{"gene":"TSC22D3","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2001,"finding":"GILZ directly interacts with c-Fos and c-Jun in vitro through its N-terminal 60-amino acid region, inhibiting AP-1 DNA binding; homodimerization of GILZ requires the leucine zipper domain. GILZ expression in Jurkat T cells blocks AP-1-driven, IL-2 promoter-driven, and FasL promoter-driven reporter constructs, and inhibits Egr-2/Egr-3-mediated FasL induction.","method":"Recombinant protein in vitro interaction assays, transient transfection reporter assays, domain-deletion mutants, anti-CD3-stimulated normal T cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, domain mutagenesis, and reporter assays in multiple cell types; replicated/extended in subsequent work","pmids":["11397794"],"is_preprint":false},{"year":2002,"finding":"In THP-1 macrophage-like cells treated with glucocorticoids or IL-10, GILZ associates with the p65 subunit of NF-κB, and GILZ transfection inhibits NF-κB function and suppresses expression of CD80, CD86, CCL5, CCL3, and TLR2.","method":"Co-immunoprecipitation in THP-1 cells, transfection of GILZ gene, flow cytometry, RT-PCR","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP in cell line, multiple functional readouts, single lab","pmids":["12393603"],"is_preprint":false},{"year":2004,"finding":"FoxO3 binding to Forkhead-responsive elements in the GILZ promoter is necessary for induction of GILZ expression upon IL-2 withdrawal. GILZ overexpression protects T cells from IL-2 withdrawal-induced apoptosis and inhibits Bim expression, while GILZ silencing accelerates cell death and enhances Bim. GILZ also inhibits FoxO3 transcriptional activity, creating a negative feedback loop.","method":"GILZ promoter characterization, FHRE mutagenesis, GILZ overexpression and siRNA knockdown in CTLL-2 cells, apoptosis assays, Western blot for Bim","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — promoter mutagenesis establishing FoxO3 binding site, combined with gain/loss-of-function and defined molecular phenotype (Bim regulation)","pmids":["15031210"],"is_preprint":false},{"year":2003,"finding":"GILZ binds directly to tandem CCAAT/enhancer-binding protein (C/EBP) binding sites in the PPARγ2 promoter and acts as a sequence-specific transcriptional repressor, inhibiting PPARγ2 transcription and blocking glucocorticoid-induced adipocyte differentiation.","method":"Promoter binding assays, ectopic GILZ expression in mesenchymal cells, adipogenic differentiation assays, marker gene expression analysis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct promoter binding established, gain-of-function with defined molecular and cellular phenotype","pmids":["12671681"],"is_preprint":false},{"year":2006,"finding":"GILZ interacts directly with Ras in vitro and in vivo (co-immunoprecipitation and colocalization in primary T cells); interaction is mediated through the TSC box domain. GILZ forms a trimeric complex with Ras and Raf. These interactions reduce ERK1/2, AKT/PKB phosphorylation, Rb phosphorylation, and cyclin D1 expression, inhibiting Ras/Raf-dependent proliferation and NIH-3T3 transformation. GILZ silencing abrogates dexamethasone antiproliferative effects.","method":"In vitro binding assays, co-immunoprecipitation, colocalization imaging, GILZ domain mutants, siRNA knockdown, cell proliferation/transformation assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution combined with co-IP in primary cells, domain mutant analysis, and loss-of-function phenotype","pmids":["17492054"],"is_preprint":false},{"year":2006,"finding":"GILZ homo-dimerization via the leucine zipper domain and the C-terminal PER domain (particularly residues 121–123) are both required for GILZ/p65 NF-κB interaction and inhibition of NF-κB transcriptional activity and IL-2 synthesis, as shown by in vitro and in vivo co-immunoprecipitation with multiple GILZ mutants.","method":"In vitro and in vivo co-immunoprecipitation, GILZ domain deletion/point mutants, NF-κB transcriptional reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — domain mutagenesis combined with co-IP and functional reporter assays in a single rigorous study","pmids":["17169985"],"is_preprint":false},{"year":2007,"finding":"GILZ and its isoform L-GILZ are expressed in skeletal muscle and C2C12 myoblasts; GILZ/L-GILZ overexpression inhibits myotube formation and reduces MyoD function and myogenin expression by binding and regulating MyoD/HDAC1 transcriptional activity. GILZ/L-GILZ silencing dampens glucocorticoid anti-myogenic effects.","method":"C2C12 myoblast differentiation assays, GILZ/L-GILZ overexpression and siRNA knockdown, co-immunoprecipitation of GILZ with MyoD/HDAC1, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying binding partner plus gain/loss-of-function with functional phenotype; single lab","pmids":["20124407"],"is_preprint":false},{"year":2007,"finding":"GILZ overexpression in mouse mesenchymal stem cells increases alkaline phosphatase activity, mineralized nodule formation, and expression of Runx2/Cbfa1, alkaline phosphatase, type I collagen, and osteocalcin, while reducing PPARγ2 and C/EBPα. Gilz knockdown reduces MSC osteogenic differentiation capacity, indicating GILZ shifts MSC commitment from adipogenic to osteogenic.","method":"GILZ overexpression and siRNA knockdown in mouse MSCs, alkaline phosphatase activity assay, mineralized nodule formation, RT-PCR for lineage markers","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss-of-function with multiple differentiation markers; single lab","pmids":["18084007"],"is_preprint":false},{"year":2008,"finding":"GILZ inhibits inflammatory cytokine (TNF-α and IL-1β)-induced COX-2 mRNA and protein expression in bone marrow mesenchymal stem cells by blocking NF-κB nuclear translocation and NF-κB-mediated COX-2 promoter activity. Knockdown of GILZ by shRNA reduces glucocorticoid inhibition of cytokine-induced COX-2.","method":"Retroviral GILZ overexpression, shRNA knockdown, COX-2 reporter assay, NF-κB nuclear translocation (fractionation/immunofluorescence), RT-PCR, Western blot","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with mechanistic pathway readout (NF-κB translocation), single lab","pmids":["17910039"],"is_preprint":false},{"year":2009,"finding":"GILZ promotes nuclear exclusion of FOXO3 in a Crm1-dependent manner: GILZ expression (exclusively cytoplasmic) causes FOXO3 to relocalize from nucleus to cytoplasm, suppressing FOXO1/3/4 transcriptional activity and downregulating FOXO targets p27KIP1 and Bim. GILZ does not physically interact with FOXO3 and does not hinder FOXO3 DNA-binding directly.","method":"Fluorescence microscopy, Crm1 inhibitor (leptomycin B) treatment, FOXO-responsive reporter assays in HL-60 and CTLL-2 cells, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging of localization tied to functional consequence, multiple cell lines, negative interaction result mechanistically informative; single lab","pmids":["20018851"],"is_preprint":false},{"year":2010,"finding":"Glucocorticoid-induced caspase-8 activation protects GILZ from proteasomal degradation and induces GILZ binding to SUMO-1; GILZ contains a SUMO-binding site, binds the SUMO E2-conjugating enzyme Ubc9 in vitro and in vivo, and co-immunoprecipitates with SUMO-1 in a caspase-8-dependent manner in thymocytes.","method":"In vitro binding assays (GILZ–Ubc9, GILZ–SUMO-1), co-immunoprecipitation, caspase-8 inhibition, proteasome inhibition, caspase-8-deficient thymocytes","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding plus in vivo co-IP, proteasome inhibitor corroboration; single lab","pmids":["20671745"],"is_preprint":false},{"year":2011,"finding":"GILZ binds to and inhibits mTORC2 (but not mTORC1) in mouse and human BCR-ABL+ cells, suppressing Ser473-AKT phosphorylation and activating FoxO3a-mediated Bim transcription, thereby inducing apoptosis and reducing imatinib/dasatinib resistance.","method":"Co-immunoprecipitation of GILZ with mTORC2 components, AKT phosphorylation (Western blot), FoxO3a reporter assays, apoptosis assays, CD34+ CML stem cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP distinguishing mTORC1 vs mTORC2, multiple functional readouts; single lab","pmids":["21804606"],"is_preprint":false},{"year":2011,"finding":"L-GILZ (long isoform of GILZ) is highly expressed in spermatogonia and primary spermatocytes; Gilz knockout mice develop complete loss of germ cells and male sterility. GILZ deficiency leads to increased ERK and Akt phosphorylation (Ras pathway hyperactivation) and aberrant spermatogonial differentiation.","method":"Gilz knockout mice, immunohistochemistry, Western blot for ERK/Akt phosphorylation, apoptosis assays, spermatogenesis phenotyping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive KO with clear cellular and molecular phenotype, replicated by multiple independent KO papers","pmids":["22110132"],"is_preprint":false},{"year":2012,"finding":"Estradiol (E2) antagonizes glucocorticoid-induced GILZ gene expression through the estrogen receptor (ERα and ERβ): both GR and ERα are recruited to GRE-containing regions of the GILZ promoter, and E2 treatment decreases GR binding there. ER antagonist ICI 182,780 and ERα siRNA block E2-mediated GILZ repression.","method":"Chromatin immunoprecipitation (ChIP) for GR and ERα at GILZ promoter, siRNA knockdown of ERα, ER antagonist treatment, nascent RNA assay, in vivo mouse uterus model","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP establishing promoter occupancy, multiple genetic and pharmacological interventions in vitro and in vivo; single lab","pmids":["23183181"],"is_preprint":false},{"year":2013,"finding":"GILZ overexpression in HUVECs inhibits TNF-induced NF-κB p65 DNA binding (without affecting p65 nuclear translocation), and suppresses p38, ERK, and JNK MAPK activation while increasing MKP-1. This reduces leukocyte rolling, adhesion, and transmigration, and decreases E-selectin, ICAM-1, CCL2, CXCL8, and IL-6.","method":"Transient transfection of GILZ in HUVECs, NF-κB reporter/DNA binding assays, p65 nuclear translocation imaging, MAPK phosphorylation (Western blot), leukocyte adhesion assays, MKP-1 quantification","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal readouts distinguishing p65 translocation from DNA binding; single lab, transfection system","pmids":["23729444"],"is_preprint":false},{"year":2013,"finding":"DC-SCRIPT coexists with GR in protein complexes and functions as a corepressor of GR-mediated transcription; DC-SCRIPT knockdown enhances GR-dependent upregulation of GILZ mRNA in dendritic cells.","method":"Co-immunoprecipitation of DC-SCRIPT with GR, DC-SCRIPT knockdown (siRNA), GILZ mRNA quantification in monocyte-derived DCs","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying complex, loss-of-function confirming functional relevance; single lab","pmids":["23440419"],"is_preprint":false},{"year":2013,"finding":"GILZ inhibits dexamethasone-suppressed airway epithelial repair by suppressing Raf-1, MEK1/2, and ERK1/2 phosphorylation (MAPK-ERK pathway), thereby inhibiting proliferation and migration. Silencing GILZ with siRNA reverses DEX-mediated inhibition of these pathway components and restores cell repair.","method":"siRNA knockdown, Western blot for pRaf/pMEK/pERK, wound-healing/migration assays, MTT proliferation assay, CFSE labeling","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with defined pathway and phenotypic readout; single lab","pmids":["23573276"],"is_preprint":false},{"year":2014,"finding":"L-GILZ (long isoform) binds preferentially to MDM2 (in the presence of both p53 and MDM2) and interferes with p53/MDM2 complex formation, stabilizing p53 by decreasing its ubiquitination and increasing MDM2 ubiquitination, leading to p21 and PUMA induction and tumor growth suppression.","method":"Co-immunoprecipitation of L-GILZ with p53 and MDM2, ubiquitination assays, p53-proficient vs -deficient cell lines, xenograft tumor growth, siRNA knockdown of L-GILZ","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — co-IP, ubiquitination assay, isogenic p53+/+ vs p53-/- cells establishing pathway dependence, in vivo xenograft; single lab","pmids":["25168242"],"is_preprint":false},{"year":2014,"finding":"GILZ promotes TGF-β signaling by binding to Smad2 and promoting its phosphorylation, thereby activating FoxP3 expression and enabling GCs to cooperate with TGF-β in peripheral regulatory T cell (pTreg) generation. GILZ-deficient mice show impaired pTreg generation and increased intestinal inflammation.","method":"GILZ overexpression transgenic mice, Gilz knockout mice, co-immunoprecipitation of GILZ with Smad2, Smad2 phosphorylation assay, FoxP3 reporter, intestinal inflammation model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — co-IP with Smad2, phosphorylation assay, combined gain (transgenic) and loss (KO) of function, in vivo model; single lab but multiple orthogonal methods","pmids":["24703841"],"is_preprint":false},{"year":2014,"finding":"GILZ physically interacts with C/EBPs and disrupts C/EBP-mediated PPARγ gene transcription, enhancing osteogenic while suppressing adipogenic differentiation. Transgenic mice expressing GILZ under a collagen promoter show increased bone mass, bone formation rate, and osteoblast numbers.","method":"Co-immunoprecipitation of GILZ with C/EBPs, PPARγ promoter reporter assays, transgenic mice, bone histomorphometry, MSC differentiation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus promoter assay plus in vivo transgenic phenotype; single lab","pmids":["24860090"],"is_preprint":false},{"year":2016,"finding":"Curcumin induces GILZ protein expression post-transcriptionally via HuR: HuR binds GILZ mRNA (confirmed by RNA immunoprecipitation), and HuR overexpression increases GILZ protein but not mRNA. GILZ induction by curcumin mediates its anti-inflammatory effects (NF-κB/ERK inhibition, TNF-α reduction) in macrophages, as shown in GILZ KO macrophages.","method":"RNA immunoprecipitation (RIP) of HuR–GILZ mRNA, HuR overexpression, GILZ KO bone marrow-derived macrophages, NF-κB/ERK activity assays, TNF-α ELISA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP establishing direct RNA–protein interaction, KO macrophage validation, multiple readouts; single lab","pmids":["27629417"],"is_preprint":false},{"year":2017,"finding":"In immunoregulatory MSC (primed with IFN-γ and TNF-α), GILZ translocates to the nucleus and binds the promoters of iNOS and Activin βA to induce their expression. Activin A produced downstream of GILZ directly represses Th17 cell differentiation via Smad3/2 activation.","method":"ChIP of GILZ at iNOS and Activin βA promoters, nuclear translocation imaging, Activin A ELISA, Smad2/3 phosphorylation, adoptive transfer experiments","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing promoter binding with functional consequence, localization experiment; single lab","pmids":["29344311"],"is_preprint":false},{"year":2018,"finding":"GILZ deletion in adults causes exhaustion of GFRα1+ spermatogonial stem cells and germline degeneration associated with mTORC1 activation and reduced USP9X (a deubiquitylase required for spermatogenesis). mTOR inhibitor treatment rescues GFRα1+ spermatogonial failure. GILZ interacts with TSC22D family proteins (forming GILZ-TSC22D complexes) and controls ERK MAPK upstream of mTORC1.","method":"Adult conditional Gilz knockout, mTOR inhibitor rescue, USP9X expression analysis, co-immunoprecipitation of GILZ with TSC22D proteins, ERK phosphorylation analysis