Affinage

STAT4

Signal transducer and activator of transcription 4 · UniProt Q14765

Length
748 aa
Mass
85.9 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 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

STAT4 is a cytokine-activated transcription factor that programs type 1 immunity, transducing IL-12 signals into IFN-γ-driven Th1, NK, dendritic cell, macrophage, and neutrophil responses (PMID:7638186, PMID:11254700, PMID:34138758). IL-12 engages JAK2/TYK2 to phosphorylate STAT4 on Y693, an event that absolutely requires the STAT4 N-terminal domain for efficient receptor-proximal phosphorylation, dimerization, and nuclear translocation (PMID:10982828, PMID:12805384), while a parallel MKK6/p38α cascade phosphorylates S721 to confer full transcriptional activity (PMID:10961885); this serine pathway is selective for STAT4 and operates independently of Ras/ERK and PI3K (PMID:10820390). Beyond the IL-12 axis, STAT4 is recruited to the human type I IFN receptor through activated STAT2 rather than direct receptor binding (PMID:10644731), and is also activated by IL-23 (as STAT3/STAT4 heterodimers) and by LIF (PMID:28878115, PMID:30770344). Once nuclear, STAT4 binds target loci and drives a feed-forward type 1 program: it sustains IL-12R and induces the IL-18 receptor (PMID:11120802), the IL-33 receptor ST2 (PMID:25829541), the Ets factor ERM (PMID:10097133), and directly transactivates IFN-γ, IL-21, IL-10, and GM-CSF (Csf2) genes (PMID:18401353, PMID:26123499, PMID:29212666). STAT4 also acts epigenetically, binding Th1 loci to induce transient histone hyperacetylation and H3K4 methylation (via Jmjd3) that excludes Dnmt3a and prevents DNA methylation, opposing Dnmt3a-mediated silencing of Th1 genes (PMID:17380127, PMID:23772023). A distinct cytoplasmic, unphosphorylated pool of STAT4 promotes innate antiviral immunity by binding the E3 ligase CHIP and blocking CHIP-mediated K48-ubiquitination and degradation of RIG-I, supporting type I IFN production (PMID:26695369). STAT4 protein abundance is itself tightly controlled by the ubiquitin-proteasome system, with chemotherapy- and lipid-peroxidation-driven degradation causing functional STAT4 loss (PMID:21998209, PMID:39488214). Loss-of-function STAT4 (p.E651V) causes autosomal dominant deficiency of IL-12-dependent IFN-γ immunity, whereas gain-of-function missense variants cause disabling pansclerotic morphea reversible by JAK inhibition (PMID:29029192, PMID:37256972).

Mechanistic history

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

    Established STAT4 as a STAT-family transcription factor with restricted tissue expression, defining the protein and the starting point for its functional study.

    Evidence Sequence deduction, antiserum immunoprecipitation, and tissue expression analysis identifying a ~89 kDa protein with conserved SH2/SH3 domains

    PMID:7545930

    Open questions at the time
    • No activating ligand or signaling pathway identified
    • No target genes known
  2. 1995 High

    Identified IL-12 as the activating cue, placing STAT4 at the center of a defined cytokine-to-transcription axis in T and NK cells.

    Evidence Tyrosine phosphorylation assays, EMSA showing GAS-element DNA binding, and Co-IP in IL-12-stimulated human T/NK cells

    PMID:7638186

    Open questions at the time
    • Kinases and phosphosites not yet mapped
    • Direct target genes not defined
  3. 2000 High

    Resolved the dual phosphorylation code—JAK-dependent Y693 plus MKK6/p38α-dependent S721—and the N-domain requirement, explaining how STAT4 achieves full activation and how it is recruited to the type I IFN receptor via STAT2.

    Evidence Site-directed mutagenesis of Y693/S721, kinase and dominant-negative MKK6 assays, N-domain (W37) and domain-swap mutagenesis, and STAT1/STAT2-deficient cell lines with phosphopeptide binding

    PMID:10644731 PMID:10820390 PMID:10961885 PMID:10982828

    Open questions at the time
    • Structural basis of N-domain-dependent receptor docking not resolved
    • How S721 phosphorylation alters transactivation mechanistically not defined
  4. 2003 High

    Confirmed in vivo that the N-terminal domain is required for JAK-mediated STAT4 phosphorylation and Th1 differentiation, linking the biochemical mechanism to physiological T-cell output.

    Evidence Transgenic mice expressing full-length or ΔN-STAT4 in a STAT4-deficient background with phosphorylation, proliferation, and IFN-γ readouts

    PMID:12805384

    Open questions at the time
    • Precise molecular contacts of the N-domain with the receptor/JAK complex unknown
  5. 2001 High

    Extended STAT4 function beyond T cells, showing it is inducibly required in dendritic cells and macrophages for IFN-γ and NO production and antimicrobial defense.

    Evidence STAT4-knockout mice with intracellular cytokine staining, Western blot, and Toxoplasma infection

    PMID:11254700

    Open questions at the time
    • Direct target loci in APCs not mapped
  6. 2004 High

    Defined the downstream type 1 gene program and delimited it, identifying ERM and the IL-18 receptor as STAT4-dependent while showing the GADD45–MEKK4–p38 route augments IFN-γ independently of STAT4.

