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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: STAT2 acts in the nucleus as part of the activated ISGF3 transcription factor complex after IFN-induced nuclear translocation. Correct, well-supported localization. Reason: Nuclear localization of activated STAT2 (within ISGF3) is established and directly supported by experimental data (PMID:11150296, PMID:23139419). |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Latent STAT2 resides in the cytoplasm where it docks to the IFN receptor and is phosphorylated before nuclear translocation. Correct localization. Reason: Cytoplasmic residence of latent STAT2 is well established experimentally (UniProt SUBCELLULAR LOCATION; PMID:11150296, PMID:23139419). |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. Reason: True but generic; superseded for core-function purposes by GO:0045944 and GO:0060337. |
| GO:0006952 defense response | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | 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. Reason: Overly general parent term; the specific child GO:0051607 (defense response to virus, IMP) captures this more precisely. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. |
| GO:0042127 regulation of cell population proliferation | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. Reason: Plausible downstream effect of IFN signaling; pleiotropic and non-core for STAT2. |
| GO:0007259 cell surface receptor signaling pathway via JAK-STAT | IBA GO_REF:0000033 | ACCEPT | Summary: STAT2 is a defining component of the JAK-STAT signaling pathway downstream of the type I IFN receptor. Core process annotation. Reason: STAT2 is centrally and experimentally established as a JAK-STAT pathway effector (UniProt FUNCTION; PMID:28165510). |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Supported by IDA evidence (PMID:9020188, PMID:31127039) that STAT2 acts as a transcription activator within the IFN-responsive complex. |
| GO:0070721 ISGF3 complex | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Definitive and central; STAT2 is a defining ISGF3 component (PMID:28165510, PMID:24065129). |
| GO:0043434 response to peptide hormone | IBA GO_REF:0000033 | REMOVE | Summary: STAT2 responds to interferons (cytokines), not peptide hormones. This IBA-propagated term is a misleading generalization from the broader STAT family. 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). |
| GO:0060337 type I interferon-mediated signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: The defining biological process of STAT2 - it is a dedicated and non-redundant component of type I interferon-mediated signaling. Reason: Core function, abundantly supported experimentally (PMID:23391734, PMID:28165510, PMID:9020188). |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | 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. Reason: STAT2 does not autonomously bind DNA (PMID:9020188); generic IEA DNA-binding over-annotates the standalone protein. |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | MODIFY | 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. Reason: Generalize/refine to GO:0000981 (Pol II-specific), which is the experimentally supported activity within ISGF3. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization of activated STAT2. Correct. Reason: Consistent with experimental localization data (PMID:11150296, PMID:23139419). |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Cytoplasmic localization of latent STAT2. Correct. Reason: Consistent with experimental localization data (PMID:11150296, PMID:23139419). |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic transcription regulation. Correct in essence but superseded by more specific RNA Pol II positive-regulation terms. Reason: Overly general; the specific GO:0045944 and GO:0060337 better capture STAT2's role. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic signal transduction. STAT2 is a signal transducer, but the specific JAK-STAT and type I IFN signaling terms are far more informative. Reason: Root-level generic term superseded by GO:0007259 and GO:0060337. |
| GO:0060337 type I interferon-mediated signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: Core type I IFN signaling process (electronic). Redundant with experimentally supported instances but correct. Reason: Core function; corroborated by IMP and IBA annotations of the same term. |
| GO:0060339 negative regulation of type I interferon-mediated signaling pathway | IEA GO_REF:0000117 | ACCEPT | 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). Reason: Well established negative-feedback function (PMID:28165510, PMID:31836668, PMID:32092142). |
| GO:0005515 protein binding | IPI PMID:12220192 Affinity of Stat2 for the subunits of the interferon alpha r... | KEEP AS NON CORE | 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. 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. |
| GO:0005515 protein binding | IPI PMID:15825084 Hepatitis C virus expression suppresses interferon signaling... | MARK AS OVER ANNOTATED | Summary: Interaction in the context of viral (HCV) antagonism of STAT signaling. Uninformative protein binding term. Reason: The generic protein binding term is uninformative; host-virus interaction context does not define a core STAT2 molecular function. |
