (DNM1L) phosphorylation at Ser616/Ser637,
      implicating STAT2 in regulating protein phosphorylation in the mitochondrial
      fission context. Real but pleiotropic/non-core, likely indirect.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported (PMID:26122121) but a non-canonical, likely indirect
      function distinct from STAT2's core IFN role.
- term:
    id: GO:0051607
    label: defense response to virus
  evidence_type: IMP
  original_reference_id: PMID:23391734
  qualifier: involved_in
  review:
    summary: Human STAT2 deficiency causes failure of type I IFN signaling and susceptibility
      to viral infection, directly implicating STAT2 in antiviral defense. Core process.
    action: ACCEPT
    reason: Strong human genetic IMP evidence (PMID:23391734); STAT2 is required for
      ISGF3-mediated antiviral defense.
- term:
    id: GO:0060337
    label: type I interferon-mediated signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23391734
  qualifier: involved_in
  review:
    summary: STAT2-deficient patient cells show profound failure of type I IFN signaling,
      providing IMP evidence for STAT2's non-redundant role. Core function.
    action: ACCEPT
    reason: Definitive human genetic IMP evidence (PMID:23391734).
- term:
    id: GO:0090140
    label: regulation of mitochondrial fission
  evidence_type: IMP
  original_reference_id: PMID:26122121
  qualifier: involved_in
  review:
    summary: STAT2 deficiency causes a mitochondrial fission defect via reduced DRP1
      Ser616 phosphorylation; STAT2 is described as a novel regulator of mitochondrial
      fission. Real but non-canonical/pleiotropic function.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported (PMID:26122121) but a non-core, likely indirect
      role separate from STAT2's defining IFN-signaling function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1015699
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from the Reactome ISGF3-binds-ISRE reaction.
      Correct; consistent with nuclear ISGF3 action.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant with nucleus annotations.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909721
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from the Reactome ISGF3 nuclear translocation
      reaction. Correct but redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome reaction-level annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909718
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome IFN signaling reaction. Redundant
      reaction-level localization.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909721
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome ISGF3 translocation reaction. Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909722
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome p-STAT2:p-STAT1 release reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909725
  qualifier: located_in
  review:
    summary: Cytosolic localization from the Reactome IRF9-with-p-STAT2:p-STAT1 reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909726
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome STAT1 phosphorylation reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909732
  qualifier: located_in
  review:
    summary: Cytosolic localization from the Reactome STAT2 phosphorylation reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9710959
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome STAT1 dimer/KPNA1 reaction. Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9710963
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome STAT1 dimer:KPNA1:KPNB1 reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-997309
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome STAT1 dephosphorylation reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8987266
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome IFNL receptor binding reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909719
  qualifier: located_in
  review:
    summary: Cytosolic localization from the Reactome STAT2-to-p-IFNAR1 recruitment
      reaction. Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909720
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome IFN/IFNAR2 binding reaction. Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909724
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome IFNAR1 recruitment reaction. Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909729
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome JAK activation reaction. Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-909730
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome IFNAR1 phosphorylation reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9678935
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome IFNAR2:JAK1:STAT2 inhibitor reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9696179
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome IFNAR2:JAK1:STAT2 ligand-analog
      reaction. Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9729454
  qualifier: located_in
  review:
    summary: Cytosolic localization from the Reactome SARS-CoV-2-N-binds-STAT1/STAT2
      reaction. Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9833155
  qualifier: located_in
  review:
    summary: Cytosolic localization from the Reactome STAT2 ubiquitination reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9920878
  qualifier: located_in
  review:
    summary: Cytosolic localization from the Reactome NS5-binds-STAT2 reaction. Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-997311
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome TYK2 dephosphorylation reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-997314
  qualifier: located_in
  review:
    summary: Cytosolic localization from a Reactome JAK1 dephosphorylation reaction.
      Redundant.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; redundant Reactome annotation.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: TAS
  original_reference_id: PMID:9020188
  qualifier: involved_in
  review:
    summary: STAT2 regulates Pol II transcription of ISGs. Correct but general; positive
      regulation (GO:0045944) is more specific and informative.
    action: KEEP_AS_NON_CORE
    reason: True but generic; superseded by GO:0045944 for the core transcription-activation
      function.