in cultured spermatogonia","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with pharmacological rescue establishing pathway, co-IP identifying complex, multiple orthogonal methods; single lab","pmids":["30126904"],"is_preprint":false},{"year":2018,"finding":"GILZ restrains neutrophil activation by reducing ERK and p38 MAPK phosphorylation as well as NOX2 and p47phox activation; GILZ-KO neutrophils show enhanced phagocytosis, oxidative burst, and bacterial killing.","method":"GILZ-KO neutrophils, Candida albicans infection model, DNBS colitis model, MAPK phosphorylation (Western blot), oxidative burst assay, phagocytosis assay","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined signaling and functional phenotype in two in vivo models; single lab","pmids":["30371949"],"is_preprint":false},{"year":2019,"finding":"Stress-induced elevation of corticosterone upregulates Tsc22d3 (GILZ) in dendritic cells, which blocks type I IFN responses in DCs and IFN-γ+ T cell activation. Enforced DC-specific Tsc22d3 expression is sufficient to abolish therapeutic tumor control, and DC-specific Tsc22d3 deletion reverses the negative impact of stress/glucocorticoid on therapy outcomes.","method":"Social defeat stress mouse model, DC-specific Tsc22d3 transgenic and conditional KO mice, glucocorticoid receptor antagonist treatment, IFN response assays, tumor challenge models","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific gain and loss of function in vivo, pharmacological rescue, multiple independent approaches establishing DC-intrinsic mechanism","pmids":["31501614"],"is_preprint":false},{"year":2019,"finding":"Cholesterol deficiency under hypoxia activates SREBP1, which induces GILZ expression; GILZ in turn binds the FVII gene locus (confirmed by chromatin immunoprecipitation in xenograft tumors) and activates FVII transcription. GILZ expression is also induced by HIF1α. Reciprocal regulation between SREBP1 and GILZ was observed.","method":"ChIP in xenograft tumor samples (HIF1α at TSC22D3 locus; GILZ at FVII locus), GILZ siRNA knockdown, SREBP1 manipulation, luciferase reporter assays","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP in vivo confirming GILZ genomic binding, siRNA functional validation; single lab","pmids":["31055798"],"is_preprint":false},{"year":2020,"finding":"Glucocorticoid-transactivated TSC22D3 (GILZ) interacts with HIF-1α (shown by co-immunoprecipitation) and promotes degradation of hypoxia-stabilized HIF-1α via the ubiquitin-proteasome pathway. TSC22D3 silencing reverses glucocorticoid-mediated HIF-1α ubiquitination and galectin-1 downregulation.","method":"Co-immunoprecipitation of TSC22D3 with HIF-1α, ubiquitination assay, TSC22D3 siRNA knockdown, HIF-1α protein stability assay, in vivo diabetic mouse retina model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay plus siRNA validation in vitro and in vivo; single lab","pmids":["32150332"],"is_preprint":false},{"year":2022,"finding":"GILZ directly binds STAT1 and prevents its nuclear translocation, thereby suppressing IFN-stimulated gene (ISG) expression and the type I IFN auto-amplification loop. GILZ deficiency permits a type I IFN signature, and GILZ overexpression prevents ISG upregulation in response to IFNα.","method":"Co-immunoprecipitation of GILZ with STAT1, nuclear translocation assay, GILZ overexpression and knockout in human PBMC, ISG reporter assays, TLR7/9 stimulation","journal":"Journal of autoimmunity","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP establishing direct GILZ–STAT1 interaction, gain/loss-of-function, defined molecular phenotype (STAT1 nuclear exclusion); single lab but multiple orthogonal methods","pmids":["35810690"],"is_preprint":false},{"year":2022,"finding":"Type I IFN suppresses GILZ expression and glucocorticoid induction of GILZ in a JAK1/Tyk2-dependent manner; IFN activation of this pathway reduces GR binding at key regulatory regions of the GILZ locus, as shown by ChIP.","method":"ChIP for GR at GILZ locus, JAK inhibitor treatment (tofacitinib/tosylate salt), in vitro IFN treatment of human PBMCs, large SLE patient dataset correlation","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing mechanism of GR displacement, pharmacological JAK inhibitor reversal; single lab","pmids":["36505447"],"is_preprint":false},{"year":2004,"finding":"GILZ overexpression in T-cell lineage transgenic mice decreases CD4+CD8+ thymocyte number, increases thymocyte apoptosis via reduced Bcl-xL expression and activated caspase-8 and caspase-3. TAT-GILZ fusion protein delivered into wild-type thymocytes decreases Bcl-xL and promotes apoptosis.","method":"Transgenic mice overexpressing GILZ in T cells, ex vivo thymocyte apoptosis assays, caspase activity assays, Bcl-xL Western blot, TAT-GILZ protein delivery","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic gain-of-function plus direct protein delivery, multiple apoptotic pathway readouts; single lab","pmids":["15319285"],"is_preprint":false},{"year":2012,"finding":"Gilz knockout male mice develop severe testis dysplasia from postnatal day 10, increased apoptosis in seminiferous tubules, increased Leydig cells, and elevated FSH and testosterone; males are infertile. Additionally, Tsc22d3-2 KO mice display subtle renal sodium/water handling deficiency but no major immunological defects under unstressed conditions.","method":"Cre/loxP conditional KO (Tsc22d3-2), testis histology, TUNEL apoptosis, hormone quantification (FSH, testosterone), renal electrolyte measurement, immune challenges","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with well-defined tissue phenotype replicated across multiple independent Gilz KO studies","pmids":["22556341"],"is_preprint":false},{"year":2015,"finding":"GILZ-deficient mice develop progressive B-cell lymphocytosis with expansion of B220+ cells dependent on increased B-cell survival; decreased B-cell apoptosis in gilz KO mice correlates with increased NF-κB transcriptional activity and Bcl-2 expression. B-cell-specific gilz KO confirms the effect is B-cell intrinsic.","method":"Global and B-cell-specific gilz KO mice, flow cytometry, apoptosis assays, NF-κB reporter, Bcl-2 Western blot","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO confirming intrinsic mechanism, defined molecular pathway (NF-κB/Bcl-2); single lab","pmids":["26276664"],"is_preprint":false},{"year":2012,"finding":"In alcohol-treated cells, unliganded GR binds GREs in the GILZ proximal promoter (shown by gel mobility shift assay) and transactivates gilz expression independent of glucocorticoids; GR knockout (CRISPR/Cas9) or GILZ depletion (siRNA) diminishes alcohol-mediated suppression of the LPS inflammatory response.","method":"Gel mobility shift assay (EMSA) for GR–GRE interaction, GRE deletion/mutation luciferase reporters, CRISPR/Cas9 GR knockout, siRNA GILZ knockdown, GR nuclear translocation, alcohol dehydrogenase inhibitor (fomepizole)","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus reporter mutagenesis plus loss-of-function; single lab","pmids":["28638383"],"is_preprint":false},{"year":2017,"finding":"IBDV VP4 suppresses GILZ K48-linked ubiquitylation, protecting GILZ from degradation and thereby inhibiting IFN-β expression. Mutation of VP4 residue R41G abolishes both VP4's inhibitory effect on IFN-β and on GILZ ubiquitylation. IBDV infection also markedly inhibits endogenous GILZ ubiquitylation.","method":"Ubiquitylation assays (K48-linkage specific), VP4 R41G point mutant, IBDV infection of cells, IFN-β reporter assays","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — linkage-specific ubiquitylation assay plus mutagenesis of viral effector; single lab","pmids":["29146236"],"is_preprint":false},{"year":2012,"finding":"Bacterial toxins YopT and