Affinage

STAT2

Signal transducer and activator of transcription 2 · UniProt P52630

Length
851 aa
Mass
97.9 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STAT2 is the essential, type I IFN-specific transcription factor of the JAK-STAT axis, required for IFN-alpha/beta antiviral responses but dispensable for canonical IFN-gamma signaling, with Stat2-null mice showing heightened viral susceptibility and loss of the type I IFN autocrine loop (PMID:7532278, PMID:11163195). In resting cells STAT2 pre-associates constitutively with the cytoplasmic domain of the IFNAR2c receptor subunit through its N-terminal/central region rather than its SH2 domain (PMID:9121453, PMID:11786546), and exists in latent heterocomplexes with STAT1 (PMID:8626752) held in an inactive anti-parallel conformation (PMID:32759968). Receptor engagement triggers ordered activation: IKKepsilon phosphorylates STAT2 on T404 to disrupt the inhibitory U-STAT1/U-STAT2 dimer (PMID:32759968), after which STAT2 is tyrosine-phosphorylated at Y690 first, licensing subsequent STAT1 recruitment and phosphorylation in a strict sequential order that builds the mature ISGF3 complex (PMID:8197134, PMID:7532278, PMID:9121453). Within ISGF3, STAT1 and IRF9 provide ISRE-specific DNA contacts while STAT2 contributes only general DNA contact and a potent C-terminal transactivation domain that engages p300/CBP to drive ISG transcription (PMID:7537377, PMID:8848048, PMID:8524306, PMID:9020188), with the IRF9-STAT2 interface mapped to the STAT2 coiled-coil domain by crystallography (PMID:29317535). STAT2 nuclear accumulation is governed primarily by regulated export: a CRM1-recognized signal in its C-terminus drives shuttling, IRF9 mediates re-import of latent STAT2, and IFN abolishes export to cause nuclear retention (PMID:15175343, PMID:16507591). Beyond ISGF3, unphosphorylated STAT2 forms STAT2/IRF9 and U-ISGF3 complexes that sustain a prolonged antiviral ISG program independently of STAT1 (PMID:19351818, PMID:24065129, PMID:25564224), and U-STAT2 bridges IRF9 with NF-kappaB p65 to drive IL6 expression (PMID:29581268); reciprocally, constitutive STAT2-STAT1 binding restrains STAT1 nuclear import in IFN-gamma, IL-6, and IL-27 signaling (PMID:27780205). Signaling magnitude is tuned by inhibitory phosphorylations—constitutive T387 phosphorylation by CDKs and SH2-domain control of TcPTP-mediated dephosphorylation—and by STAT2 serving as the adaptor that recruits USP18 to IFNAR2 for negative feedback (PMID:17442890, PMID:27852626, PMID:28165510). As the pivotal specificity node of type I IFN signaling, STAT2 is a recurrent target of viral antagonists that degrade it (dengue/ZIKV NS5 via ZSWIM8-CUL3, RSV NS1 via Elongin-Cullin, EBV BGLF2 via cullin 1, paramyxovirus V proteins), sequester it (Nipah V protein), or cleave it (porcine deltacoronavirus nsp5) (PMID:12388709, PMID:17251292, PMID:19279106, PMID:34319780, PMID:39145933, PMID:28250121).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1994 High

    Established that STAT2 and STAT1 are activated in a defined sequence rather than independently, defining the basic logic of ISGF3 assembly.

    Evidence Tyrosine phosphorylation and nuclear translocation assays in STAT-deficient cell lines

    PMID:8197134

    Open questions at the time
    • Did not identify the kinase or receptor docking events ordering the phosphorylation
    • Localization of complex assembly not resolved
  2. 1995 High

    Demonstrated that STAT2 is selectively required for IFN-alpha but not IFN-gamma signaling and that Y690 phosphorylation gates downstream STAT1 receptor binding, fixing the activation order.

    Evidence STAT2-null U6A cell complementation with Y690F mutagenesis; DNA-contact mapping of ISGF3 by EMSA

    PMID:7532278 PMID:7537377

    Open questions at the time
    • Mechanism of STAT2-receptor preassociation not yet mapped
    • How STAT2 contributes transactivation without sequence-specific DNA contact unresolved
  3. 1996 High

    Localized STAT2's transcriptional output to a C-terminal transactivation domain binding p300/CBP and showed latent STAT1-STAT2 heterocomplexes preexist before stimulation, separating activation from DNA-binding specificity.

    Evidence Domain mapping, co-IP, transactivation reporter assays, E1A inhibition, and co-immunoadsorption of latent complexes

    PMID:8524306 PMID:8621447 PMID:8626752 PMID:8647845 PMID:8848048

    Open questions at the time
    • Whether STAT2-containing non-ISGF3 complexes have physiological promoter targets unclear at this stage
    • Structural basis of p300/CBP recruitment not defined
  4. 1997 High

    Defined STAT2 as the constitutive IFNAR2c-docking subunit and showed it can pair with IRF9 alone but needs STAT1 for ISRE specificity, clarifying division of labor within ISGF3.

    Evidence Receptor cytoplasmic-domain pulldowns, STAT2-STAT1 chimeras in U6A cells, and in vitro reconstitution of STAT2-p48 complex

    PMID:9020188 PMID:9121453

    Open questions at the time
    • The functional role of the constitutive receptor association versus inducible SH2 recruitment not fully separated
    • Regulation of complex disassembly unaddressed
  5. 2000 High

    Genetically confirmed STAT2's non-redundant role in antiviral defense and the type I IFN autocrine loop in vivo, with tissue-specific signaling dependence.

    Evidence Stat2 knockout mice with viral challenge and IFN response assays in primary fibroblasts and macrophages

    PMID:11163195

    Open questions at the time
    • Molecular basis of tissue-specific differences not defined
    • Did not address non-canonical STAT2 complexes
  6. 2004 High

    Resolved the trafficking logic of STAT2, showing IRF9-dependent import of latent STAT2 and CRM1-dependent export, with phosphorylation-driven nuclear retention.