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: TAS
  original_reference_id: PMID:9020188
  qualifier: involved_in
  review:
    summary: STAT2 as a JAK-STAT pathway component (TAS). Correct core process; corroborated
      by IDA/IBA.
    action: ACCEPT
    reason: Core process; corroborated by experimental annotations.
core_functions:
- description: Acts within the ISGF3 complex (STAT1:STAT2:IRF9) as a sequence-specific
    RNA polymerase II transcription activator, contributing the strong C-terminal transactivation
    domain that drives transcription of interferon-stimulated genes from ISRE elements
  molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  directly_involved_in:
  - id: GO:0060337
    label: type I interferon-mediated signaling pathway
  - id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  in_complex:
    id: GO:0070721
    label: ISGF3 complex
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0000785
    label: chromatin
  supported_by:
  - reference_id: PMID:9020188
    supporting_text: Although Stat2 is a potent transactivator, it does not interact
      stably with DNA in complex with p48 alone. Adding Stat1 increases the affinity
      and alters the sequence selectivity of p48-DNA interactions
  - reference_id: PMID:31127039
    supporting_text: HDAC4 is recruited to ISG promoters after IFN-α stimulation and
      that HDAC4 is required for normal STAT2 recruitment to these promoters
- description: Functions as a dedicated, non-redundant signal transducer of type I
    (and type III) interferon signaling - docking to the activated IFNAR receptor via
    its SH2 domain, becoming tyrosine phosphorylated, and assembling ISGF3 to establish
    an antiviral state
  molecular_function:
    id: GO:0035591
    label: signaling adaptor activity
  directly_involved_in:
  - id: GO:0060337
    label: type I interferon-mediated signaling pathway
  - id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  - id: GO:0051607
    label: defense response to virus
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:28165510
    supporting_text: Activated TYK2 and JAK1 in turn phosphorylate IFNAR2-associated
      STAT2 and STAT1, which results in formation of the DNA binding STAT1/STAT2/IRF9
      ternary complex IFN-stimulated gene factor 3 (ISGF3). ISGF3 promotes expression
      of genes with the IFN-stimulated response element in their promoters
  - reference_id: PMID:23391734
    supporting_text: The complete lack of STAT2 provided a ready explanation for the
      failure to induce ISGs dependent upon activation by the ISGF3 complex
- description: Serves as the essential adaptor recruiting the negative regulator USP18
    to the type I IFN receptor subunit IFNAR2, mediating negative-feedback desensitization
    of type I interferon signaling
  molecular_function:
    id: GO:0035591
    label: signaling adaptor activity
  directly_involved_in:
  - id: GO:0060339
    label: negative regulation of type I interferon-mediated signaling pathway
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:28165510
    supporting_text: STAT2 directly interacts with USP18 and thus mediates its recruitment
      to IFNAR2.
  - reference_id: PMID:32092142
    supporting_text: fails to appropriately traffic USP18 to IFNAR2
proposed_new_terms: []
suggested_questions:
- question: To what extent are STAT2's non-canonical roles (regulation of mitochondrial
    fission via DRP1/DNM1L phosphorylation) direct versus indirect downstream consequences
    of altered type I interferon tone?
- question: Is the unphosphorylated U-ISGF3 complex (driven by IFN-induced STAT1/STAT2/IRF9
    accumulation) a distinct functional state of STAT2 warranting separate annotation
    from canonical phospho-ISGF3?
suggested_experiments:
- description: Genome-wide ChIP-seq/CUT&RUN for STAT2 (and STAT1, IRF9) under type I
    IFN stimulation to define the ISRE-bound cistrome and confirm that STAT2 chromatin
    occupancy strictly depends on STAT1/IRF9 (no autonomous GAS binding).
- description: Separation-of-function STAT2 mutants that selectively disrupt the USP18-recruiting
    interface (CC/DB domains) versus the transactivation domain, to dissect the positive
    effector role from the negative-feedback adaptor role in the same cells.
- description: Define the mechanism linking STAT2 to DRP1 (DNM1L) Ser616/Ser637 phosphorylation
    (e.g., identify the intermediate kinase/phosphatase and test IFN-dependence) in
    STAT2-null versus reconstituted cells.
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000113
  title: Gene Ontology annotation of human sequence-specific DNA binding transcription
    factors (DbTFs) based on the TFClass database
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11150296
  title: Arginine/lysine-rich structural element is involved in interferon-induced
    nuclear import of STATs.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text confirms experimental cytoplasm and nucleus localization
      of STAT2 and IFN-induced nuclear import; supports the localization annotations.
- id: PMID:12220192
  title: Affinity of Stat2 for the subunits of the interferon alpha receptor.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract confirms SH2-dependent STAT2 docking to phospho-IFNAR1
      (Tyr466) and constitutive IFNAR2 binding; supports receptor-interaction annotation.