| GO:0005515 protein binding | IPI PMID:16227264 Simian virus 5 V protein acts as an adaptor, linking DDB1 to... | MARK AS OVER ANNOTATED | Summary: STAT2 interaction documented in the context of SV5 V protein linking DDB1 to STAT2. Uninformative term. Reason: The generic protein binding term is uninformative; viral-adaptor context not a core function. |
| GO:0005515 protein binding | IPI PMID:17923090 Acetylation-dependent signal transduction for type I interfe... | MARK AS OVER ANNOTATED | Summary: Interaction in the context of acetylation-dependent IFN receptor signaling. Uninformative term. Reason: The generic protein binding term is uninformative for defining function. |
| GO:0005515 protein binding | IPI PMID:18579593 STAT2 is a primary target for measles virus V protein-mediat... | MARK AS OVER ANNOTATED | Summary: STAT2-measles V protein interaction (viral antagonism). Uninformative term. Reason: The generic protein binding term is uninformative; host-virus interaction not a core MF. |
| GO:0005515 protein binding | IPI PMID:20404187 Divergent susceptibilities of human herpesvirus 6 variants t... | MARK AS OVER ANNOTATED | Summary: Interaction documented in a study of HHV-6 susceptibility to type I IFN. Uninformative term. Reason: The generic protein binding term is uninformative for function. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | MARK AS OVER ANNOTATED | Summary: Interaction from an innate-immunity protein interaction network study. Uninformative term. Reason: The generic protein binding term is uninformative; network-screen interaction not a core MF. |
| GO:0005515 protein binding | IPI PMID:24065129 IFNΞ²-dependent increases in STAT1, STAT2, and IRF9 mediate r... | KEEP AS NON CORE | Summary: Interaction in the IFNbeta/U-ISGF3 (STAT1, STAT2, IRF9) resistance study. Uninformative term, though it underpins the functionally important ISGF3 associations. Reason: The generic protein binding term is uninformative; the underlying STAT1/STAT2/IRF9 association is biologically central but better captured by ISGF3 complex membership. |
| GO:0005515 protein binding | IPI PMID:26966684 PIPINO: A Software Package to Facilitate the Identification ... | MARK AS OVER ANNOTATED | Summary: Interaction from a methods/software (PIPINO AP-MS) paper. Uninformative and low-specificity. Reason: The generic protein binding term from a high-throughput methods paper is uninformative. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Interaction from a large-scale interactome study. Uninformative term. Reason: The generic protein binding term from a high-throughput interactome screen is uninformative. |
| GO:0005515 protein binding | IPI PMID:32953130 SARS-CoV-2 N protein antagonizes type I interferon signaling... | MARK AS OVER ANNOTATED | Summary: STAT2 interaction in the context of SARS-CoV-2 N protein antagonism of IFN signaling. Uninformative term. Reason: The generic protein binding term is uninformative; host-virus interaction not a core MF. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Interaction from a large-scale dual proteome-scale interactome study. Uninformative term. Reason: The generic protein binding term from a high-throughput interactome screen is uninformative. |
| GO:0005515 protein binding | IPI PMID:34471099 A dual-role of SARS-CoV-2 nucleocapsid protein in regulating... | MARK AS OVER ANNOTATED | Summary: STAT2 interaction in the context of SARS-CoV-2 N protein innate-immune regulation. Uninformative term. Reason: The generic protein binding term is uninformative; host-virus interaction not a core MF. |
| GO:0005515 protein binding | IPI PMID:34521819 Unresolvable identifier - no record in NCBI PubMed (likely a... | MARK AS OVER ANNOTATED | Summary: Interaction with an unverified cached reference (title not fetched). Uninformative protein binding term regardless. Reason: The generic protein binding term is uninformative; cannot verify the specific interaction and it would not define a core function in any case. |
| GO:0005515 protein binding | IPI PMID:35140242 Human transcription factor protein interaction networks. | MARK AS OVER ANNOTATED | Summary: Interaction from a human transcription factor interaction network study. Uninformative term. Reason: The generic protein binding term from a high-throughput interactome screen is uninformative. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Interaction from a multimodal cell-map structural/functional genomics study. Uninformative term. Reason: The generic protein binding term from a high-throughput map is uninformative. |
| GO:0005515 protein binding | IPI PMID:8605876 Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) ... | KEEP AS NON CORE | Summary: Documents SH2-dependent docking of latent STAT2 to phospho-IFNAR1 (Tyr466). Functionally important receptor interaction, but the term itself is uninformative. 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. |
| GO:0005515 protein binding | IPI PMID:8605877 The SH2 domains of Stat1 and Stat2 mediate multiple interact... | KEEP AS NON CORE | 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. Reason: The generic protein binding term is uninformative; the dimerization activity is captured better by GO:0042802. |
| GO:0005515 protein binding | IPI PMID:9121453 Functional subdomains of STAT2 required for preassociation w... | KEEP AS NON CORE | Summary: Documents STAT2 subdomains required for IFNAR preassociation and signaling. Functionally relevant receptor interaction; uninformative term. Reason: The generic protein binding term is uninformative; receptor preassociation interaction relevant but not a standalone core MF. |