    Evidence Live-cell imaging, leptomycin B treatment, and nuclear fractionation in STAT1-deficient cells

    PMID:15175343 PMID:16507591

    Open questions at the time
    • Identity of the second CRM1-independent export pathway unknown
    • How export is shut off by IFN at the molecular level unclear
  7. 2007 High

    Identified phosphatase- and ligase-based control points—TcPTP dephosphorylation gated by the STAT2 SH2 PYTK motif and RSV NS1-directed Elongin-Cullin degradation—showing STAT2 signaling magnitude is actively limited.

    Evidence Y631F mutagenesis with TcPTP dephosphorylation kinetics; in vitro E3 component interaction and siRNA rescue

    PMID:17251292 PMID:17442890

    Open questions at the time
    • Physiological CDK/kinase generating inhibitory phosphorylation not yet identified
    • Generality of viral degradation strategy across virus families not yet mapped
  8. 2009 High

    Revealed receptor-proximal and unphosphorylated-state functions: IFNAR1 palmitoylation selectively licenses STAT2 activation, and unphosphorylated STAT2/IRF9 drives a STAT1-independent ISG program.

    Evidence IFNAR1 cysteine mutagenesis and palmitoylation inhibition; siRNA and reporter assays for IRF9/U-STAT2-driven RIG-G; dengue NS5 degradation assays

    PMID:19279106 PMID:19351818 PMID:19561067

    Open questions at the time
    • The promoter spectrum of U-STAT2/IRF9 not yet genome-wide
    • How palmitoylation selectively favors STAT2 mechanistically unresolved
  9. 2011 Medium

    Showed that unphosphorylated STAT2 is prebound to ISG promoters and that phosphorylation status determines activation versus repression, decoupling STAT2 function from its activation state.

    Evidence ChIP-chip of total and phospho-STAT2 across 113 promoters in hepatocytes

    PMID:21498520

    Open questions at the time
    • Single-lab genome-wide dataset
    • Mechanism linking P-STAT2 occupancy to repression not established
  10. 2015 High

    Established that STAT2/IRF9 without STAT1 can drive a prolonged, partly distinct antiviral transcriptome, expanding STAT2's role beyond canonical ISGF3.

    Evidence STAT1-deficient cells overexpressing STAT2, microarray, phosphorylation and antiviral assays; U-ISGF3 characterization

    PMID:24065129 PMID:25564224

    Open questions at the time
    • Endogenous physiological contexts where STAT1-independent program dominates underdefined
    • Promoter features distinguishing shared vs specific ISGs not fully mapped
  11. 2016 High

    Uncovered cross-pathway and inhibitory roles: constitutive STAT2-STAT1 binding restrains STAT1 nuclear import in IFN-gamma/IL-6/IL-27 signaling, and CDK-mediated T387 phosphorylation constitutively limits IFN-I responses.

    Evidence Co-IP, importin-alpha binding and nuclear translocation assays with STAT2-KO; T387A mutagenesis with CDK inhibitor treatment

    PMID:27780205 PMID:27852626

    Open questions at the time
    • Specific CDK responsible for T387 phosphorylation not pinned down
    • Physiological balance between positive and negative STAT2 functions unclear
  12. 2017 High

    Defined STAT2 as the obligate adaptor recruiting USP18 to IFNAR2 for negative feedback, linking the activating subunit to signal termination.

    Evidence Co-IP and IFNAR2/USP18 interaction mapping with STAT2-KO complementation in human and mouse cells

    PMID:28165510

    Open questions at the time
    • Structural basis of the USP18-STAT2-IFNAR2 ternary assembly not resolved
    • Kinetics relative to TcPTP-mediated control not integrated
  13. 2018 High

    Provided atomic-level definition of the IRF9-STAT2 coiled-coil interface and modeled ISGF3 on the ISRE, structurally explaining STAT2's specificity contribution.

    Evidence X-ray crystallography of IRF9-IAD/STAT2-CCD with structure-guided mutagenesis and cellular assays

    PMID:29317535

    Open questions at the time
    • Full ISGF3-DNA complex not crystallized
    • Conformational changes accompanying activation not captured
  14. 2019 High

    Demonstrated that ISGF3 assembles on promoter DNA rather than in the cytoplasm and that preformed STAT2-IRF9 controls basal ISG expression, revising the canonical assembly model.

    Evidence Integrated transcriptomics, proteomics, in vivo BioID proximity labeling and ChIP-seq in macrophages

    PMID:31266943

    Open questions at the time
    • Whether on-DNA assembly is universal across cell types and IFN doses not established
    • Dynamics of subunit exchange on chromatin not resolved
  15. 2020 High

    Identified IKKepsilon-mediated T404 phosphorylation as the trigger disrupting the inactive anti-parallel U-STAT1/U-STAT2 dimer, defining a kinase-controlled activation switch validated in vivo.

    Evidence Electron microscopy of the anti-parallel dimer, in vitro IKKepsilon kinase assay, and T403A knockin mice with viral challenge

    PMID:32759968

    Open questions at the time
    • Integration of T404 with the downstream Y690/T387 phosphorylation hierarchy not fully ordered
    • Which infections engage IKKepsilon versus JAK-driven activation unclear
  16. 2024 High

    Resolved the structural and ligase machinery of viral STAT2 antagonism, showing flavivirus NS5 occludes the IRF9 interface and recruits the ZSWIM8-CUL3 ligase for STAT2 degradation, alongside EBV BGLF2-cullin1 and porcine deltacoronavirus nsp5 cleavage.