    Evidence STAT4-/- vs STAT1-/- T cells, MEKK4-deficient mice with p38 inhibition, retroviral complementation, and IL-18R/NF-κB assays

    PMID:10097133 PMID:11120802 PMID:15044949

    Open questions at the time
    • Direct vs indirect STAT4 binding at some target loci not all resolved
  7. 2007 High

    Revealed STAT4 as an epigenetic programmer that maintains Th1 loci in an active state by inducing histone hyperacetylation and excluding Dnmt3a-mediated DNA methylation.

    Evidence ChIP, bisulfite sequencing, histone acetylation analysis, and TSA treatment in STAT4-deficient Th1 cultures at Il18r1 and other loci

    PMID:17380127

    Open questions at the time
    • Mechanism of Dnmt3a exclusion (steric vs cofactor competition) not defined
  8. 2008 High

    Broadened the epigenetic and gene-regulatory repertoire, identifying a STAT4-binding element driving NK cell IL-10 (T-bet-independent) and showing isoform-specific (STAT4β) control of inflammatory cytokine output.

    Evidence STAT4- and T-bet-deficient mice with ChIP at Il10, and STAT4 isoform-specific constructs in a T-cell transfer colitis model

    PMID:18401353 PMID:18802110

    Open questions at the time
    • Structural basis of STAT4α/β functional divergence not resolved
    • Isoform colitis study from a single lab
  9. 2011 High

    Established that STAT4 abundance is rate-limiting and proteasome-controlled, demonstrating that chemotherapy-induced STAT4 degradation produces acquired functional deficiency reversible by bortezomib.

    Evidence Protein half-life and ubiquitination assays with bortezomib rescue in patient PBMCs and an NK cell line

    PMID:21998209

    Open questions at the time
    • The specific E3 ligase mediating chemotherapy-induced STAT4 degradation not identified
  10. 2013 High

    Defined the molecular opposition between STAT4 and Dnmt3a, showing STAT4 recruits Jmjd3 to remove H3K27me3 and that double deficiency derepresses Th1 genes, providing in vivo causal weight in EAE.

    Evidence ChIP for H3K4me/H3K27me3/Dnmt3a, STAT4/Dnmt3a double-KO mice, and conditional Dnmt3a deletion in an EAE model

    PMID:23772023

    Open questions at the time
    • Direct biochemical recruitment of Jmjd3 by STAT4 not shown
  11. 2015 High

    Uncovered a non-canonical cytoplasmic, phosphorylation-independent function in which STAT4 stabilizes RIG-I against CHIP-mediated degradation to support antiviral type I IFN, and expanded its nuclear role to ST2 induction and direct GM-CSF transactivation.

    Evidence Reciprocal Co-IP, K48-ubiquitination assays, and siRNA in macrophages (RIG-I); bone marrow chimeras and ChIP-PCR for ST2 and Csf2 in EAE

    PMID:25829541 PMID:26123499 PMID:26695369

    Open questions at the time
    • How unphosphorylated STAT4 partitions between cytoplasmic and nuclear pools not defined
    • Structural basis of STAT4–CHIP competition unresolved
  12. 2017 High

    Placed STAT4 atop the Tfh transcriptional hierarchy and broadened its activating inputs to IL-23 and type I IFN, while linking it to MLL1-dependent epigenetic control in macrophages and to a loss-of-function human immunodeficiency.

    Evidence STAT4-deficient mice in LCMV/vaccinia (Tfh epistasis), IL-23-driven differentiation and EAE with STAT3/STAT4 heterodimers, MLL1-conditional KO macrophages, and patient p.E651V functional characterization

    PMID:28733487 PMID:28878115 PMID:29029192 PMID:29212666

    Open questions at the time
    • Stoichiometry and target specificity of STAT3/STAT4 heterodimers not defined
    • MLL1 axis from a single Medium-confidence study
  13. 2019 Medium

    Demonstrated context-dependent transcriptional antagonism, with LIF-activated STAT4 blocking STAT3-driven Il17a/Il17f activation at non-canonical elements to limit intestinal inflammation.

    Evidence Phosphorylation mapping of C-terminal SPXX motifs, SIE/AGG element reporter assays, and a mouse colitis model with lamina propria lymphocytes

    PMID:30770344

    Open questions at the time
    • Single lab
    • Direct competition mechanism at AGG elements not structurally resolved
  14. 2021 Medium

    Extended STAT4 to neutrophil effector functions and to type I IFN-driven pathogenic Tfh activity, connecting JAK2-dependent activation to antibacterial defense and to human lupus disease activity.

    Evidence Neutrophil/myeloid-specific conditional KO with ROS/NET/chemotaxis assays and MRSA infection; phospho-STAT4 analysis in murine lupus and human SLE Tfh-like cells

    PMID:33512094 PMID:34138758

    Open questions at the time
    • Lupus Tfh study from a single lab
    • Neutrophil target genes not mapped
  15. 2023 High

    Defined opposing STAT4 functions in innate lymphocyte differentiation and established gain-of-function STAT4 disease, showing GOF variants drive fibroblast hyperinflammation in disabling pansclerotic morphea reversible by ruxolitinib.