- id: PMID:15825084
  title: Hepatitis C virus expression suppresses interferon signaling by degrading
    STAT1.
  findings: []
- id: PMID:16227264
  title: Simian virus 5 V protein acts as an adaptor, linking DDB1 to STAT2, to facilitate
    the ubiquitination of STAT1.
  findings: []
- id: PMID:17923090
  title: Acetylation-dependent signal transduction for type I interferon receptor.
  findings: []
- id: PMID:18579593
  title: STAT2 is a primary target for measles virus V protein-mediated alpha/beta
    interferon signaling inhibition.
  findings: []
- id: PMID:20404187
  title: Divergent susceptibilities of human herpesvirus 6 variants to type I interferons.
  findings: []
- id: PMID:21903422
  title: Mapping a dynamic innate immunity protein interaction network regulating
    type I interferon production.
  findings: []
- id: PMID:23139419
  title: Identification of STAT2 serine 287 as a novel regulatory phosphorylation
    site in type I interferon-induced cellular responses.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text confirms STAT2 as a positive modulator of type I
      IFN transcription and identifies Ser287 as a negative regulatory phosphosite;
      supports localization and transcription annotations.
- id: PMID:23391734
  title: STAT2 deficiency and susceptibility to viral illness in humans.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text; human STAT2 deficiency causes profound failure
      of type I IFN signaling and viral susceptibility, with loss of ISGF3-dependent
      ISG induction. Strongly supports defense response to virus and type I IFN signaling.
- id: PMID:24058793
  title: 'STAT heterodimers in immunity: A mixed message or a unique signal?'
  findings: []
- id: PMID:24065129
  title: IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to
    viruses and DNA damage.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract supports STAT2 membership in ISGF3/U-ISGF3 and its
      role in driving antiviral ISG transcription.
- id: PMID:26122121
  title: Signal transducer and activator of transcription 2 deficiency is a novel
    disorder of mitochondrial fission.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached full text; STAT2 deficiency reduces DRP1 (DNM1L) Ser616 phosphorylation
      and impairs mitochondrial fission. Supports the non-core mitochondrial fission
      and protein phosphorylation annotations.
- id: PMID:26966684
  title: 'PIPINO: A Software Package to Facilitate the Identification of Protein-Protein
    Interactions from Affinity Purification Mass Spectrometry Data.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Methods/software paper; source of an uninformative high-throughput
      protein binding annotation.
- id: PMID:27782195
  title: Global functional profiling of human ubiquitome identifies E3 ubiquitin ligase
    DCST1 as a novel negative regulator of Type-I interferon signaling.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract confirms DCST1 as an E3 ligase that binds and ubiquitinates
      STAT2 to negatively regulate type I IFN signaling; supports GO:0044389 and cytoplasm
      annotations.
- id: PMID:28165510
  title: STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon
    signaling.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text; establishes STAT2 both as a positive effector and
      as the essential adaptor recruiting USP18 to IFNAR2 for negative feedback. Key
      support for core functions and GO:0060339.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale interactome study; source of an uninformative protein
      binding annotation.
- id: PMID:31127039
  title: Histone deacetylase 4 promotes type I interferon signaling, restricts DNA
    viruses, and is degraded via vaccinia virus protein C6.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text; ChIP shows STAT2 recruitment to ISRE-containing
      ISG promoters and that the STAT2 transactivation domain mediates HDAC4 interaction.
      Supports DNA-binding TF activity and chromatin annotations.
- id: PMID:31836668
  title: Severe type I interferonopathy and unrestrained interferon signaling due
    to a homozygous germline mutation in STAT2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text; homozygous STAT2 variant causes unrestrained IFN
      signaling by compromising USP18-mediated negative regulation. Supports type I
      IFN signaling and negative-feedback roles.
- id: PMID:32092142
  title: Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a
    patient with type I interferonopathy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text; STAT2 R148Q is a GOF that fails to traffic USP18
      to IFNAR2, preventing negative regulation of IFN-I. Supports type I IFN signaling
      and USP18-adaptor core functions.
- id: PMID:32953130
  title: SARS-CoV-2 N protein antagonizes type I interferon signaling by suppressing
    phosphorylation and nuclear translocation of STAT1 and STAT2.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale interactome study; source of an uninformative protein
      binding annotation.
- id: PMID:34471099
  title: A dual-role of SARS-CoV-2 nucleocapsid protein in regulating innate immune
    response.
  findings: []
- id: PMID:34521819
  title: Unresolvable identifier - no record in NCBI PubMed (likely a GOA data error)
  findings: []
  reference_review:
    relevance: LOW
    correctness: WRONG_IDENTIFIER
    review_notes: Verified via NCBI eutils esummary that PMID:34521819 returns "cannot
      get document summary" - the identifier does not resolve to any PubMed record
      and is most likely an error in the GOA source. The entry is retained only
      because a GOA annotation (existing_annotations[32], a generic uninformative
      protein binding IPI already marked MARK_AS_OVER_ANNOTATED) references it, so
      it cannot be deleted without failing reference-integrity validation. Carries
      no supporting_text and informs no core function.
- id: PMID:35140242
  title: Human transcription factor protein interaction networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale TF interaction network study; source of an uninformative
      protein binding annotation.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale cell-map study; source of uninformative protein binding
      and identical protein binding annotations.