    Evidence Cryo-EM/crystallography of NS5-STAT2; genome-wide CRISPR screen identifying ZSWIM8 with knockout rescue; co-IP, ubiquitination and cleavage-site mapping

    PMID:32778820 PMID:34319780 PMID:39145933

    Open questions at the time
    • Whether host pathways also use ZSWIM8 to regulate STAT2 unknown
    • Conservation of these antagonism mechanisms across additional virus families not exhaustively tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple inhibitory phosphorylations (T387, the SH2-PYTK/TcPTP axis) and the activating T404/Y690 events are temporally and spatially integrated to set ISG amplitude and duration in vivo remains unresolved.
  • No unified kinetic model linking activating and inhibitory modifications
  • Cell-type-specific deployment of canonical ISGF3 versus U-STAT2/IRF9 and U-ISGF3 programs not defined
  • Endogenous (non-viral) regulators of STAT2 stability not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0003677 DNA binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
IFNAR1IFNAR2IRF9P300/CBP (CREBBP/EP300)RELASTAT1USP18
Complex memberships
ISGF3 (STAT1-STAT2-IRF9)STAT1-STAT2 heterodimerSTAT2-IRF9 complexU-ISGF3

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 STAT2 (Stat113) is phosphorylated on tyrosine independently of STAT1 (Stat91/84), but phosphorylated STAT2 is required for efficient nuclear translocation of STAT1; in the absence of phosphorylated Stat91/84, Stat113 phosphoprotein moves to the nucleus much less efficiently, establishing a sequential phosphorylation model for ISGF3 formation. Cell lines lacking Stat91 or Stat84, tyrosine phosphorylation analysis, nuclear translocation assays Proceedings of the National Academy of Sciences of the United States of America High 8197134
1995 STAT2 is required for IFN-alpha signaling: U6A cells lacking STAT2 are almost completely defective in IFN-alpha response but normal for IFN-gamma; STAT2 phosphorylation on Y690 is essential; phosphorylated STAT2 is required to allow unphosphorylated STAT1 to bind to the activated IFN-alpha receptor, establishing a sequential phosphorylation order. Mutant cell line complementation (U6A cells), site-directed mutagenesis (Y690F), tyrosine phosphorylation assays Molecular and cellular biology High 7532278
1995 In the ISGF3 complex, tyrosine-phosphorylated STAT1 and STAT2 form a heterodimer; STAT1 and the 48-kDa protein (IRF9) make precise DNA contacts with the ISRE, while STAT2 makes only general contact with DNA. DNA contact analysis, electrophoretic mobility shift assay, immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 7537377
1996 The carboxy-terminal segment of STAT2 has transactivation potential and interacts specifically with the first cysteine-histidine-rich region of p300/CBP; this domain is essential for ISGF3 function; adenovirus E1A represses STAT2 transactivation and IFN-alpha-activated transcription by inhibiting p300/CBP function. Co-immunoprecipitation, domain mapping, transactivation assays, E1A inhibition studies Nature High 8848048
1996 The C-terminal 50 amino acids of STAT2 are required for transcriptional activation in response to IFN-alpha; truncation mutants lacking this region can be phosphorylated, form ISGF3, and translocate to the nucleus but cannot stimulate IFN-alpha-dependent transcription; dominant negative STAT2 mutants that cannot be phosphorylated suppress wild-type STAT2 phosphorylation by competition at receptor-kinase interaction sites. Mutant complementation in U6A cells, deletion analysis, transcriptional reporter assays Molecular and cellular biology High 8524306
1996 STAT1-STAT2 heterodimers form in response to IFN-alpha and, without p48/IRF9, bind to IR elements in the IRF-1 promoter; these heterodimers are more potent transcriptional activators of IRF-1 than STAT1 homodimers; the C-terminal domain of STAT2 is important for transcriptional activation by both STAT1-STAT2 heterodimers and ISGF3. EMSA, U2A cell lines lacking p48, deletion analysis, reporter assays The Journal of biological chemistry High 8621447
1996 STAT1 and STAT2 form preexisting heterocomplexes in unstimulated cells (prior to cytokine stimulation); IFN-alpha-induced tyrosine phosphorylation increases the stability of this pre-existing latent STAT1-STAT2 complex; STAT2 and STAT3 exist in separate heterocomplexes with STAT1. Co-immunoadsorption from hypotonic cytosol, in vitro mixing of translated proteins The Journal of biological chemistry Medium 8626752
1996 IFN-alpha activates multiple STAT2-containing complexes beyond ISGF3, including a STAT2:STAT1 complex (without p48) that binds with low affinity to the palindromic IRE of IRF-1, and a complex that co-precipitates STAT3 with STAT2. Genomic DNA affinity chromatography, EMSA, immunoprecipitation The Journal of biological chemistry Medium 8647845
1997 STAT2 binds constitutively to the cytoplasmic domain of IFNAR2c (IFNAR2-2) in extracts of untreated cells; STAT1 also binds to IFNAR2c but only when STAT2 is present; the N-terminal third of STAT2 (not the SH2 domain) mediates its specific pre-association with IFNAR2c; upon IFN-alpha activation, IFNAR1 is phosphorylated on Y466, allowing SH2-mediated STAT2 recruitment followed by sequential phosphorylation of STAT2 then STAT1. Pulldown with cytoplasmic domain of IFNAR2c, chimeric STAT2-STAT1 proteins in U6A complementation, co-immunoprecipitation Molecular and cellular biology High 9121453
1997 STAT2 alone can form a stable homodimer with p48/IRF9 that is recruited to DNA; however, STAT2 cannot contact DNA directly with sequence specificity — it requires STAT1, which contacts a half-site of the ISRE and stabilizes the heteromeric ISGF3 complex; STAT2 contributes a potent transactivation domain to ISGF3. In vitro reconstitution of STAT2 homodimer-p48 complex, EMSA, transcriptional activation assays The Journal of biological chemistry High 9020188
1999 Murine STAT2 is highly divergent from human STAT2, most strikingly in the C-terminal transcriptional activation domain; murine STAT2 functions in IFN-alpha-dependent activation, nuclear translocation, DNA binding, and reporter gene activation; the murine and human C-termini interact with an overlapping but distinct set of proteins. Molecular cloning, sequence analysis, functional reporter assays, protein interaction studies Nucleic acids research Medium 10518610
1999 Urokinase (uPA) activates STAT2 and STAT4 (but not STAT3, STAT5, or STAT6) in human vascular smooth muscle cells; the activated STAT2 forms a STAT2-STAT1 heterodimer lacking p48 that binds to GAS elements (not ISRE), representing a non-canonical STAT2 complex distinct from ISGF3. Nuclear translocation assays, EMSA, immunoprecipitation The Journal of biological chemistry Medium 10446176