Clostridium difficile toxin B induce GILZ expression in epithelial cells by inactivating Rho GTPases; MAPK activation is required. USF-1 and USF-2 bind a canonical E-box (c-Myc binding site) in the GILZ promoter, which is essential for both basal and toxin-B-induced GILZ transcription.","method":"GILZ promoter reporter assays, gel shift analysis (EMSA for USF1/2 binding), USF-1/2 siRNA knockdown, MAPK inhibitors, Yersinia mutant strains, RhoA/RhoB overexpression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus promoter mutagenesis plus siRNA establishing USF pathway; single lab","pmids":["22792400"],"is_preprint":false},{"year":2023,"finding":"RBM47-ISGylation (at K329) negatively regulates TSC22D3 mRNA expression; K329R knockin mice with defective RBM47 ISGylation show elevated TSC22D3 and broad immunosuppression. A nanobody-targeted E3 ligase inducing site-specific RBM47 ISGylation in human cells directly inhibits TSC22D3 expression.","method":"K329R knockin mice, nanobody-targeted site-specific ISGylation in human cells, TSC22D3 mRNA quantification, LPS-induced lung injury and tumor models","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockin mouse plus orthogonal site-specific ISGylation tool in human cells; single lab","pmids":["38036512"],"is_preprint":false}],"current_model":"TSC22D3/GILZ is a glucocorticoid-inducible transcriptional regulator that mediates anti-inflammatory and immunosuppressive effects of glucocorticoids by directly binding and inhibiting multiple signaling nodes: it physically associates with NF-κB p65 (requiring LZ-mediated homodimerization and the C-terminal PER domain), AP-1 components c-Fos and c-Jun (via its N-terminal 60 aa), Ras and Raf (via its TSC box), mTORC2, Smad2, STAT1, MDM2, MyoD/HDAC1, C/EBPs, HIF-1α, and USP9X; promotes nuclear exclusion of FOXO3 in a Crm1-dependent manner; is itself transcriptionally induced by GR binding to GREs and by FoxO3 (upon IL-2 withdrawal), and is post-translationally regulated by caspase-8-dependent SUMO-1 conjugation and by K48-ubiquitylation; in spermatogonia its TSC22D complex form controls mTORC1 activity to maintain stem cell homeostasis; and GILZ-mediated suppression of type I IFN signaling occurs through direct STAT1 sequestration that prevents its nuclear translocation."},"narrative":{"mechanistic_narrative":"TSC22D3 (GILZ) is a glucocorticoid-inducible leucine-zipper protein that executes the anti-inflammatory and immunosuppressive program of glucocorticoids by physically intercepting multiple pro-inflammatory and proliferative signaling nodes [PMID:11397794, PMID:17169985, PMID:17492054]. It transcriptionally couples to upstream hormonal control: glucocorticoid receptor binding to GREs drives GILZ induction (including ligand-independent GR activation), and additional inputs—FoxO3 upon IL-2 withdrawal, SREBP1/HIF1α, and USF1/2 at an E-box—tune its expression, while estradiol/ERα and type I IFN (JAK1/Tyk2-dependent) displace GR to repress it [PMID:15031210, PMID:31055798, PMID:22792400, PMID:23183181, PMID:36505447]. Mechanistically, GILZ acts largely by sequestration and direct binding: homodimerization via its leucine zipper plus the C-terminal PER domain is required for binding NF-κB p65 and inhibiting NF-κB-driven transcription, its N-terminal 60 residues bind c-Fos/c-Jun to block AP-1, and its TSC box engages Ras and Raf to form a trimeric complex that dampens ERK/AKT signaling and proliferation [PMID:17169985, PMID:11397794, PMID:17492054]. It further binds STAT1 to block its nuclear translocation and suppress type I IFN/ISG responses, promotes Crm1-dependent nuclear exclusion of FOXO3, binds Smad2 to promote TGF-β/FoxP3-driven regulatory T cell generation, and represses adipogenic lineage genes (PPARγ2) through C/EBP sites while favoring osteogenic commitment [PMID:35810690, PMID:20018851, PMID:24703841, PMID:12671681, PMID:24860090]. The long isoform L-GILZ binds MDM2 to stabilize p53, and in spermatogonia GILZ forms TSC22D-family complexes that restrain ERK and mTORC1 to maintain stem-cell homeostasis—Gilz loss causes germ-cell exhaustion and male sterility [PMID:25168242, PMID:30126904, PMID:22110132]. Genetic loss-of-function across tissues establishes GILZ as a brake on immune and proliferative output, including B-cell survival via NF-κB/Bcl-2 and neutrophil oxidative activation, and as a stress/glucocorticoid-driven suppressor of antitumor immunity in dendritic cells [PMID:26276664, PMID:30371949, PMID:31501614]. GILZ stability is itself controlled post-translationally through caspase-8-linked SUMO-1 conjugation and K48-ubiquitylation [PMID:20671745, PMID:29146236].","teleology":[{"year":2001,"claim":"Established the first direct molecular mechanism for GILZ as a transcriptional brake, showing it binds AP-1 components and requires leucine-zipper-mediated dimerization, defining its mode of action on immune gene promoters.","evidence":"Recombinant in vitro interaction assays, domain-deletion mutants, and reporter assays in Jurkat/primary T cells","pmids":["11397794"],"confidence":"High","gaps":["Did not address NF-κB or other transcription factor targets","No in vivo validation of AP-1 inhibition"]},{"year":2002,"claim":"Extended GILZ's inhibitory repertoire to NF-κB, linking glucocorticoid/IL-10 signaling to suppression of macrophage costimulatory and chemokine genes.","evidence":"Co-immunoprecipitation and GILZ transfection in THP-1 macrophage-like cells with flow cytometry/RT-PCR readouts","pmids":["12393603"],"confidence":"Medium","gaps":["Domain requirements for p65 binding not defined here","Single cell line"]},{"year":2003,"claim":"Demonstrated GILZ acts as a sequence-specific transcriptional repressor at C/EBP sites, mechanistically explaining glucocorticoid inhibition of adipocyte differentiation.","evidence":"Promoter binding assays and ectopic expression in mesenchymal cells with adipogenic differentiation readouts","pmids":["12671681"],"confidence":"High","gaps":["No structural basis for promoter recognition","Direct DNA-binding versus C/EBP tethering not fully resolved"]},{"year":2004,"claim":"Placed GILZ in a FoxO3-driven survival circuit, showing reciprocal regulation (FoxO3 induces GILZ; GILZ inhibits FoxO3) controlling Bim and T-cell apoptosis.","evidence":"GILZ promoter FHRE mutagenesis with gain/loss-of-function in CTLL-2 cells and apoptosis assays","pmids":["15031210"],"confidence":"High","gaps":["Mechanism of FoxO3 inhibition not defined at this stage"]},{"year":2004,"claim":"Established GILZ as a pro-apoptotic regulator of thymocyte selection in vivo through Bcl-xL downregulation and caspase activation.","evidence":"T-cell GILZ transgenic mice and TAT-GILZ protein delivery with caspase/Bcl-xL readouts","pmids":["15319285"],"confidence":"Medium","gaps":["Molecular target driving Bcl-xL loss not identified","Single lab"]},{"year":2006,"claim":"Defined the bipartite structural requirement (leucine zipper plus PER domain) for GILZ/p65 binding, mechanistically dissecting NF-κB inhibition.","evidence":"In vitro and in vivo co-IP with multiple GILZ deletion/point mutants and NF-κB reporters","pmids":["17169985"],"confidence":"High","gaps":["No co-crystal structure of GILZ/p65","Stoichiometry of the inhibitory complex unresolved"]},{"year":2006,"claim":"Identified the TSC box as the Ras-binding module and showed GILZ forms a Ras/Raf trimeric complex, connecting GILZ to glucocorticoid antiproliferative effects.","evidence":"In vitro binding, co-IP and colocalization in primary T cells, domain mutants, siRNA, and transformation assays","pmids":["17492054"],"confidence":"High","gaps":["Whether GILZ blocks Ras GTPase activity or only effector coupling not resolved"]},{"year":2007,"claim":"Showed GILZ governs mesenchymal lineage choice, promoting osteogenesis