- id: PMID:8605876
  title: Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking
    site for the latent form of the 113 kDa STAT2 protein.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract confirms SH2-dependent docking of latent STAT2 to
      phospho-IFNAR1 (Tyr466); supports receptor-interaction annotation.
- id: PMID:8605877
  title: The SH2 domains of Stat1 and Stat2 mediate multiple interactions in the transduction
    of IFN-alpha signals.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Confirms SH2-mediated STAT1/STAT2 homo- and heterodimerization; supports
      identical protein binding (homodimerization) annotation.
- id: PMID:9020188
  title: Stat2 is a transcriptional activator that requires sequence-specific contacts
    provided by stat1 and p48 for stable interaction with DNA.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract; establishes that STAT2 is a potent transactivator
      that cannot stably contact DNA alone and requires STAT1/p48(IRF9) within ISGF3.
      Central to the DNA-binding/transactivation core function.
- id: PMID:9121453
  title: Functional subdomains of STAT2 required for preassociation with the alpha
    interferon receptor and for signaling.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Maps STAT2 subdomains required for IFNAR preassociation and signaling;
      supports receptor-interaction annotation.
- id: PMID:9677371
  title: Identification of amino acid residues critical for the Src-homology 2 domain-dependent
    docking of Stat2 to the interferon alpha receptor.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Maps SH2 residues for STAT2-IFNAR1 docking; supports receptor-interaction
      annotation.
- id: Reactome:R-HSA-1015699
  title: ISGF3 binds the ISRE promoter elements in IFN-stimulated genes
  findings: []
- id: Reactome:R-HSA-8986985
  title: IFNL1:p-Y343,Y517-IFNLR1:p-JAK1:IL10RB:p-TYK2:STAT1 phosphorylates STAT1,
    STAT2, STAT3, STAT4 and STAT5
  findings: []
- id: Reactome:R-HSA-8987033
  title: p-STAT1, p-Y-STAT2, p-STAT3, p-STAT4, p-STAT5 dissociates from IFNL1:p-Y343,Y517-IFNLR1:p-JAK1:IL10RB:p-TYK2:p-STAT1,p-STAT2,p-STAT3,p-STAT4,p-STAT5
  findings: []
- id: Reactome:R-HSA-8987266
  title: IFNL1:p-Y434,Y517-IFNLR1:p-JAK1:IL10RB:p-TYK2 binds STAT1, STAT2, STAT3,
    STAT4, STAT5
  findings: []
- id: Reactome:R-HSA-909718
  title: Formation of p-STAT1 homodimer
  findings: []
- id: Reactome:R-HSA-909719
  title: Recruitment of STAT2 to p-IFNAR1
  findings: []
- id: Reactome:R-HSA-909720
  title: IFN alpha/beta binds to IFNAR2
  findings: []
- id: Reactome:R-HSA-909721
  title: Translocation of ISGF3 complex to nucleus
  findings: []
- id: Reactome:R-HSA-909722
  title: Release of p-STAT2:p-STAT1 dimer
  findings: []
- id: Reactome:R-HSA-909724
  title: Recruitment of IFNAR1
  findings: []
- id: Reactome:R-HSA-909725
  title: Interaction of IRF9 with p-STAT2:p-STAT1
  findings: []
- id: Reactome:R-HSA-909726
  title: Phosphorylation of STAT1
  findings: []
- id: Reactome:R-HSA-909729
  title: Activation of JAK kinases
  findings: []
- id: Reactome:R-HSA-909730
  title: Phosphorylation of INFAR1 by TYK2
  findings: []
- id: Reactome:R-HSA-909732
  title: Phosphorylation of STAT2
  findings: []
- id: Reactome:R-HSA-9678935
  title: IFNAR2:JAK1:STAT2 binds JAK1,2 inhibitors
  findings: []
- id: Reactome:R-HSA-9696179
  title: IFNAR2:JAK1:STAT2 binds type 1 interferon analogs
  findings: []
- id: Reactome:R-HSA-9710959
  title: p-STAT1 dimer binds KPNA1
  findings: []
- id: Reactome:R-HSA-9710963
  title: p-STAT1dimer:KPNA1 binds KPNB1
  findings: []
- id: Reactome:R-HSA-9729454
  title: SARS-CoV-2 N protein binds STAT1, STAT2
  findings: []
- id: Reactome:R-HSA-9833155
  title: Ubiquitination of STAT2
  findings: []
- id: Reactome:R-HSA-9920878
  title: NS5 binds STAT2
  findings: []
- id: Reactome:R-HSA-997309
  title: Dephosphorylation of STAT1 by SHP2
  findings: []
- id: Reactome:R-HSA-997311
  title: Dephosphorylation of TYK2 by PTP1B
  findings: []
- id: Reactome:R-HSA-997314
  title: Dephosphorylation of JAK1 by SHP1
  findings: []