2000 Stat2-null mice exhibit increased susceptibility to viral infection and loss of a type I IFN autocrine/paracrine loop; Stat2-deficient fibroblasts exhibit a more significant defect in type I IFN response than macrophages, demonstrating tissue-specific differences; Stat2 is uniquely required for type I IFN but not type II IFN signaling. Gene targeting (knockout mice), viral challenge, IFN response assays in primary cells Immunity High 11163195
2002 STAT2 constitutively binds to IFNAR2 through a central region (residues 136–702) independently of STAT SH2 domain; this interaction maps to IFNAR2 residues 418–444; mutating this region paradoxically enhances rather than reduces IFN-alpha signaling, suggesting this particular IFNAR2-STAT2 interaction acts as a negative modulator rather than being required for signaling. In vitro binding assays, site-directed mutagenesis of IFNAR2, complementation in IFNAR2-deficient U5A cells, reporter assay The Journal of biological chemistry Medium 11786546
2002 Nipah virus V protein inhibits IFN signaling by forming high-molecular-weight cytoplasmic complexes with both STAT1 and STAT2, sequestering them in the cytoplasm via a CRM1-dependent mechanism, preventing IFN-stimulated tyrosine phosphorylation and nuclear translocation of both STATs. Co-immunoprecipitation, subcellular fractionation, leptomycin B treatment, immunofluorescence Journal of virology High 12388709
2002 Paramyxovirus-induced STAT protein degradation requires both STAT1 and STAT2 in the host cell but is independent of the IFN receptor, JAK1, TYK2, or IRF9; V proteins physically interact with STAT proteins; tyrosine phosphorylation and functional SH2 domains are dispensable for degradation-permissive environment, but the N-terminus of the missing STAT is essential. Somatic cell lines deficient in IFN signaling components, complementation, co-immunoprecipitation, proteasome inhibitor treatment Journal of virology High 11932384
2004 Unphosphorylated STAT2 dynamically shuttles between cytoplasm and nucleus; nuclear import of latent STAT2 depends on its constitutive association with IRF9; nuclear export requires an intrinsic CRM1-recognized nuclear export signal in the STAT2 C-terminus; after tyrosine phosphorylation, STAT2 accumulates in the nucleus dependent on STAT1 dimerization, then redistributes to the cytoplasm coordinate with dephosphorylation. Live-cell imaging, leptomycin B treatment, nuclear fractionation, STAT1-deficient cells The Journal of biological chemistry High 15175343
2005 STAT2 plays a dual role in IFN-gamma signaling: a cytomegalovirus protein (pM27) that specifically binds and down-regulates STAT2 (without affecting STAT1) blocks both type I and type II IFN responses; IFN-gamma directly activates STAT2 (tyrosine phosphorylation) in an IFN receptor-dependent, type I IFN-independent manner. MCMV M27 mutant virus, STAT2 pulldown, IFN signaling assays, M27+/M27- comparative analysis The Journal of experimental medicine High 15883169
2006 The main regulatory mechanism controlling STAT2 nuclear accumulation is nuclear export; in the absence of IFN, STAT2 permanently and rapidly shuttles between cytoplasm and nucleus via at least two export pathways (one CRM1-dependent, one unidentified); upon IFN type I treatment, nuclear export of STAT2 is completely abolished while import continues, causing nuclear accumulation; the C-terminus of STAT2 is essential for CRM1-dependent export. Live-cell kinetic imaging in living cells, leptomycin B, FRAP-related nuclear transport assays Journal of cell science High 16507591
2007 RSV NS1 protein uses the Elongin-Cullin E3 ubiquitin ligase to degrade STAT2 via the proteasome; NS1 contains elongin C and cullin 2 binding consensus sequences and interacts with these proteins in vitro; siRNA knockdown of specific E3 ligase components prevents NS1/2-induced STAT2 degradation. In vitro protein-protein interaction, siRNA knockdown of E3 components, proteasomal inhibitor treatment Journal of virology High 17251292
2007 A Y631F mutation in the SH2 domain PYTK motif of STAT2 causes prolonged tyrosine phosphorylation of STAT1 and STAT2 heterodimers due to resistance to dephosphorylation by the nuclear tyrosine phosphatase TcPTP, leading to sustained ISG induction and IFN-alpha-induced apoptosis. Site-directed mutagenesis, phosphorylation kinetics, TcPTP dephosphorylation assays, apoptosis assays Molecular biology of the cell High 17442890
2008 Measles virus V protein C-terminal zinc finger domain is necessary and sufficient to bind STAT2 and disrupt IFN-alpha/beta signaling; D248 in the V protein is critical for STAT2 interaction and IFN antiviral immune suppression; STAT1 interference by MV-V requires cellular STAT2 to be present. Mutagenesis, co-immunoprecipitation, IFN signaling reporter assays, molecular modeling Journal of virology High 18579593
2009 Dengue virus NS5 protein binds to STAT2 and is necessary and sufficient to target it for proteasomal degradation; degradation requires ubiquitination and proteasome activity; degradation (but not binding) requires NS5 to be expressed in the context of a viral polyprotein and undergo proteolytic processing — mature NS5 alone can bind but not degrade STAT2. Co-immunoprecipitation, proteasome inhibitor treatment, ubiquitination assays, expression of individual vs. polyprotein-derived NS5 Journal of virology High 19279106
2009 Palmitoylation of IFNAR1 at cysteine 463 is required for selective activation of STAT2 (but not overall receptor stability or endocytosis); loss of IFNAR1 palmitoylation impairs STAT2 activation, which results in reduced STAT1 activation and nuclear translocation, demonstrating palmitoylation as a regulatory mechanism for JAK-STAT signaling. Site-directed mutagenesis of IFNAR1 cysteines, palmitoylation inhibition, biochemical fractionation, signaling assays The Journal of biological chemistry High 19561067
2009 IRF9 and unphosphorylated STAT2 form a functional complex sufficient to drive transcription of the RIG-G gene in a STAT1-independent manner, even without STAT2 tyrosine phosphorylation; this IRF9/STAT2 complex is both necessary and sufficient for RIG-G expression. siRNA knockdown, reporter assays, co-immunoprecipitation, STAT1-deficient cells Cancer research High 19351818
2010 Dengue virus NS5-mediated binding and degradation of STAT2 is species-specific: NS5 binds and degrades human STAT2 but not mouse STAT2; the species-specific difference maps to the STAT2 coiled-coil domain; NS5-mediated IFN antagonism is essential for efficient dengue virus replication. Species comparison, chimeric STAT2 proteins, STAT2-/- mice, viral replication assays Cell host & microbe High 21075352