    Evidence Ncr1-Cre conditional KO with RNA-seq (NK vs ILC1) and patient fibroblast functional assays with JAK inhibitor rescue and clinical resolution

    PMID:37256972 PMID:37756335

    Open questions at the time
    • Mechanism by which STAT4 restrains STAT5-driven ILC1 program not defined
    • How GOF variants alter STAT4 activation thresholds not structurally resolved
  16. 2024 High

    Linked metabolic stress to STAT4 stability, showing hyperglycemia-induced lipid peroxidation carbonylates STAT4 to trigger its degradation and impair Th1 differentiation, reversible by an LPO scavenger.

    Evidence STAT4 carbonylation and LPO assays in CD4+ T cells with pharmacological rescue and concordant human/mouse T2D data

    PMID:39488214

    Open questions at the time
    • Which carbonylated residues destabilize STAT4 not identified
    • Whether carbonylation feeds into the same E3/proteasome route as chemotherapy-induced degradation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How STAT4 partitions between its canonical nuclear transcriptional role and its non-canonical cytoplasmic RIG-I-stabilizing role, and the structural basis governing this choice, remain unresolved.
  • No structural model of phospho-state-dependent localization
  • Regulators that direct STAT4 toward cytoplasmic vs nuclear function not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 2
Partners
CHIPDNMT3ASTAT2STAT3