at the expense of adipogenesis via lineage marker reprogramming.","evidence":"GILZ overexpression and knockdown in mouse MSCs with differentiation assays and lineage marker RT-PCR","pmids":["18084007"],"confidence":"Medium","gaps":["Direct transcriptional targets in osteogenic program not mapped here","Single lab"]},{"year":2007,"claim":"Extended GILZ transcriptional inhibition to the myogenic program through MyoD/HDAC1 regulation, explaining glucocorticoid anti-myogenic effects.","evidence":"C2C12 differentiation with GILZ/L-GILZ gain/loss-of-function and co-IP with MyoD/HDAC1","pmids":["20124407"],"confidence":"Medium","gaps":["Direct versus indirect binding to MyoD not fully separated","Single lab"]},{"year":2008,"claim":"Refined GILZ's NF-κB inhibition mechanism in MSCs, showing it blocks p65 nuclear translocation to suppress COX-2.","evidence":"Retroviral overexpression/shRNA, NF-κB translocation imaging/fractionation, COX-2 reporters","pmids":["17910039"],"confidence":"Medium","gaps":["Apparent discrepancy with later reports that GILZ does not affect p65 translocation"]},{"year":2009,"claim":"Resolved how GILZ inhibits FOXO3 without binding it, identifying Crm1-dependent nuclear exclusion as the mechanism.","evidence":"Live-cell imaging, leptomycin B treatment, FOXO reporters and fractionation in HL-60/CTLL-2","pmids":["20018851"],"confidence":"Medium","gaps":["Intermediate kinase/adaptor linking cytoplasmic GILZ to FOXO3 export unknown"]},{"year":2010,"claim":"Defined post-translational control of GILZ stability, linking glucocorticoid-induced caspase-8 to SUMO-1 conjugation via Ubc9 and protection from proteasomal degradation.","evidence":"In vitro GILZ–Ubc9/SUMO-1 binding, co-IP, caspase-8-deficient thymocytes, proteasome inhibition","pmids":["20671745"],"confidence":"Medium","gaps":["Functional consequence of GILZ SUMOylation on activity not established","SUMO acceptor lysine not mapped"]},{"year":2011,"claim":"Distinguished GILZ inhibition of mTORC2 (not mTORC1), connecting it to AKT-S473/FoxO3a/Bim-driven apoptosis and drug sensitization in BCR-ABL+ cells.","evidence":"Reciprocal co-IP with mTOR complex components, AKT phosphorylation, FoxO3a reporters in CML cells","pmids":["21804606"],"confidence":"Medium","gaps":["Binding interface with mTORC2 not mapped","Apparent contrast with later spermatogonial mTORC1 control"]},{"year":2011,"claim":"Established GILZ as essential for spermatogenesis in vivo, with KO germline loss linked to Ras pathway (ERK/Akt) hyperactivation.","evidence":"Gilz knockout mice with IHC, ERK/Akt phosphorylation, and spermatogenesis phenotyping","pmids":["22110132"],"confidence":"High","gaps":["Whether germline defect is cell-intrinsic versus somatic not resolved here"]},{"year":2012,"claim":"Confirmed and elaborated the Gilz-null testis phenotype while showing minimal baseline immune deficit, distinguishing tissue-specific essentiality.","evidence":"Conditional Tsc22d3-2 KO with testis histology, TUNEL, hormone and renal electrolyte measurements","pmids":["22556341"],"confidence":"High","gaps":["Renal sodium/water handling mechanism not defined","Immune phenotypes emerge mainly under challenge"]},{"year":2012,"claim":"Showed ligand-independent GR can transactivate GILZ at GREs, broadening the upstream control of GILZ to non-glucocorticoid (alcohol) contexts.","evidence":"EMSA for GR–GRE, GRE reporter mutagenesis, CRISPR GR KO, GILZ siRNA","pmids":["28638383"],"confidence":"Medium","gaps":["How unliganded GR is activated by alcohol not mechanistically resolved"]},{"year":2012,"claim":"Identified a Rho-GTPase/MAPK/USF input controlling GILZ, showing bacterial toxins induce GILZ through an E-box bound by USF1/2.","evidence":"GILZ promoter reporters, EMSA for USF binding, USF siRNA, MAPK inhibitors, Rho manipulation","pmids":["22792400"],"confidence":"Medium","gaps":["Functional consequence of toxin-induced GILZ for host defense not defined here"]},{"year":2012,"claim":"Identified estradiol/ERα as a repressor of GILZ that reduces GR occupancy at the promoter, defining cross-talk between estrogen and glucocorticoid control.","evidence":"ChIP for GR/ERα at GILZ promoter, ERα siRNA, ER antagonist, in vivo uterus model","pmids":["23183181"],"confidence":"High","gaps":["Mechanism by which ERα displaces GR not structurally defined"]},{"year":2013,"claim":"Clarified that GILZ can inhibit NF-κB at the level of p65 DNA binding (not translocation) and broadly dampens MAPK signaling to limit endothelial leukocyte recruitment.","evidence":"GILZ transfection in HUVECs, NF-κB DNA-binding versus translocation assays, MAPK and MKP-1 readouts, adhesion assays","pmids":["23729444"],"confidence":"Medium","gaps":["Reconciliation with translocation-blocking reports unresolved","Transfection system only"]},{"year":2013,"claim":"Placed GILZ induction under corepressor control, showing DC-SCRIPT restrains GR-driven GILZ expression in dendritic cells.","evidence":"Co-IP of DC-SCRIPT with GR and DC-SCRIPT knockdown in monocyte-derived DCs","pmids":["23440419"],"confidence":"Medium","gaps":["Direct versus indirect effect on GILZ locus not separated"]},{"year":2013,"claim":"Showed GILZ mediates glucocorticoid suppression of airway epithelial repair via Raf-1/MEK/ERK inhibition, linking GILZ to tissue regeneration outcomes.","evidence":"GILZ siRNA, pRaf/pMEK/pERK Western blot, wound-healing and proliferation assays","pmids":["23573276"],"confidence":"Medium","gaps":["Whether GILZ acts via direct Raf binding here not tested"]},{"year":2014,"claim":"Defined a p53-stabilizing function for L-GILZ via MDM2 binding, connecting GILZ to tumor suppression.","evidence":"Co-IP with p53/MDM2, ubiquitination assays, isogenic p53+/+ vs p53-/- cells, xenografts, L-GILZ siRNA","pmids":["25168242"],"confidence":"High","gaps":["Isoform specificity (L-GILZ vs GILZ) for MDM2 binding interface not mapped"]},{"year":2014,"claim":"Identified GILZ as a positive regulator of TGF-β/Smad2 signaling driving FoxP3+ regulatory T-cell generation, defining a pro-tolerogenic axis.","evidence":"GILZ transgenic and KO mice, co-IP with Smad2, Smad2 phosphorylation, FoxP3 reporter, intestinal inflammation model","pmids":["24703841"],"confidence":"High","gaps":["How GILZ promotes Smad2 phosphorylation mechanistically not defined"]},{"year":2014,"claim":"Confirmed in vivo that GILZ drives osteogenic over adipogenic commitment through C/EBP-mediated PPARγ repression, with transgenic mice showing increased bone mass.","evidence":"Co-IP with C/EBPs, PPARγ reporters, collagen-promoter GILZ transgenic mice, bone histomorphometry","pmids":["24860090"],"confidence":"Medium","gaps":["Direct DNA contact versus C/EBP tethering at PPARγ not separated"]},{"year":2015,"claim":"Established a B-cell-intrinsic role for GILZ in restraining survival, with KO lymphocytosis tied to elevated NF-κB activity and Bcl-2.","evidence":"Global and B-cell-specific gilz KO, flow cytometry, apoptosis assays, NF-κB reporter, Bcl-2 Western blot","pmids":["26276664"],"confidence":"High","gaps":["Direct molecular link from GILZ loss to Bcl-2 induction not fully resolved"]},{"year":2016,"claim":"Identified post-transcriptional control of GILZ by HuR, explaining curcumin-driven anti-inflammatory GILZ induction independent of transcription.","evidence":"RNA immunoprecipitation of HuR–GILZ mRNA, HuR overexpression, GILZ KO macrophages, inflammatory readouts","pmids":["27629417"],"confidence":"Medium","gaps":["HuR binding element on GILZ mRNA not mapped"]},{"year":2017,"claim":"Revealed a nuclear, transcription-activating mode for GILZ in primed MSCs, binding iNOS and Activin βA promoters to repress Th17 differentiation.","evidence":"ChIP at iNOS/Activin βA promoters, nuclear translocation imaging, Activin A ELISA, Smad2/3 readouts, adoptive