2011 Unphosphorylated STAT2 (U-STAT2) is prebound to many ISG promoters before IFN-alpha treatment; phosphorylated STAT2 (P-STAT2) is involved in ISG repression; STAT2 regulates ISG expression independently of its tyrosine phosphorylation status; P-STAT2 occupancy correlates with gene repression. ChIP-chip analysis of STAT2 and phospho-STAT2 on 113 target promoters in Huh7 cells and primary hepatocytes The Journal of biological chemistry Medium 21498520
2013 A sustained second-phase IFN response is driven by un-phosphorylated ISGF3 (U-ISGF3), formed by IFN-beta-induced high levels of IRF9 and unphosphorylated STATs 1 and 2; U-ISGF3 drives prolonged antiviral gene expression at distinct ISREs; continuous low-level IFNβ (as in cancers) leads to constitutive U-ISGF3-dependent gene expression and DNA damage resistance. IFN stimulation kinetics, STAT overexpression, reporter assays, gene expression analysis, antiviral and DNA damage assays The EMBO journal High 24065129
2015 STAT2/IRF9 complex (without STAT1) can induce a prolonged ISGF3-like transcriptional response and antiviral state; STAT2 phosphorylation and the STAT2 transactivation domain are required for this activity; ~120 ISGs are commonly induced by STAT2/IRF9 and ISGF3, while a subset of 'STAT2/IRF9-specific' ISGs are induced independently of STAT1. STAT1-deficient cells stably overexpressing STAT2, microarray, phosphorylation analysis, antiviral assays The Biochemical journal High 25564224
2016 STAT2 constitutively binds STAT1 (but not STAT3) via a conserved interface; this interaction is irrelevant for type I IFN signaling but prevents nuclear translocation of STAT1 in response to IFN-γ, IL-6, and IL-27 by forming semi-phosphorylated STAT1-U-STAT2 dimers that cannot bind importin-α; this attenuates IFN-γ responses including MHC expression, senescence, and anti-parasitic immunity. Co-immunoprecipitation, nuclear translocation assays, importin-α binding, STAT2-KO genetic analysis, anti-parasitic immunity assay PLoS biology High 27780205
2016 STAT2 T387 is constitutively phosphorylated in most untreated cell types, negatively regulating IFN-I signaling; T387A STAT2 is much more effective than wild-type in driving ISG expression, antiviral protection, and cell growth inhibition; CDK inhibitors decrease T387 phosphorylation and can potentiate IFN-I responses. Site-directed mutagenesis (T387A), CDK inhibitor treatment, ISG expression, antiviral assays, ISGF3-ISRE binding assays The EMBO journal High 27852626
2017 STAT2 recruits USP18 to the type I IFN receptor subunit IFNAR2 via a constitutive membrane-distal STAT2-binding site, thereby serving as an essential adaptor for USP18-mediated negative-feedback control of type I IFN signaling in both human and mouse cells. Co-immunoprecipitation, IFNAR2 binding assays, USP18-STAT2 interaction mapping, STAT2-KO complementation Nature structural & molecular biology High 28165510
2017 Porcine deltacoronavirus nsp5 (3C-like protease) cleaves STAT2 at glutamine 685 and glutamine 758 in a protease-activity-dependent manner, impairing STAT2 function and ISG induction; nsp5 does not cleave JAK1, TYK2, STAT1, or IRF9. Overexpression, cleavage site mapping by mutagenesis, protease activity mutants, ISG reporter assays Journal of virology High 28250121
2018 Crystal structure of IRF9-IAD in complex with the STAT2 coiled-coil domain (CCD) reveals specific diverged surface features enabling selective IRF9-STAT2 interaction; this interface is required for ISGF3 function in cells; a model for ISGF3 bound to an ISRE was derived. X-ray crystallography, structure-guided mutagenesis, cellular functional assays Proceedings of the National Academy of Sciences of the United States of America High 29317535
2018 Unphosphorylated STAT2 (U-STAT2) binds tightly to IRF9 and also to the p65 subunit of NF-κB, bridging the ISRE and κB elements in the IL6 promoter; U-STAT2/IRF9 complex drives strong IL6 expression in response to NF-κB activators (IL-1, TNF, LPS), distinct from the ISGF3-mediated early response. ChIP, co-immunoprecipitation, reporter assays, siRNA knockdown, IL6 ISRE mutation Proceedings of the National Academy of Sciences of the United States of America High 29581268
2019 Resting macrophages contain preformed STAT2-IRF9 complexes that control basal ISG expression; upon IFN stimulation, a complete ISGF3 complex (STAT1+STAT2+IRF9) forms and binds promoters; assembly of ISGF3 occurs on DNA rather than in the cytoplasm, contradicting the canonical cytoplasmic assembly model. Integrated transcriptomics, proteomics, in vivo proximity labeling (BioID), ChIP-seq, in macrophages Nature communications High 31266943
2019 In naive cells, unphosphorylated STAT2 (U-STAT2) forms a heterodimer with U-STAT1 in an inactive anti-parallel conformation as visualized by electron microscopy; IKKε (activated by virus infection) phosphorylates STAT2 on T404 directly, disrupting the U-STAT1-U-STAT2 anti-parallel dimer and promoting IFN-I signaling; mice with T403A mutation are highly susceptible to viral infections. Electron microscopy, IKKε kinase assay (direct phosphorylation), T403A knockin mice, viral challenge Cell research High 32759968
2020 Cryo-EM and crystal structures of human STAT2 in complex with ZIKV and DENV NS5 reveal two-pronged interactions: the NS5 methyltransferase and RdRP domains form an interdomain cleft harboring the STAT2 coiled-coil domain (blocking IRF9 association), and the NS5 RdRP domain also binds the STAT2 N-terminal domain; disruption of these interfaces compromised NS5-mediated STAT2 degradation and IFN suppression. Cryo-EM structure, X-ray crystallography, mutagenesis of NS5-STAT2 interface, IFN signaling and viral replication assays Nature structural & molecular biology High 32778820
2021 EBV tegument protein BGLF2 associates with STAT2 and promotes K48-linked polyubiquitination and proteasomal degradation of STAT2 by recruiting cullin 1 E3 ubiquitin ligase to STAT2, thereby suppressing ISG induction; separately, BGLF2 recruits SHP1 phosphatase to STAT1 to inhibit its tyrosine phosphorylation. Co-immunoprecipitation, ubiquitination assays, cullin 1 knockdown, SHP1 recruitment assays, EBV BGLF2 genetic disruption Journal of virology High 34319780
2024 ZIKV NS5 uses the ZSWIM8-CUL3 E3 ubiquitin ligase complex as the substrate receptor for STAT2 proteasomal degradation; genome-wide CRISPR screen identified ZSWIM8; NS5 acts as a scaffold enhancing STAT2-ZSWIM8 interaction; ZSWIM8 knockout restores STAT2 levels and IFN signaling. Genome-wide CRISPR/Cas9 screen, genetic knockout of ZSWIM8 and CUL3, co-immunoprecipitation, ubiquitination assays, human neural progenitor cells Proceedings of the National Academy of Sciences of the United States of America High 39145933