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 STAT4 is a member of the STAT family of signal transducers and activators of transcription, deduced from amino acid sequence comparison showing conserved SH2 and SH3 domains. Expression is restricted to testis, thymus, and spleen; anti-STAT4 antiserum precipitates a single major ~89 kDa protein. Amino acid sequence deduction, antiserum immunoprecipitation, tissue expression analysis Proceedings of the National Academy of Sciences of the United States of America High 7545930
1995 IL-12 induces tyrosine phosphorylation and activation of STAT4 in human T and NK cells. IL-12 stimulates formation of a DNA-binding complex containing STAT4 that recognizes GAS-related sequences. STAT4 expression is upregulated by T-cell activation. Tyrosine phosphorylation assay, DNA-binding/EMSA, immunoprecipitation, Western blot Proceedings of the National Academy of Sciences of the United States of America High 7638186
2000 IL-12 induces STAT4 phosphorylation on serine 721, and mutation of S721 impairs STAT4 transcriptional activity. IL-12 also activates p38 MAPK; p38α and its upstream activator MKK6 phosphorylate STAT4 on S721 and are required for full IL-12-induced STAT4 transcriptional activity. Mutation of tyrosine 693 abrogates IL-12-induced STAT4 tyrosine phosphorylation and transcriptional activity. Site-directed mutagenesis, kinase assays, reporter gene assays, dominant-negative MKK6 expression, pharmacological inhibitors Blood High 10961885
2000 Recruitment of STAT4 to the human IFN-α/β receptor requires activated STAT2, not direct interaction with receptor cytoplasmic domains. Phosphopeptide binding analysis shows STAT4 does not bind tyrosine-phosphorylated residues in the IFN-α receptor subunits. In STAT2-deficient U6A cells, IFN-α-induced STAT4 phosphorylation is abolished; STAT1 deficiency does not prevent it. Phosphopeptide binding assay, expression of murine STAT4 in STAT1-deficient and STAT2-deficient cell lines, tyrosine phosphorylation assays The Journal of biological chemistry High 10644731
2000 The STAT4 N-terminal domain is required for efficient receptor-proximal tyrosine phosphorylation. Mutation of N-domain residue W37 (predicted to disrupt N-domain dimer formation) prevents IFN-α-induced tyrosine phosphorylation of STAT4 monomer, blocking dimer formation and nuclear translocation. Interchanging N-domains between STAT1 and STAT4 disrupts receptor-mediated phosphorylation and STAT-specific gene activation, indicating the N-domain exerts STAT-private functions. N-domain point mutagenesis (W37), domain-swap constructs, tyrosine phosphorylation assay, nuclear translocation assay, gene activation reporter assay Molecular and cellular biology High 10982828
2000 IL-12 activates STAT4 via PI3K- and Ras/ERK-independent pathways in human T cells. IL-12 does not stimulate Ras guanine nucleotide exchange, ERK1/2, or PI3K activation, and inhibitors of these pathways do not affect IL-12-induced STAT4 serine phosphorylation. IL-12 selectively induces serine phosphorylation of STAT4 but not STAT1 or STAT3. Pharmacological inhibition (PI3K inhibitors, MEK inhibitors), Ras activation assay, ERK phosphorylation assay, STAT serine phosphorylation assays in human T cells European journal of immunology Medium 10820390
2000 STAT4 activation by IL-12 is required for IL-18 receptor (IL-18Rα) expression on T cells. In STAT4-deficient activated T cells, IL-18R expression is absent, IL-18-induced NF-κB DNA-binding activity is defective, and IFN-γ production in response to IL-18 (alone or combined with IL-12) is minimal. STAT4 also maintains IL-12Rβ1 and IL-12Rβ2 basal expression. STAT4-knockout mice, IL-18R expression assay, NF-κB EMSA, intracellular cytokine staining, RT-PCR Journal of immunology (Baltimore, Md. : 1950) High 11120802
2003 STAT4 requires its N-terminal domain for efficient phosphorylation by JAKs. Deletion of the N-terminal 51 amino acids (ΔN-STAT4) in transgenic mice yields T cells that fail to be phosphorylated on STAT4 following IL-12 stimulation despite normal JAK2 and TYK2 phosphorylation, and fail to proliferate or differentiate to Th1 cells. Transgenic mice expressing full-length or ΔN-STAT4 in STAT4-deficient background, phosphorylation assays, T-cell proliferation, IFN-γ production The Journal of biological chemistry High 12805384
2004 IL-12 induction of the Ets transcription factor ERM occurs in a STAT4-dependent (and STAT1-independent) manner in T cells. ERM induction is absent in STAT4-deficient T cells but present in STAT1-deficient T cells, placing ERM as a downstream target gene of the IL-12/STAT4 pathway. Subtractive cloning, gene expression in STAT4-deficient and STAT1-deficient T cells, retroviral expression Proceedings of the National Academy of Sciences of the United States of America Medium 10097133
2001 STAT4 expression is inducibly upregulated in dendritic cells (DCs) in a maturation-dependent manner and in macrophages in an activation-dependent manner. STAT4 levels directly correlate with IL-12-dependent IFN-γ production by APCs. STAT4-deficient DCs and macrophages fail to produce IFN-γ, and STAT4-deficient macrophages are defective in NO production in response to IL-12 and are susceptible to Toxoplasma. STAT4-knockout mice, intracellular cytokine staining, Western blot, in vitro infection model Journal of immunology (Baltimore, Md. : 1950) High 11254700