| GO:0005515 protein binding | IPI PMID:9677371 Identification of amino acid residues critical for the Src-h... | KEEP AS NON CORE | Summary: Maps residues critical for SH2-dependent docking of STAT2 to IFNAR1. Functionally relevant; uninformative term. Reason: The generic protein binding term is uninformative; receptor-docking interaction relevant but not a standalone core MF. |
| GO:0042802 identical protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | 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. Reason: STAT2 homodimerization is documented (PMID:9020188); identical protein binding is non-core relative to the heterodimeric ISGF3 function. |
| GO:0042802 identical protein binding | IPI PMID:8605877 The SH2 domains of Stat1 and Stat2 mediate multiple interact... | KEEP AS NON CORE | Summary: SH2-mediated STAT2 homodimerization documented experimentally. Real but non-core; the functionally dominant species is the STAT1:STAT2 heterodimer within ISGF3. Reason: STAT2 can self-associate (PMID:9020188, PMID:8605877); non-core relative to its heterodimeric ISGF3 role. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Cytosolic localization of latent STAT2 by immunofluorescence (HPA). Correct. Reason: Correct localization but non-core; consistent with cytoplasmic residence of latent STAT2 and with the redundant Reactome cytosol annotations. |
| GO:0005634 nucleus | EXP PMID:11150296 Arginine/lysine-rich structural element is involved in inter... | ACCEPT | Summary: Experimental demonstration of IFN-induced nuclear import of STAT2 via an arginine/lysine-rich element. Correct. Reason: Directly demonstrated experimentally (PMID:11150296). |
| GO:0005737 cytoplasm | EXP PMID:11150296 Arginine/lysine-rich structural element is involved in inter... | ACCEPT | Summary: Experimental cytoplasmic localization of latent STAT2 prior to nuclear import. Correct. Reason: Directly demonstrated experimentally (PMID:11150296). |
| GO:0005737 cytoplasm | EXP PMID:23139419 Identification of STAT2 serine 287 as a novel regulatory pho... | ACCEPT | Summary: Cytoplasmic localization of STAT2 demonstrated in the Ser287 phosphoregulation study. Correct. Reason: Directly supported experimentally (PMID:23139419). |
| GO:0005737 cytoplasm | EXP PMID:27782195 Global functional profiling of human ubiquitome identifies E... | ACCEPT | Summary: Cytoplasmic localization documented in the DCST1 ubiquitination/degradation study. Correct. Reason: Directly supported experimentally (PMID:27782195). |
| GO:0007259 cell surface receptor signaling pathway via JAK-STAT | NAS PMID:24058793 STAT heterodimers in immunity: A mixed message or a unique s... | ACCEPT | Summary: STAT2 as a JAK-STAT pathway component (asserted in a STAT heterodimer review). Correct core process, though NAS evidence; corroborated by IDA/IBA. Reason: Core process annotation, corroborated by experimental annotations of the same term. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | NAS PMID:24058793 STAT heterodimers in immunity: A mixed message or a unique s... | ACCEPT | Summary: STAT2 positively regulates Pol II transcription of ISGs via its transactivation domain in ISGF3. Correct; corroborated by IDA (PMID:24065129). Reason: Core transcriptional-activation function; corroborated by IDA annotation. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:24065129 IFNΞ²-dependent increases in STAT1, STAT2, and IRF9 mediate r... | ACCEPT | 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. Reason: Experimentally supported positive transcriptional regulation by STAT2-containing complexes (PMID:24065129). |
| GO:0070721 ISGF3 complex | IPI PMID:24065129 IFNΞ²-dependent increases in STAT1, STAT2, and IRF9 mediate r... | ACCEPT | Summary: Direct evidence (IPI) for STAT2 membership in the ISGF3 complex (with STAT1 and IRF9). Core complex annotation. Reason: STAT2 is an obligate ISGF3 subunit, experimentally demonstrated (PMID:24065129). |
| GO:0090575 RNA polymerase II transcription regulator complex | NAS PMID:24058793 STAT heterodimers in immunity: A mixed message or a unique s... | KEEP AS NON CORE | Summary: ISGF3 is an RNA Pol II transcription regulator complex; this is a correct parent of the ISGF3 complex annotation. Redundant with GO:0070721. Reason: Correct but a more general parent of the specific ISGF3 complex term (GO:0070721). |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:31127039 Histone deacetylase 4 promotes type I interferon signaling, ... | MODIFY | 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. 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 replacements: DNA-binding transcription factor activity, RNA polymerase II-specific |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:9020188 Stat2 is a transcriptional activator that requires sequence-... | MODIFY | 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. Reason: Refine to GO:0000981 (Pol II-specific); STAT2's transactivation requires the complex and is Pol II-directed (PMID:9020188). Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific |
| GO:0005634 nucleus | IDA PMID:23139419 Identification of STAT2 serine 287 as a novel regulatory pho... | ACCEPT | Summary: STAT2 is active in the nucleus following IFN-induced phosphorylation and translocation. Correct. Reason: Directly supported experimentally (PMID:23139419). |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:9020188 Stat2 is a transcriptional activator that requires sequence-... | ACCEPT | 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). Reason: Experimentally supported transactivator role (PMID:9020188); the most specific and appropriate MF term for STAT2. |