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha. Nature 428 8848048
2009 NS5 of dengue virus mediates STAT2 binding and degradation. Journal of virology 372 19279106
2000 Immune response in Stat2 knockout mice. Immunity 297 11163195
2013 IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. The EMBO journal 289 24065129
1995 Role of STAT2 in the alpha interferon signaling pathway. Molecular and cellular biology 256 7532278
2013 Transcriptional regulation by STAT1 and STAT2 in the interferon JAK-STAT pathway. JAK-STAT 244 24069549
2002 Nipah virus V protein evades alpha and gamma interferons by preventing STAT1 and STAT2 activation and nuclear accumulation. Journal of virology 238 12388709
2005 Dengue virus inhibits alpha interferon signaling by reducing STAT2 expression. Journal of virology 216 15827155
2013 STAT2 deficiency and susceptibility to viral illness in humans. Proceedings of the National Academy of Sciences of the United States of America 205 23391734
1995 Tyrosine-phosphorylated Stat1 and Stat2 plus a 48-kDa protein all contact DNA in forming interferon-stimulated-gene factor 3. Proceedings of the National Academy of Sciences of the United States of America 192 7537377
1996 Formation of STAT1-STAT2 heterodimers and their role in the activation of IRF-1 gene transcription by interferon-alpha. The Journal of biological chemistry 176 8621447
2019 A molecular switch from STAT2-IRF9 to ISGF3 underlies interferon-induced gene transcription. Nature communications 174 31266943
2010 Mouse STAT2 restricts early dengue virus replication. Cell host & microbe 170 21075352
1997 Functional subdomains of STAT2 required for preassociation with the alpha interferon receptor and for signaling. Molecular and cellular biology 163 9121453
2007 Respiratory syncytial virus NS1 protein degrades STAT2 by using the Elongin-Cullin E3 ligase. Journal of virology 158 17251292
2017 STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling. Nature structural & molecular biology 156 28165510
1996 Function of Stat2 protein in transcriptional activation by alpha interferon. Molecular and cellular biology 148 8524306
2002 Degradation of STAT1 and STAT2 by the V proteins of simian virus 5 and human parainfluenza virus type 2, respectively: consequences for virus replication in the presence of alpha/beta and gamma interferons. Journal of virology 139 11836393
1994 Transcription factor ISGF-3 formation requires phosphorylated Stat91 protein, but Stat113 protein is phosphorylated independently of Stat91 protein. Proceedings of the National Academy of Sciences of the United States of America 138 8197134
1996 Preassociation of STAT1 with STAT2 and STAT3 in separate signalling complexes prior to cytokine stimulation. The Journal of biological chemistry 135 8626752
2005 A cytomegaloviral protein reveals a dual role for STAT2 in IFN-{gamma} signaling and antiviral responses. The Journal of experimental medicine 129 15883169
2015 Disruption of type I interferon signaling by the nonstructural protein of severe fever with thrombocytopenia syndrome virus via the hijacking of STAT2 and STAT1 into inclusion bodies. Journal of virology 127 25631085
2016 The unique role of STAT2 in constitutive and IFN-induced transcription and antiviral responses. Cytokine & growth factor reviews 126 27053489
2003 Hendra virus V protein inhibits interferon signaling by preventing STAT1 and STAT2 nuclear accumulation. Journal of virology 125 14557668
2002 Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of alpha/beta interferon signal transduction. Journal of virology 125 11932384
2022 The Fibrillin-1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells. Cancer communications (London, England) 123 35234370
2017 Porcine Deltacoronavirus nsp5 Antagonizes Type I Interferon Signaling by Cleaving STAT2. Journal of virology 123 28250121
2020 Stat2-Drp1 mediated mitochondrial mass increase is necessary for pro-inflammatory differentiation of macrophages. Redox biology 122 33080440
2008 JAK2/STAT2/STAT3 are required for myogenic differentiation. The Journal of biological chemistry 121 18835816
1997 Stat2 is a transcriptional activator that requires sequence-specific contacts provided by stat1 and p48 for stable interaction with DNA. The Journal of biological chemistry 119 9020188
2013 STAT2 and IRF9: Beyond ISGF3. JAK-STAT 115 24498542
2004 STAT2 nuclear trafficking. The Journal of biological chemistry 109 15175343
2003 Cloning of a new type II cytokine receptor activating signal transducer and activator of transcription (STAT)1, STAT2 and STAT3. The Biochemical journal 108 12521379
2014 3Cpro of foot-and-mouth disease virus antagonizes the interferon signaling pathway by blocking STAT1/STAT2 nuclear translocation. Journal of virology 104 24554650
2008 STAT2 is a primary target for measles virus V protein-mediated alpha/beta interferon signaling inhibition. Journal of virology 98 18579593
2018 IRF9 and unphosphorylated STAT2 cooperate with NF-κB to drive IL6 expression. Proceedings of the National Academy of Sciences of the United States of America 96 29581268