2004 The GADD45β/GADD45γ–MEKK4–p38 pathway promotes IFN-γ production in CD4 T cells independently of STAT4. GADD45β and GADD45γ require MEKK4 and downstream p38 activation to stimulate IFN-γ. During Th1 differentiation, this pathway integrates TCR and IL-12/STAT4 signals to augment IFN-γ production. MEKK4-deficient mice, p38 inhibitor, retroviral expression of GADD45 proteins, intracellular cytokine staining The EMBO journal High 15044949
2005 STAT4 expression in human T cells is regulated by DNA methylation. Treatment with a DNA methyltransferase inhibitor dramatically increases STAT4 expression. Truncation of methylation sites in the proximal STAT4 promoter markedly enhances transcriptional activity. Disruption of CREB, OCT1, and SP1 motifs in the promoter significantly reduces STAT4 activity. A -149A/G promoter polymorphism has no effect on promoter activity. Promoter deletion/mutation reporter assays, DNA methyltransferase inhibitor treatment, Western blot, RT-PCR Journal of immunology (Baltimore, Md. : 1950) Medium 16301617
2007 STAT4 binds the Il18r1 promoter following IL-12 stimulation, induces transient histone H3 and H4 hyperacetylation, and prevents recruitment of DNA methyltransferase Dnmt3a and its cofactor Dnmt3L to the Il18r1 locus and other STAT4-dependent gene promoters, thereby maintaining their demethylated/active state. In STAT4-deficient Th1 cultures, Dnmt3a association and DNA methylation of Il18r1 and other Th1 genes are increased. ChIP assay, bisulfite sequencing (DNA methylation), histone acetylation analysis, STAT4-deficient T cells, trichostatin A treatment The EMBO journal High 17380127
2008 STAT4 is required for IL-12-induced IL-10 production in NK cells in a T-bet-independent manner. A conserved STAT4-binding element in the fourth intron of the Il10 gene is a target for cytokine-induced histone acetylation. STAT4-deficient NK cells have markedly reduced IL-10 production in response to IL-2+IL-12. STAT4-deficient and T-bet-deficient mice, intracellular cytokine staining, ChIP (histone acetylation), STAT4 binding site identification Genes and immunity High 18401353
2013 STAT4 acts epigenetically through a sequence including histone H3K4 methylation, Jmjd3 recruitment to STAT4 target loci, and Jmjd3-dependent decrease in H3K27me3 and Dnmt3a association with those loci. STAT4 and Dnmt3a play opposing roles in Th1 gene expression: in STAT4/Dnmt3a double-deficient T cells, a subset of Th1 genes is derepressed, restoring IFN-γ production. STAT4-deficient mice protected from EAE develop paralysis when also conditionally deficient in Dnmt3a in T cells. ChIP (H3K4me, H3K27me3, Dnmt3a), STAT4/Dnmt3a double-KO mice, EAE model, IFN-γ production assay, ectopic expression of T-bet and Hlx1 Journal of immunology (Baltimore, Md. : 1950) High 23772023
2015 Cytoplasmic STAT4 (without Y693 phosphorylation and nuclear translocation) promotes antiviral type I IFN production by interacting with the E3 ubiquitin ligase CHIP and blocking CHIP-mediated K48-linked ubiquitination and proteasomal degradation of RIG-I. Silencing STAT4 increases RIG-I degradation and impairs IFN-β production in macrophages upon RNA virus infection. Co-immunoprecipitation (STAT4-CHIP interaction), ubiquitination assay (K48-linked), siRNA knockdown, IFN-β promoter reporter, overexpression studies, Western blot Journal of immunology (Baltimore, Md. : 1950) High 26695369
2015 T-bet and STAT4 are required for transient expression of the IL-33 receptor ST2 on Th1 effector cells during viral infection. ST2 deficiency intrinsically impairs LCMV-specific Th1 cell expansion, effector differentiation, and antiviral cytokine production. Thus IL-33 acts as a direct cofactor for Th1 effector activation downstream of STAT4-driven ST2 expression. Mixed bone marrow chimeric mice, adoptive cell transfer, intracellular cytokine staining, in vitro Th1 differentiation in STAT4-deficient cells, T-bet-deficient mice Proceedings of the National Academy of Sciences of the United States of America High 25829541
2015 STAT4 directly interacts with the Csf2 (GM-CSF) gene locus in MOG-activated effector CD4 T cells, as shown by ChIP-PCR, and is required cell-intrinsically for GM-CSF production by both Th1 and Th17 CD4 T cells during EAE. Novel mixed bone marrow chimeric mice demonstrate this is a T-cell-intrinsic requirement. ChIP-PCR, intracellular cytokine staining, STAT4-deficient mice, mixed bone marrow chimeras, EAE model Journal of neuroinflammation High 26123499
2017 STAT4, phosphorylated in Tfh cells after viral infection, is required for expression of T-bet and Bcl6 in Tfh cells and for IFN-γ and IL-21 production. T-bet is required for Tfh IFN-γ but not IL-21 production. STAT4 is thus upstream of T-bet and Bcl6 in the Tfh transcriptional hierarchy during acute viral infection. STAT4-deficient mice, intracellular cytokine staining, phospho-STAT4 detection, viral infection model (LCMV/vaccinia), transcription factor expression analysis The Journal of experimental medicine High 29212666
2017 IL-23 signals through both STAT3 and STAT4 (forming p-STAT3/p-STAT4 heterodimers), and disruption of STAT4 signaling impairs CNS autoimmunity induced by IL-23, independent of IL-12. This explains why IL-12-deficient mice develop CNS autoimmunity while STAT4-deficient mice are resistant. Cytokine-driven T-cell differentiation, adoptive transfer EAE, STAT4-deficient cells, phospho-STAT detection, human MS patient CD4+ T cell analysis JCI insight Medium 28878115