| GO:0007259 cell surface receptor signaling pathway via JAK-STAT | IDA PMID:23139419 Identification of STAT2 serine 287 as a novel regulatory pho... | ACCEPT | Summary: Direct evidence for STAT2 in JAK-STAT signaling downstream of the type I IFN receptor. Core process. Reason: Experimentally supported core JAK-STAT involvement (PMID:23139419). |
| GO:0000785 chromatin | IC PMID:31127039 Histone deacetylase 4 promotes type I interferon signaling, ... | ACCEPT | Summary: STAT2 is recruited to ISRE-containing chromatin (ISG promoters) upon IFN stimulation, consistent with its transcription-activator role within ISGF3. Reason: Supported by ChIP evidence of STAT2 promoter recruitment (PMID:31127039); consistent with active transcription factor localization. |
| GO:0060339 negative regulation of type I interferon-mediated signaling pathway | IMP PMID:28165510 STAT2 is an essential adaptor in USP18-mediated suppression ... | ACCEPT | 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. Reason: Definitive IMP/mechanistic evidence (PMID:28165510); a non-redundant negative-feedback role. |
| GO:0005515 protein binding | IPI PMID:28165510 STAT2 is an essential adaptor in USP18-mediated suppression ... | KEEP AS NON CORE | 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. Reason: The generic protein binding term is uninformative; the STAT2-USP18 interaction is captured better by GO:0044389 and the negative-regulation process term. |
| GO:0005515 protein binding | IPI PMID:31836668 Severe type I interferonopathy and unrestrained interferon s... | KEEP AS NON CORE | Summary: Interaction (with USP18) documented in the PTORCH3 interferonopathy study. Uninformative term; the USP18 interaction is functionally important. Reason: The generic protein binding term is uninformative; the underlying STAT2-USP18 interaction is relevant but better captured by GO:0044389. |
| GO:0005515 protein binding | IPI PMID:32092142 Homozygous STAT2 gain-of-function mutation by loss of USP18 ... | KEEP AS NON CORE | Summary: Interaction (with USP18) documented in the gain-of-function interferonopathy study. Uninformative term. Reason: The generic protein binding term is uninformative; the STAT2-USP18 interaction is relevant but better captured by GO:0044389. |
| GO:0060337 type I interferon-mediated signaling pathway | IMP PMID:32092142 Homozygous STAT2 gain-of-function mutation by loss of USP18 ... | ACCEPT | 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. Reason: Human genetic IMP evidence for STAT2 in type I IFN signaling (PMID:32092142). |
| GO:0060337 type I interferon-mediated signaling pathway | IMP PMID:31836668 Severe type I interferonopathy and unrestrained interferon s... | ACCEPT | Summary: A homozygous STAT2 mutation causing unrestrained interferon signaling provides IMP evidence for STAT2's role in type I IFN signaling. Core function. Reason: Human genetic IMP evidence for STAT2 in type I IFN signaling (PMID:31836668). |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: Chromatin localization inferred from sequence analysis (DbTF classification). Consistent with STAT2's role within a chromatin-associated transcription complex. Reason: Consistent with experimental ChIP evidence of STAT2 promoter recruitment (PMID:31127039). |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: Pol II-specific transcription factor activity inferred from sequence analysis. Consistent with the IDA-supported activity within ISGF3. Reason: Consistent with experimental transactivator evidence (PMID:9020188, PMID:31127039). |
| GO:0044389 ubiquitin-like protein ligase binding | IPI PMID:27782195 Global functional profiling of human ubiquitome identifies E... | KEEP AS NON CORE | 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. Reason: Real, specific interaction (PMID:27782195) relevant to STAT2 turnover/regulation, but not a defining core molecular function of STAT2 itself. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8986985 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome type III IFN (IFNL) phosphorylation reaction. Correct but redundant reaction-level localization. Reason: Correct localization; redundant with experimental cytoplasm/cytosol annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8987033 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome IFNL dissociation reaction. Redundant reaction-level localization. Reason: Correct localization; redundant Reactome reaction-level annotation. |
| GO:0001932 regulation of protein phosphorylation | IMP PMID:26122121 Signal transducer and activator of transcription 2 deficienc... | KEEP AS NON CORE | 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. Reason: Experimentally supported (PMID:26122121) but a non-canonical, likely indirect function distinct from STAT2's core IFN role. |
| GO:0051607 defense response to virus | IMP PMID:23391734 STAT2 deficiency and susceptibility to viral illness in huma... | ACCEPT | Summary: Human STAT2 deficiency causes failure of type I IFN signaling and susceptibility to viral infection, directly implicating STAT2 in antiviral defense. Core process. Reason: Strong human genetic IMP evidence (PMID:23391734); STAT2 is required for ISGF3-mediated antiviral defense. |