2015 STAT2/IRF9 directs a prolonged ISGF3-like transcriptional response and antiviral activity in the absence of STAT1. The Biochemical journal 83 25564224
1997 Retinoic acid induces signal transducer and activator of transcription (STAT) 1, STAT2, and p48 expression in myeloid leukemia cells and enhances their responsiveness to interferons. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 73 9186002
2008 NF-kappaB-driven STAT2 and CCL2 expression in astrocytes in response to brain injury. Journal of immunology (Baltimore, Md. : 1950) 72 18981150
2018 Structural basis of STAT2 recognition by IRF9 reveals molecular insights into ISGF3 function. Proceedings of the National Academy of Sciences of the United States of America 70 29317535
2003 Oncogenic Ki-ras inhibits the expression of interferon-responsive genes through inhibition of STAT1 and STAT2 expression. The Journal of biological chemistry 69 12972432
2016 Interferon-induced transmembrane protein 1 (IFITM1) overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a signal transducer and activator of transcription 2 (STAT2)-dependent manner. Breast cancer research : BCR 67 26897526
2022 circCAPRIN1 interacts with STAT2 to promote tumor progression and lipid synthesis via upregulating ACC1 expression in colorectal cancer. Cancer communications (London, England) 66 36328987
2010 STAT2 contributes to promotion of colorectal and skin carcinogenesis. Cancer prevention research (Philadelphia, Pa.) 66 20233899
2008 Inhibition of IFN-alpha/beta signaling by two discrete peptides within measles virus V protein that specifically bind STAT1 and STAT2. Virology 63 19007958
2020 Structural basis for STAT2 suppression by flavivirus NS5. Nature structural & molecular biology 60 32778820
2009 IRF-9/STAT2 [corrected] functional interaction drives retinoic acid-induced gene G expression independently of STAT1. Cancer research 59 19351818
1999 Murine Stat2 is uncharacteristically divergent. Nucleic acids research 59 10518610
1996 Application of genomic DNA affinity chromatography identifies multiple interferon-alpha-regulated Stat2 complexes. The Journal of biological chemistry 58 8647845
2016 STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways. PLoS biology 57 27780205
2016 Vaccinia Virus Protein C6 Inhibits Type I IFN Signalling in the Nucleus and Binds to the Transactivation Domain of STAT2. PLoS pathogens 56 27907166
2020 Stat2 stability regulation: an intersection between immunity and carcinogenesis. Experimental & molecular medicine 54 32973222
2005 Stat1 and Stat2 but not Stat3 arbitrate contradictory growth signals elicited by alpha/beta interferon in T lymphocytes. Molecular and cellular biology 53 15964802
2011 Chromatin dynamics of gene activation and repression in response to interferon alpha (IFN(alpha)) reveal new roles for phosphorylated and unphosphorylated forms of the transcription factor STAT2. The Journal of biological chemistry 49 21498520
2017 Zika virus infection of adult and fetal STAT2 knock-out hamsters. Virology 47 28431283
2015 STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control. PLoS pathogens 47 26291525
2019 Viral Resistance and IFN Signaling in STAT2 Knockout Fish Cells. Journal of immunology (Baltimore, Md. : 1950) 45 31142600
2022 Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency. The Journal of allergy and clinical immunology 44 35182547
2019 Heartland virus antagonizes type I and III interferon antiviral signaling by inhibiting phosphorylation and nuclear translocation of STAT2 and STAT1. The Journal of biological chemistry 44 31040183
2020 A virus-induced conformational switch of STAT1-STAT2 dimers boosts antiviral defenses. Cell research 43 32759968
2019 Role of SNHG7-miR-653-5p-STAT2 feedback loop in regulating neuroblastoma progression. Journal of cellular physiology 43 30623419
2019 Nonstructural Protein 11 of Porcine Reproductive and Respiratory Syndrome Virus Induces STAT2 Degradation To Inhibit Interferon Signaling. Journal of virology 43 31462568
2012 Mice deficient in STAT1 but not STAT2 or IRF9 develop a lethal CD4+ T-cell-mediated disease following infection with lymphocytic choriomeningitis virus. Journal of virology 42 22496215
2009 Palmitoylation of interferon-alpha (IFN-alpha) receptor subunit IFNAR1 is required for the activation of Stat1 and Stat2 by IFN-alpha. The Journal of biological chemistry 41 19561067
2002 Roles of Stat1, Stat2, and interferon regulatory factor-9 (IRF-9) in interferon tau regulation of IRF-1. Biology of reproduction 41 11804954
2013 Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis. Proceedings of the National Academy of Sciences of the United States of America 40 23653476
2017 STAT2 is involved in the pathogenesis of psoriasis by promoting CXCL11 and CCL5 production by keratinocytes. PloS one 39 28472186
2021 FABP4 activates the JAK2/STAT2 pathway via Rap1a in the homocysteine-induced macrophage inflammatory response in ApoE-/- mice atherosclerosis. Laboratory investigation; a journal of technical methods and pathology 38 34725437