2011 Cancer chemotherapy promotes ubiquitination and proteasomal degradation of STAT4 protein (reducing its half-life), causing acquired STAT4 deficiency and defective IL-12-induced IFN-γ production in lymphoma patients. Proteasome inhibitor bortezomib reverses chemotherapy-induced STAT4 deficiency and restores IFN-γ production. Western blot (STAT4 protein levels), pulse-chase/half-life assay, ubiquitination assay, in vitro chemotherapy treatment of PBMCs and NK cell line, bortezomib rescue experiment Blood High 21998209
2017 STAT4 controls MLL1-dependent epigenetic regulation in macrophages. STAT4-dependent type I IFNs drive MLL1 expression in macrophages; MLL1-knockout macrophages have decreased activating H3K4 methylation at the STAT4 promoter, revealing a STAT4/MLL1 epigenetic axis that regulates macrophage antimicrobial gene expression. MLL1-conditional KO macrophages (Lys2-Cre), RNA profiling, ChIP (H3K4me), cytokine stimulation Journal of immunology (Baltimore, Md. : 1950) Medium 28733487
2019 LIF activates STAT4 phosphorylation on multiple SPXX elements in the C-terminal transcription regulation domain. In lamina propria lymphocytes, activated STAT4 blocks STAT3-dependent Il17a/Il17f promoter activation, thereby limiting Th17 differentiation and intestinal inflammation. STAT4 and STAT3 act reciprocally on canonical SIE and noncanonical 'AGG' elements at different loci. Phosphorylation mapping (SPXX motifs), reporter gene assays (SIE and AGG elements), STAT4/STAT3 co-expression studies, mouse colitis model, lamina propria lymphocyte isolation The EMBO journal Medium 30770344
2017 A heterozygous missense mutation (p.E651V) in STAT4 causes reduced STAT4 phosphorylation and impaired nuclear translocation in patient lymphocytes, resulting in defective IFN-γ production and impaired macrophage fungicidal activity, identifying autosomal dominant STAT4 deficiency as an inborn error of IL-12-dependent IFN-γ immunity. Whole-exome and Sanger sequencing, phospho-STAT4 assay, nuclear translocation assay, site-directed mutagenesis in B-LCL and U3A cells, IFN-γ production, macrophage fungicidal assay The Journal of infectious diseases High 29029192
2023 Three novel heterozygous missense gain-of-function variants in STAT4 cause disabling pansclerotic morphea (DPM). Primary skin fibroblasts from patients show enhanced IL-6 secretion, impaired wound healing, impaired collagen matrix contraction and secretion. JAK inhibitor ruxolitinib reverses the hyperinflammatory fibroblast phenotype in vitro and resolves clinical symptoms. Genomic sequencing, primary fibroblast functional assays (IL-6 secretion, wound healing, collagen contraction), JAK inhibitor treatment, single-cell RNA sequencing The New England journal of medicine High 37256972
2021 STAT4 is expressed in neutrophils and activated by IL-12 via a JAK2-dependent pathway. STAT4 is required for multiple neutrophil functions including IL-12-induced ROS production, chemotaxis, and NET formation. Myeloid-specific and neutrophil-specific deletion of STAT4 results in enhanced susceptibility to MRSA infection in vivo. Flow cytometry, conditional KO (myeloid-specific and neutrophil-specific Cre), ROS assay, chemotaxis assay, NET assay, MRSA infection model JCI insight High 34138758
2024 Hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis in CD4+ T cells, leading to lipid peroxidation (LPO) that drives carbonylation of STAT4 protein, causing its rapid proteasomal degradation, reduced T-bet induction, and impaired Th1 differentiation. LPO scavenger restores STAT4 stability and Th1 responses. STAT4 carbonylation assay, LPO measurement, mitochondrial function assay, CD4+ T-cell functional assays, LPO scavenger treatment (in vitro and in vivo), T2D patient samples and T2D mouse model Cell metabolism High 39488214
2023 STAT4 has divergent roles in NK cells versus ILC1 differentiation during gut inflammation. Ncr1-specific Stat4 deletion impairs NK cell terminal differentiation but unexpectedly increases cytotoxic ILC1 generation. STAT4-deficient ILC1 exhibit aberrant STAT5-regulated gene module upregulation and enhanced differentiation upon IL-2 stimulation, indicating STAT4 restrains STAT5-driven ILC1 differentiation. Ncr1-Cre conditional Stat4 KO, RNA-seq transcriptomics, in vitro IL-2 stimulation, DSS-induced colitis model, flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 37756335
2008 The STAT4β isoform (lacking C-terminal transactivation domain) promotes greater colonic inflammation and tissue destruction than STAT4α in a T-cell transfer colitis model. STAT4β-expressing T cells produce higher levels of TNF-α and GM-CSF (but similar IFN-γ and IL-17) compared to STAT4α-expressing T cells, correlating with disease severity. CD4+ T-cell transfer into SCID mice, intracellular cytokine staining, STAT4 isoform-specific expression constructs, colitis model histology Journal of immunology (Baltimore, Md. : 1950) Medium 18802110
2021 Type I IFN signaling drives STAT4 phosphorylation in follicular helper T (Tfh) cells, maintaining IL-21 and IFN-γ co-production during murine lupus. In human SLE circulating Tfh-like cells, IFNβ enhances STAT4 phosphorylation and correlates with clinical disease activity, identifying type I IFN as an activating signal for STAT4 in pathogenic Tfh cells. Phospho-STAT4 detection, RNA-seq, cytokine blocking, lupus mouse model (temporal analysis), human SLE Tfh cell analysis Arthritis & rheumatology (Hoboken, N.J.) Medium 33512094