transfer","pmids":["29344311"],"confidence":"Medium","gaps":["Signals controlling cytoplasmic-to-nuclear GILZ shift not defined","Direct versus cofactor-dependent DNA binding unclear"]},{"year":2017,"claim":"Showed viral immune evasion converges on GILZ stability, with IBDV VP4 suppressing GILZ K48-ubiquitylation to limit IFN-β.","evidence":"K48-linkage-specific ubiquitylation assays, VP4 R41G mutant, IBDV infection, IFN-β reporters","pmids":["29146236"],"confidence":"Medium","gaps":["E3 ligase and deubiquitylase acting on GILZ not identified"]},{"year":2018,"claim":"Defined the spermatogonial stem-cell mechanism, showing GILZ forms TSC22D-family complexes and restrains ERK/mTORC1, with mTOR inhibition rescuing germline failure.","evidence":"Adult conditional Gilz KO, mTOR inhibitor rescue, USP9X analysis, co-IP with TSC22D proteins, ERK phosphorylation","pmids":["30126904"],"confidence":"High","gaps":["Direct GILZ–mTORC1 regulatory link versus ERK-mediated effect not separated","Role of USP9X mechanistically incomplete"]},{"year":2018,"claim":"Established GILZ as a brake on neutrophil effector function through MAPK and NOX2/p47phox suppression.","evidence":"GILZ-KO neutrophils, Candida and DNBS colitis models, MAPK and oxidative burst/phagocytosis assays","pmids":["30371949"],"confidence":"Medium","gaps":["Direct GILZ target controlling NOX2 not identified"]},{"year":2019,"claim":"Connected psychological stress to immunosuppression via DC-intrinsic GILZ, showing corticosterone-induced GILZ blocks type I IFN and abolishes antitumor therapy control.","evidence":"Social-defeat stress model, DC-specific Tsc22d3 transgenic and conditional KO mice, GR antagonist, tumor challenge","pmids":["31501614"],"confidence":"High","gaps":["Molecular target of GILZ in the DC IFN block not defined in this study"]},{"year":2019,"claim":"Identified a metabolic/hypoxic transcriptional circuit, with SREBP1 and HIF1α inducing GILZ, which in turn binds and activates the FVII locus.","evidence":"ChIP for HIF1α at TSC22D3 and GILZ at FVII in xenografts, GILZ siRNA, SREBP1 manipulation, reporters","pmids":["31055798"],"confidence":"Medium","gaps":["GILZ DNA-binding mode at FVII versus cofactor dependence unclear"]},{"year":2020,"claim":"Showed GILZ promotes ubiquitin-proteasomal degradation of HIF-1α, defining a glucocorticoid mechanism for HIF-1α turnover in disease tissue.","evidence":"Co-IP with HIF-1α, ubiquitination assays, TSC22D3 siRNA, in vivo diabetic retina model","pmids":["32150332"],"confidence":"Medium","gaps":["Whether GILZ recruits a specific E3 ligase to HIF-1α not established","Apparent contrast with HIF1α-induced GILZ expression"]},{"year":2022,"claim":"Defined the molecular basis of GILZ suppression of type I IFN, showing direct STAT1 binding that blocks STAT1 nuclear translocation and ISG induction.","evidence":"Co-IP with STAT1, nuclear translocation assays, GILZ overexpression/KO in human PBMC, ISG reporters","pmids":["35810690"],"confidence":"High","gaps":["STAT1-binding domain on GILZ not mapped","Effect on STAT2/STAT3 not addressed"]},{"year":2022,"claim":"Established a feedback antagonism whereby type I IFN suppresses GILZ via JAK1/Tyk2 by reducing GR occupancy at the GILZ locus.","evidence":"ChIP for GR at GILZ locus, JAK inhibitors, IFN treatment of human PBMCs, SLE patient correlation","pmids":["36505447"],"confidence":"Medium","gaps":["Mechanism by which JAK signaling displaces GR not defined"]},{"year":2023,"claim":"Identified an ISGylation-dependent RNA-binding control of TSC22D3 mRNA, where RBM47 ISGylation at K329 negatively regulates GILZ expression.","evidence":"K329R knockin mice, nanobody-targeted site-specific RBM47 ISGylation in human cells, mRNA quantification, injury/tumor models","pmids":["38036512"],"confidence":"Medium","gaps":["Whether RBM47 binds TSC22D3 mRNA directly not established","Mechanism of ISGylation-driven repression unclear"]},{"year":null,"claim":"A unifying structural and mechanistic account of how a single small leucine-zipper protein selects among its many binding partners (NF-κB, AP-1, Ras/Raf, STAT1, Smad2, MDM2, mTORC2, C/EBPs, HIF-1α) in a context-dependent manner remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-structure of GILZ with any partner","Determinants of partner selectivity across cell types unknown","Cytoplasmic-sequestration versus nuclear-DNA-binding switch not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3,5,19,21,25]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,21,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5,11,17,27]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[9,27]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,18,24,27,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,11,14,18,27]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,5,19,21]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,12,19,22]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,29,31]}],"complexes":["GILZ-TSC22D complex"],"partners":["RELA","JUN","FOS","RAF1","SMAD2","STAT1","MDM2","HIF1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99576","full_name":"TSC22 domain family protein 3","aliases":["DSIP-immunoreactive peptide","Protein DIP","hDIP","Delta sleep-inducing peptide immunoreactor","Glucocorticoid-induced leucine zipper protein","GILZ","TSC-22-like protein","TSC-22-related protein","TSC-22R"],"length_aa":134,"mass_kda":14.8,"function":"Protects T-cells from IL2 deprivation-induced apoptosis through the inhibition of FOXO3A transcriptional activity that leads to the down-regulation of the pro-apoptotic factor BCL2L11 (PubMed:15031210). In macrophages, plays a role in the anti-inflammatory and immunosuppressive effects of glucocorticoids and IL10 (PubMed:12393603). In T-cells, inhibits anti-CD3-induced NFKB1 nuclear translocation and thereby NFKB1 DNA-binding activities (PubMed:11468175). In vitro, suppresses AP-1 transcription factor complex DNA-binding activities (By similarity) Inhibits myogenic differentiation and mediates anti-myogenic effects of glucocorticoids by binding and regulating MYOD1 and HDAC1 transcriptional activity resulting in reduced expression of MYOG","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q99576/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TSC22D3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1207,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NRBP1","stoichiometry":0.2},{"gene":"PABPC4","stoichiometry":0.2},{"gene":"RNF40","stoichiometry":0.2},{"gene":"SLC7A6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TSC22D3","total_profiled":1310},"omim":[{"mim_id":"617476","title":"CNKSR FAMILY, MEMBER 3; CNKSR3","url":"https://www.omim.org/entry/617476"},{"mim_id":"615733","title":"rRNA METHYLTRANSFERASE AND RIBOSOME MATURATION FACTOR BUD23; BUD23","url":"https://www.omim.org/entry/615733"},{"mim_id":"612268","title":"TUBULIN TYROSINE LIGASE-LIKE 5; TTLL5","url":"https://www.omim.org/entry/612268"},{"mim_id":"611914","title":"TSC22 DOMAIN FAMILY, MEMBER 4; TSC22D4","url":"https://www.omim.org/entry/611914"},{"mim_id":"300506","title":"TSC22 DOMAIN FAMILY, MEMBER 3; TSC22D3","url":"https://www.omim.org/entry/300506"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TSC22D3"},"hgnc":{"alias_symbol":["DIP","GILZ","TSC-22R","hDIP"],"prev_symbol":["DSIPI"]},"alphafold":{"accession":"Q99576","domains":[{"cath_id":"1.20.58","chopping":"9-28_45-109","consensus_level":"high","plddt":82.2904,"start":9,"end":109}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99576","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99576-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99576-F1-predicted_aligned_error_v6.png","plddt_mean":71.