1999 Urokinase induces activation and formation of Stat4 and Stat1-Stat2 complexes in human vascular smooth muscle cells. The Journal of biological chemistry 38 10446176
2024 Zika virus NS5 protein inhibits type I interferon signaling via CRL3 E3 ubiquitin ligase-mediated degradation of STAT2. Proceedings of the National Academy of Sciences of the United States of America 37 39145933
2019 Virus-induced autophagic degradation of STAT2 as a mechanism for interferon signaling blockade. EMBO reports 37 31603272
2002 Stat2 binding to the interferon-alpha receptor 2 subunit is not required for interferon-alpha signaling. The Journal of biological chemistry 37 11786546
2015 The non-pathogenic Henipavirus Cedar paramyxovirus phosphoprotein has a compromised ability to target STAT1 and STAT2. Antiviral research 36 26526590
2016 STAT2 Is Required for TLR-Induced Murine Dendritic Cell Activation and Cross-Presentation. Journal of immunology (Baltimore, Md. : 1950) 35 27233962
2013 STAT2: A shape-shifting anti-viral super STAT. JAK-STAT 35 24058798
2023 Human inherited complete STAT2 deficiency underlies inflammatory viral diseases. The Journal of clinical investigation 33 36976641
2017 Nipah and Hendra Virus Nucleoproteins Inhibit Nuclear Accumulation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT2 by Interfering with Their Complex Formation. Journal of virology 33 28835499
2007 Stat2-dependent regulation of MHC class II expression. Journal of immunology (Baltimore, Md. : 1950) 33 17579067
2019 STAT2 dependent Type I Interferon response promotes dysbiosis and luminal expansion of the enteric pathogen Salmonella Typhimurium. PLoS pathogens 32 31009517
2014 Host STAT2/type I interferon axis controls tumor growth. International journal of cancer 32 24895110
2014 Respiratory syncytial virus NS1 protein degrades STAT2 by inducing SOCS1 expression. Intervirology 31 24480984
2024 STAT2/SLC27A3/PINK1-Mediated Mitophagy Remodeling Lipid Metabolism Contributes to Pazopanib Resistance in Clear Cell Renal Cell Carcinoma. Research (Washington, D.C.) 30 39600540
2021 Suppression of JAK-STAT Signaling by Epstein-Barr Virus Tegument Protein BGLF2 through Recruitment of SHP1 Phosphatase and Promotion of STAT2 Degradation. Journal of virology 29 34319780
2021 African Swine Fever Virus Induces STAT1 and STAT2 Degradation to Counteract IFN-I Signaling. Frontiers in microbiology 29 34512601
2018 Nonstructural protein of severe fever with thrombocytopenia syndrome phlebovirus targets STAT2 and not STAT1 to inhibit type I interferon-stimulated JAK-STAT signaling. Microbes and infection 29 29886262
2014 Structural and functional characterization of salmon STAT1, STAT2 and IRF9 homologs sheds light on interferon signaling in teleosts. FEBS open bio 29 25379383
2016 Negative regulation of type I IFN signaling by phosphorylation of STAT2 on T387. The EMBO journal 28 27852626
2023 African swine fever virus ubiquitin-conjugating enzyme pI215L inhibits IFN-I signaling pathway through STAT2 degradation. Frontiers in microbiology 27 36713190
2007 A Mutation in the SH2 domain of STAT2 prolongs tyrosine phosphorylation of STAT1 and promotes type I IFN-induced apoptosis. Molecular biology of the cell 27 17442890
2023 African Swine Fever Virus Cysteine Protease pS273R Inhibits Type I Interferon Signaling by Mediating STAT2 Degradation. Journal of virology 26 36856422
2009 Interferon-resistant Daudi cell line with a Stat2 defect is resistant to apoptosis induced by chemotherapeutic agents. The Journal of biological chemistry 26 19687011
2008 IFN-beta-mediated inhibition of IL-8 expression requires the ISGF3 components Stat1, Stat2, and IRF-9. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 26 18370868
2024 IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling. Gut 25 37884352
2019 Porcine circovirus 3 Cap inhibits type I interferon signaling through interaction with STAT2. Virus research 25 31697988
2005 IL-12, but not IFN-alpha, promotes STAT4 activation and Th1 development in murine CD4+ T cells expressing a chimeric murine/human Stat2 gene. Journal of immunology (Baltimore, Md. : 1950) 25 15611252
2019 Differential roles of STAT1 and STAT2 in the sensitivity of JAK2V617F- vs. BCR-ABL-positive cells to interferon alpha. Journal of hematology & oncology 23 30940163
2005 Expression of STAT1 and STAT2 in malignant melanoma does not correlate with response to interferon-alpha adjuvant therapy. Cancer immunology, immunotherapy : CII 23 15668815
2003 Dominant negative signal transducer and activator of transcription 2 (STAT2) protein: stable expression blocks interferon alpha action in skin squamous cell carcinoma cells. Molecular cancer therapeutics 23 12748307
2022 Increased IRF9-STAT2 Signaling Leads to Adaptive Resistance toward Targeted Therapy in Melanoma by Restraining GSDME-Dependent Pyroptosis. The Journal of investigative dermatology 22 35148998
2006 IFN-type-I-mediated signaling is regulated by modulation of STAT2 nuclear export. Journal of cell science 22 16507591

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