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. The New England journal of medicine 817 17804842
2004 Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunological reviews 426 15546391
1994 Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Proceedings of the National Academy of Sciences of the United States of America 372 7545930
1995 Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proceedings of the National Academy of Sciences of the United States of America 365 7638186
2000 The biology of Stat4 and Stat6. Oncogene 232 10851056
2001 Inducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses. Journal of immunology (Baltimore, Md. : 1950) 165 11254700
2015 T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses. Proceedings of the National Academy of Sciences of the United States of America 152 25829541
2009 The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Human molecular genetics 144 19286670
2008 STAT4: genetics, mechanisms, and implications for autoimmunity. Current allergy and asthma reports 144 18682104
2014 STAT3, STAT4, NFATc1, and CTCF regulate PD-1 through multiple novel regulatory regions in murine T cells. Journal of immunology (Baltimore, Md. : 1950) 142 24711622
2003 Contrasting roles for STAT4 and STAT6 signal transduction pathways in murine renal ischemia-reperfusion injury. American journal of physiology. Renal physiology 135 12709397
2017 STAT4 and T-bet control follicular helper T cell development in viral infections. The Journal of experimental medicine 111 29212666
2008 Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis and rheumatism 111 18759272
2000 Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood 108 10961885
2004 GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells. The EMBO journal 90 15044949
2020 STAT4: an immunoregulator contributing to diverse human diseases. International journal of biological sciences 89 32226303
2009 Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis. Arthritis and rheumatism 86 19404967
2003 Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection. Hepatology (Baltimore, Md.) 85 12540779
1999 The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. Proceedings of the National Academy of Sciences of the United States of America 85 10097133
2000 Stat4 regulates multiple components of IFN-gamma-inducing signaling pathways. Journal of immunology (Baltimore, Md. : 1950) 79 11120802
2017 IL-23R-activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunity. JCI insight 78 28878115
2000 Recruitment of Stat4 to the human interferon-alpha/beta receptor requires activated Stat2. The Journal of biological chemistry 75 10644731
2004 The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals. International immunology 73 15226272
2004 Early target genes of IL-12 and STAT4 signaling in th cells. Journal of immunology (Baltimore, Md. : 1950) 72 15153495
2015 Cytoplasmic STAT4 Promotes Antiviral Type I IFN Production by Blocking CHIP-Mediated Degradation of RIG-I. Journal of immunology (Baltimore, Md. : 1950) 65 26695369
2012 Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta-analysis. Molecular biology reports 63 22714917
2009 Association of STAT4 and BLK, but not BANK1 or IRF5, with primary antiphospholipid syndrome. Arthritis and rheumatism 63 19644876
1999 T helper differentiation proceeds through Stat1-dependent, Stat4-dependent and Stat4-independent phases. Current topics in microbiology and immunology 62 10087648
2014 Analysis of STAT4 expression in cutaneous T-cell lymphoma (CTCL) patients and patient-derived cell lines. Cell cycle (Georgetown, Tex.) 60 25486484
2021 Investigation of the relationship between CTLA4 and the tumor suppressor RASSF1A and the possible mediating role of STAT4 in a cohort of Egyptian patients infected with hepatitis C virus with and without hepatocellular carcinoma. Archives of virology 59 33796885
2002 Reduced expression of STAT4 and IFN-gamma in macrophages from BALB/c mice. Journal of immunology (Baltimore, Md. : 1950) 59 12023341
2008 Stat4-dependent, T-bet-independent regulation of IL-10 in NK cells. Genes and immunity 58 18401353
2019 STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation. The EMBO journal 55 30770344
2023 Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome. The New England journal of medicine 53 37256972
2015 STAT4 controls GM-CSF production by both Th1 and Th17 cells during EAE. Journal of neuroinflammation 51 26123499
2007 Stat4 limits DNA methyltransferase recruitment and DNA methylation of the IL-18Ralpha gene during Th1 differentiation. The EMBO journal 48 17380127
2013 Opposing roles of STAT4 and Dnmt3a in Th1 gene regulation. Journal of immunology (Baltimore, Md. : 1950) 47 23772023
2001 STAT4 and STAT6 regulate systemic inflammation and protect against lethal endotoxemia. The Journal of clinical investigation 47 11714739
2021 MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas. Journal for immunotherapy of cancer 45 34667077
2019 STAT3 but not STAT4 is critical for γδT17 cell responses and skin inflammation. EMBO reports 45 31549795
2006 STAT4 deficiency reduces autoantibody production and glomerulonephritis in a mouse model of lupus. Clinical immunology (Orlando, Fla.) 45 16713741
2004 Mechanistic insights into impaired dendritic cell function by rapamycin: inhibition of Jak2/Stat4 signaling pathway. Journal of immunology (Baltimore, Md. : 1950) 44 14734710
2021 Type I Interferon-Activated STAT4 Regulation of Follicular Helper T Cell-Dependent Cytokine and Immunoglobulin Production in Lupus. Arthritis & rheumatology (Hoboken, N.J.) 43 33512094
2013 Meta-analysis reveals an association of STAT4 polymorphisms with systemic autoimmune disorders and anti-dsDNA antibody. Human immunology 43 23628400
2005 STAT4 expression in human T cells is regulated by DNA methylation but not by promoter polymorphism. Journal of immunology (Baltimore, Md. : 1950) 43 16301617
2019 A novel transthyretin/STAT4/miR-223-3p/FBXW7 signaling pathway affects neovascularization in diabetic retinopathy. Molecular and cellular endocrinology 42 31415795
2013 STAT4 deficiency reduces obesity-induced insulin resistance and adipose tissue inflammation. Diabetes 40 23939393
2000 Role of the Stat4 N domain in receptor proximal tyrosine phosphorylation. Molecular and cellular biology 40 10982828
2021 STAT4 is expressed in neutrophils and promotes antimicrobial immunity. JCI insight 37 34138758
2012 Positive association between STAT4 polymorphisms and polymyositis/dermatomyositis in a Japanese population. Annals of the rheumatic diseases 36 22402141
2020 Entinostat augments NK cell functions via epigenetic upregulation of IFIT1-STING-STAT4 pathway. Oncotarget 34 32499867
2000 Role of STAT4 and STAT6 signaling in allograft rejection and CTLA4-Ig-mediated tolerance. Journal of immunology (Baltimore, Md. : 1950) 33 11067913
2008 STAT4 isoforms differentially regulate Th1 cytokine production and the severity of inflammatory bowel disease. Journal of immunology (Baltimore, Md. : 1950) 31 18802110