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TSC22D3","jax_strain_url":"https://www.jax.org/strain/search?query=TSC22D3"},"sequence":{"accession":"Q99576","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99576.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99576/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99576"}},"corpus_meta":[{"pmid":"31501614","id":"PMC_31501614","title":"Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity.","date":"2019","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31501614","citation_count":295,"is_preprint":false},{"pmid":"19567371","id":"PMC_19567371","title":"Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action.","date":"2009","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/19567371","citation_count":267,"is_preprint":false},{"pmid":"11397794","id":"PMC_11397794","title":"Inhibition of AP-1 by the glucocorticoid-inducible protein GILZ.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11397794","citation_count":233,"is_preprint":false},{"pmid":"12393603","id":"PMC_12393603","title":"Synthesis of glucocorticoid-induced leucine zipper (GILZ) by macrophages: an anti-inflammatory and immunosuppressive mechanism shared by glucocorticoids and IL-10.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12393603","citation_count":226,"is_preprint":false},{"pmid":"22832853","id":"PMC_22832853","title":"Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder.","date":"2012","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/22832853","citation_count":145,"is_preprint":false},{"pmid":"17492054","id":"PMC_17492054","title":"GILZ mediates the antiproliferative activity of glucocorticoids by negative regulation of Ras signaling.","date":"2007","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/17492054","citation_count":134,"is_preprint":false},{"pmid":"16293609","id":"PMC_16293609","title":"GILZ expression in human dendritic cells redirects their maturation and prevents antigen-specific T lymphocyte response.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16293609","citation_count":128,"is_preprint":false},{"pmid":"15031210","id":"PMC_15031210","title":"GILZ, a new target for the transcription factor FoxO3, protects T lymphocytes from interleukin-2 withdrawal-induced apoptosis.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15031210","citation_count":121,"is_preprint":false},{"pmid":"18084007","id":"PMC_18084007","title":"Regulation of mesenchymal stem cell osteogenic differentiation by glucocorticoid-induced leucine zipper (GILZ).","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18084007","citation_count":115,"is_preprint":false},{"pmid":"12671681","id":"PMC_12671681","title":"A glucocorticoid-induced leucine-zipper protein, GILZ, inhibits adipogenesis of mesenchymal cells.","date":"2003","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/12671681","citation_count":109,"is_preprint":false},{"pmid":"24703841","id":"PMC_24703841","title":"GILZ promotes production of peripherally induced Treg cells and mediates the crosstalk between glucocorticoids and TGF-β signaling.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24703841","citation_count":108,"is_preprint":false},{"pmid":"17169985","id":"PMC_17169985","title":"Glucocorticoid-induced leucine zipper (GILZ)/NF-kappaB interaction: role of GILZ homo-dimerization and C-terminal domain.","date":"2006","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/17169985","citation_count":107,"is_preprint":false},{"pmid":"26617572","id":"PMC_26617572","title":"GILZ as a Mediator of the Anti-Inflammatory Effects of Glucocorticoids.","date":"2015","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/26617572","citation_count":106,"is_preprint":false},{"pmid":"21556028","id":"PMC_21556028","title":"Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid arthritis.","date":"2011","source":"Nature reviews. Rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/21556028","citation_count":102,"is_preprint":false},{"pmid":"15319285","id":"PMC_15319285","title":"Decrease of Bcl-xL and augmentation of thymocyte apoptosis in GILZ overexpressing transgenic mice.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15319285","citation_count":89,"is_preprint":false},{"pmid":"16720863","id":"PMC_16720863","title":"Disinhibitory pathways for control of sodium transport: regulation of ENaC by SGK1 and GILZ.","date":"2006","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16720863","citation_count":82,"is_preprint":false},{"pmid":"12707381","id":"PMC_12707381","title":"Mineralocorticoid effects in the kidney: correlation between alphaENaC, GILZ, and Sgk-1 mRNA expression and urinary excretion of Na+ and K+.","date":"2003","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/12707381","citation_count":79,"is_preprint":false},{"pmid":"16204313","id":"PMC_16204313","title":"Increased GILZ expression in transgenic mice up-regulates Th-2 lymphokines.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16204313","citation_count":76,"is_preprint":false},{"pmid":"22110132","id":"PMC_22110132","title":"Long glucocorticoid-induced leucine zipper (L-GILZ) protein interacts with ras protein pathway and contributes to spermatogenesis control.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22110132","citation_count":71,"is_preprint":false},{"pmid":"20124407","id":"PMC_20124407","title":"Glucocorticoid-induced leucine zipper (GILZ) and long GILZ inhibit myogenic differentiation and mediate anti-myogenic effects of glucocorticoids.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20124407","citation_count":56,"is_preprint":false},{"pmid":"17910039","id":"PMC_17910039","title":"Glucocorticoid-induced leucine zipper (GILZ) mediates glucocorticoid action and inhibits inflammatory cytokine-induced COX-2 expression.","date":"2008","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17910039","citation_count":56,"is_preprint":false},{"pmid":"23495141","id":"PMC_23495141","title":"LPS resistance of SPRET/Ei mice is mediated by Gilz, encoded by the Tsc22d3 gene on the X chromosome.","date":"2013","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23495141","citation_count":55,"is_preprint":false},{"pmid":"23729444","id":"PMC_23729444","title":"GILZ overexpression inhibits endothelial cell adhesive function through regulation of NF-κB and MAPK activity.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23729444","citation_count":52,"is_preprint":false},{"pmid":"31440237","id":"PMC_31440237","title":"Implicating the Role of GILZ in Glucocorticoid Modulation of T-Cell Activation.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31440237","citation_count":50,"is_preprint":false},{"pmid":"24747114","id":"PMC_24747114","title":"Downregulation of the glucocorticoid-induced leucine zipper (GILZ) promotes vascular inflammation.","date":"2014","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/24747114","citation_count":50,"is_preprint":false},{"pmid":"26276664","id":"PMC_26276664","title":"Lack of glucocorticoid-induced leucine zipper (GILZ) deregulates B-cell survival and results in B-cell lymphocytosis in mice.","date":"2015","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/26276664","citation_count":47,"is_preprint":false},{"pmid":"26077873","id":"PMC_26077873","title":"GILZ regulates Th17 responses and restrains IL-17-mediated skin inflammation.","date":"2015","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/26077873","citation_count":46,"is_preprint":false},{"pmid":"27629417","id":"PMC_27629417","title":"Induction of Glucocorticoid-induced Leucine Zipper (GILZ) Contributes to Anti-inflammatory Effects of the Natural Product Curcumin in Macrophages.