| GO:0060337 type I interferon-mediated signaling pathway | IMP PMID:23391734 STAT2 deficiency and susceptibility to viral illness in huma... | ACCEPT | Summary: STAT2-deficient patient cells show profound failure of type I IFN signaling, providing IMP evidence for STAT2's non-redundant role. Core function. Reason: Definitive human genetic IMP evidence (PMID:23391734). |
| GO:0090140 regulation of mitochondrial fission | IMP PMID:26122121 Signal transducer and activator of transcription 2 deficienc... | KEEP AS NON CORE | 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. Reason: Experimentally supported (PMID:26122121) but a non-core, likely indirect role separate from STAT2's defining IFN-signaling function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-1015699 | KEEP AS NON CORE | Summary: Nucleoplasm localization from the Reactome ISGF3-binds-ISRE reaction. Correct; consistent with nuclear ISGF3 action. Reason: Correct localization; redundant with nucleus annotations. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-909721 | KEEP AS NON CORE | Summary: Nucleoplasm localization from the Reactome ISGF3 nuclear translocation reaction. Correct but redundant. Reason: Correct localization; redundant Reactome reaction-level annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909718 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome IFN signaling reaction. Redundant reaction-level localization. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909721 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome ISGF3 translocation reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909722 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome p-STAT2:p-STAT1 release reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909725 | KEEP AS NON CORE | Summary: Cytosolic localization from the Reactome IRF9-with-p-STAT2:p-STAT1 reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909726 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome STAT1 phosphorylation reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909732 | KEEP AS NON CORE | Summary: Cytosolic localization from the Reactome STAT2 phosphorylation reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9710959 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome STAT1 dimer/KPNA1 reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9710963 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome STAT1 dimer:KPNA1:KPNB1 reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-997309 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome STAT1 dephosphorylation reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8987266 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome IFNL receptor binding reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909719 | KEEP AS NON CORE | Summary: Cytosolic localization from the Reactome STAT2-to-p-IFNAR1 recruitment reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909720 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome IFN/IFNAR2 binding reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909724 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome IFNAR1 recruitment reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909729 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome JAK activation reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909730 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome IFNAR1 phosphorylation reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9678935 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome IFNAR2:JAK1:STAT2 inhibitor reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9696179 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome IFNAR2:JAK1:STAT2 ligand-analog reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9729454 | KEEP AS NON CORE | Summary: Cytosolic localization from the Reactome SARS-CoV-2-N-binds-STAT1/STAT2 reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9833155 | KEEP AS NON CORE | Summary: Cytosolic localization from the Reactome STAT2 ubiquitination reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9920878 | KEEP AS NON CORE | Summary: Cytosolic localization from the Reactome NS5-binds-STAT2 reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-997311 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome TYK2 dephosphorylation reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-997314 | KEEP AS NON CORE | Summary: Cytosolic localization from a Reactome JAK1 dephosphorylation reaction. Redundant. Reason: Correct localization; redundant Reactome annotation. |
| GO:0006357 regulation of transcription by RNA polymerase II | TAS PMID:9020188 Stat2 is a transcriptional activator that requires sequence-... | KEEP AS NON CORE | Summary: STAT2 regulates Pol II transcription of ISGs. Correct but general; positive regulation (GO:0045944) is more specific and informative. Reason: True but generic; superseded by GO:0045944 for the core transcription-activation function. |
| GO:0007259 cell surface receptor signaling pathway via JAK-STAT | TAS PMID:9020188 Stat2 is a transcriptional activator that requires sequence-... | ACCEPT | Summary: STAT2 as a JAK-STAT pathway component (TAS). Correct core process; corroborated by IDA/IBA. Reason: Core process; corroborated by experimental annotations. |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Experiment: 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).
Experiment: 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.
Experiment: 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.
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