2007 Increased expression and activation of IL-12-induced Stat4 signaling in the mucosa of ulcerative colitis patients. Cellular immunology 31 18048021
2020 Immune Suppression Mediated by STAT4 Deficiency Promotes Lymphatic Metastasis in HNSCC. Frontiers in immunology 30 32010142
2017 The STAT4/MLL1 Epigenetic Axis Regulates the Antimicrobial Functions of Murine Macrophages. Journal of immunology (Baltimore, Md. : 1950) 30 28733487
2015 Silencing of stat4 gene inhibits cell proliferation and invasion of colorectal cancer cells. Journal of biological regulators and homeostatic agents 29 25864744
2019 STAT4, TRAF3IP2, IL10, and HCP5 Polymorphisms in Sjögren's Syndrome: Association with Disease Susceptibility and Clinical Aspects. Journal of immunology research 28 30882006
2017 Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-γ Immunity. The Journal of infectious diseases 28 29029192
2024 STAT4 and STAT6, their role in cellular and humoral immunity and in diverse human diseases. International reviews of immunology 27 39188021
2016 STAT4-associated natural killer cell tolerance following liver transplantation. Gut 27 26887815
2014 Gene-gene interactions of IRF5, STAT4, IKZF1 and ETS1 in systemic lupus erythematosus. Tissue antigens 27 24697319
2009 Cigarette smoking, STAT4 and TNFRSF1B polymorphisms, and systemic lupus erythematosus in a Japanese population. The Journal of rheumatology 27 19684152
2022 Occludin facilitates tumour angiogenesis in bladder cancer by regulating IL8/STAT3 through STAT4. Journal of cellular and molecular medicine 26 35224833
2010 STAT4 gene influences genetic predisposition to ulcerative colitis but not Crohn's disease in the Spanish population: a replication study. Human immunology 26 20153791
2010 Influence of STAT4 polymorphism in primary Sjögren's syndrome. The Journal of rheumatology 26 20360187
2015 STAT4 contributes to adipose tissue inflammation and atherosclerosis. The Journal of endocrinology 25 26285907
2024 Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes. Cell metabolism 24 39488214
2022 STAT4 and COL1A2 are potential diagnostic biomarkers and therapeutic targets for heart failure comorbided with depression. Brain research bulletin 24 35367598
2015 Association of PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with rheumatoid arthritis: A meta-analysis update. Immunobiology 24 25963842
2013 Association between polymorphism in STAT4 gene and risk of rheumatoid arthritis: a meta-analysis. Human immunology 23 23295549
2003 Kinetics and STAT4- or STAT6-mediated regulation of genes involved in lymphocyte polarization to Th1 and Th2 cells. European journal of immunology 23 12672077
2000 IL-12 selectively regulates STAT4 via phosphatidylinositol 3-kinase and Ras-independent signal transduction pathways. European journal of immunology 22 10820390
2024 Single-cell deconvolution algorithms analysis unveils autocrine IL11-mediated resistance to docetaxel in prostate cancer via activation of the JAK1/STAT4 pathway. Journal of experimental & clinical cancer research : CR 21 38429845
2023 Mediating oxidative stress through the Palbociclib/miR-141-3p/STAT4 axis in osteoporosis: a bioinformatics and experimental validation study. Scientific reports 21 37949959
2014 Association between STAT4 gene polymorphisms and autoimmune thyroid diseases in a Chinese population. International journal of molecular sciences 21 25019342
2010 A meta-analysis of the association of STAT4 polymorphism with systemic lupus erythematosus. Modern rheumatology 21 20169389
2019 The IL-12-STAT4 axis in the pathogenesis of human systemic lupus erythematosus. European journal of immunology 20 31762023
2017 STAT4 Regulates the CD8+ Regulatory T Cell/T Follicular Helper Cell Axis and Promotes Atherogenesis in Insulin-Resistant Ldlr Mice. Journal of immunology (Baltimore, Md. : 1950) 20 29055004
2003 STAT4 requires the N-terminal domain for efficient phosphorylation. The Journal of biological chemistry 19 12805384
2019 STAT4 Directs a Protective Innate Lymphoid Cell Response to Gastrointestinal Infection. Journal of immunology (Baltimore, Md. : 1950) 18 31562212
2011 Acquired STAT4 deficiency as a consequence of cancer chemotherapy. Blood 18 21998209
2017 Complement Activation and STAT4 Expression Are Associated with Early Inflammation in Diabetic Wounds. PloS one 17 28107529
2016 Clinicopathological significance of STAT4 in hepatocellular carcinoma and its effect on cell growth and apoptosis. OncoTargets and therapy 17 27051307
2020 STAT4 targets KISS1 to promote the apoptosis of ovarian granulosa cells. Journal of ovarian research 16 33218349
2015 Association of STAT4 rs7574865 polymorphism with susceptibility to inflammatory bowel disease: A systematic review and meta-analysis. Clinics and research in hepatology and gastroenterology 16 26066297
2014 STAT4 deficiency protects against neointima formation following arterial injury in mice. Journal of molecular and cellular cardiology 16 24933129
2003 Activated STAT4 and a functional role for IL-12 in human Peyer's patches. Journal of immunology (Baltimore, Md. : 1950) 16 12496413
2019 Association of STAT3 and STAT4 polymorphisms with susceptibility to chronic hepatitis B virus infection and risk of hepatocellular carcinoma: a meta-analysis. Bioscience reports 15 31160486
2014 STAT4 gene polymorphisms are associated with susceptibility and ANA status in primary biliary cirrhosis. Disease markers 15 24648611
2011 STAT4 is required for IFN-β-induced MCP-1 mRNA expression in murine mast cells. International archives of allergy and immunology 15 21646799
2010 Association of IRF5, STAT4 and BLK with systemic lupus erythematosus and other rheumatic diseases. Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 15 20453440
2023 STAT4 facilitates PD-L1 level via IL-12R/JAK2/STAT3 axis and predicts immunotherapy response in breast cancer. MedComm 14 38107057
2021 Overexpression of STAT4 under hypoxia promotes EMT through miR-200a/STAT4 signal pathway. Life sciences 14 33636177
2020 Association of STAT4 Gene Rs7574865, Rs10168266 Polymorphisms and Systemic Lupus Erythematosus Susceptibility: A Meta-analysis. Immunological investigations 14 32429712
2019 Studying the Association between STAT4 Gene Polymorphism and Susceptibility to Rheumatoid Arthritis Disease: An Updated Meta-Analysis. Iranian journal of immunology : IJI 14 30864557
2016 STAT4 single nucleotide gene polymorphisms and susceptibility to endometriosis-related infertility. European journal of obstetrics, gynecology, and reproductive biology 14 27235632
2015 STAT4 deficiency reduces the development of atherosclerosis in mice. Atherosclerosis 14 26386214
2023 Divergent roles for STAT4 in shaping differentiation of cytotoxic ILC1 and NK cells during gut inflammation. Proceedings of the National Academy of Sciences of the United States of America 13 37756335
2015 Altered STAT4 Isoform Expression in Patients with Inflammatory Bowel Disease. Inflammatory bowel diseases 13 26177303

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