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27629417","citation_count":43,"is_preprint":false},{"pmid":"22125095","id":"PMC_22125095","title":"Glucocorticoid-induced leucine zipper (GILZ) over-expression in T lymphocytes inhibits inflammation and tissue damage in spinal cord injury.","date":"2012","source":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/22125095","citation_count":40,"is_preprint":false},{"pmid":"30371949","id":"PMC_30371949","title":"GILZ restrains neutrophil activation by inhibiting the MAPK pathway.","date":"2018","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/30371949","citation_count":39,"is_preprint":false},{"pmid":"21804606","id":"PMC_21804606","title":"GILZ inhibits the mTORC2/AKT pathway in BCR-ABL(+) cells.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21804606","citation_count":39,"is_preprint":false},{"pmid":"23183181","id":"PMC_23183181","title":"Estradiol antagonism of glucocorticoid-induced GILZ expression in human uterine epithelial cells and murine uterus.","date":"2012","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23183181","citation_count":39,"is_preprint":false},{"pmid":"22556341","id":"PMC_22556341","title":"The glucocorticoid-induced leucine zipper (gilz/Tsc22d3-2) gene locus plays a crucial role in male fertility.","date":"2012","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/22556341","citation_count":38,"is_preprint":false},{"pmid":"25100999","id":"PMC_25100999","title":"Development of novel treatment strategies for inflammatory diseases-similarities and divergence between glucocorticoids and GILZ.","date":"2014","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25100999","citation_count":38,"is_preprint":false},{"pmid":"26639395","id":"PMC_26639395","title":"Decreased expression of the glucocorticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice.","date":"2015","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/26639395","citation_count":38,"is_preprint":false},{"pmid":"16714216","id":"PMC_16714216","title":"Inhibited cell death, NF-kappaB activity and increased IL-10 in TCR-triggered thymocytes of transgenic mice overexpressing the glucocorticoid-induced protein GILZ.","date":"2006","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16714216","citation_count":38,"is_preprint":false},{"pmid":"26612340","id":"PMC_26612340","title":"Glucocorticoid-induced leucine zipper (GILZ) inhibits B cell activation in systemic lupus erythematosus.","date":"2015","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26612340","citation_count":34,"is_preprint":false},{"pmid":"18499442","id":"PMC_18499442","title":"Dual regulation of glucocorticoid-induced leucine zipper (GILZ) by the glucocorticoid receptor and the PI3-kinase/AKT pathways in multiple myeloma.","date":"2008","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18499442","citation_count":34,"is_preprint":false},{"pmid":"30126904","id":"PMC_30126904","title":"GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance.","date":"2018","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/30126904","citation_count":33,"is_preprint":false},{"pmid":"20018851","id":"PMC_20018851","title":"Glucocorticoid-induced leucine zipper (GILZ) promotes the nuclear exclusion of FOXO3 in a Crm1-dependent manner.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20018851","citation_count":33,"is_preprint":false},{"pmid":"35011684","id":"PMC_35011684","title":"GILZ as a Regulator of Cell Fate and Inflammation.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35011684","citation_count":32,"is_preprint":false},{"pmid":"23516608","id":"PMC_23516608","title":"Glucocorticoid-induced leucine zipper (GILZ) regulates testicular FOXO1 activity and spermatogonial stem cell (SSC) function.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23516608","citation_count":32,"is_preprint":false},{"pmid":"22369971","id":"PMC_22369971","title":"Targeting the side effects of steroid therapy in autoimmune diseases: the role of GILZ.","date":"2012","source":"Discovery medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22369971","citation_count":32,"is_preprint":false},{"pmid":"30723476","id":"PMC_30723476","title":"Amplified Host Defense by Toll-Like Receptor-Mediated Downregulation of the Glucocorticoid-Induced Leucine Zipper (GILZ) in Macrophages.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30723476","citation_count":31,"is_preprint":false},{"pmid":"23573276","id":"PMC_23573276","title":"Dexamethasone inhibits repair of human airway epithelial cells mediated by glucocorticoid-induced leucine zipper (GILZ).","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23573276","citation_count":31,"is_preprint":false},{"pmid":"25168242","id":"PMC_25168242","title":"L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells.","date":"2014","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/25168242","citation_count":30,"is_preprint":false},{"pmid":"19875485","id":"PMC_19875485","title":"The glucocorticoid-induced leucine zipper gene (GILZ) expression decreases after successful treatment of patients with endogenous Cushing's syndrome and may play a role in glucocorticoid-induced osteoporosis.","date":"2009","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/19875485","citation_count":30,"is_preprint":false},{"pmid":"21907305","id":"PMC_21907305","title":"Medaka osmotic stress transcription factor 1b (Ostf1b/TSC22D3-2) triggers hyperosmotic responses of different ion transporters in medaka gill and human embryonic kidney cells via the JNK signalling pathway.","date":"2011","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21907305","citation_count":28,"is_preprint":false},{"pmid":"24931768","id":"PMC_24931768","title":"GILZ: Glitzing up our understanding of the glucocorticoid receptor in psychopathology.","date":"2014","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/24931768","citation_count":27,"is_preprint":false},{"pmid":"23440419","id":"PMC_23440419","title":"DC-SCRIPT regulates glucocorticoid receptor function and expression of its target GILZ in dendritic cells.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23440419","citation_count":27,"is_preprint":false},{"pmid":"24860090","id":"PMC_24860090","title":"Role of glucocorticoid-induced leucine zipper (GILZ) in bone acquisition.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24860090","citation_count":26,"is_preprint":false},{"pmid":"26056061","id":"PMC_26056061","title":"Quantitative tissue-specific dynamics of in vivo GILZ mRNA expression and regulation by endogenous and exogenous glucocorticoids.","date":"2015","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/26056061","citation_count":26,"is_preprint":false},{"pmid":"15336700","id":"PMC_15336700","title":"Cell type-specific bidirectional regulation of the glucocorticoid-induced leucine zipper (GILZ) gene by estrogen.","date":"2004","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15336700","citation_count":25,"is_preprint":false},{"pmid":"24215840","id":"PMC_24215840","title":"Activation of GILZ gene by photoactivated 8-methoxypsoralen: potential role of immunoregulatory dendritic cells in extracorporeal photochemotherapy.","date":"2013","source":"Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis","url":"https://pubmed.ncbi.nlm.nih.gov/24215840","citation_count":25,"is_preprint":false},{"pmid":"27465291","id":"PMC_27465291","title":"Melanoma dormancy in a mouse model is linked to GILZ/FOXO3A-dependent quiescence of disseminated stem-like cells.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27465291","citation_count":25,"is_preprint":false},{"pmid":"30124596","id":"PMC_30124596","title":"Overexpression of Gilz Protects Mice Against Lethal Septic Peritonitis.","date":"2019","source":"Shock (Augusta, Ga.)","url":"https://pubmed.ncbi.nlm.nih.gov/30124596","citation_count":23,"is_preprint":false},{"pmid":"26498359","id":"PMC_26498359","title":"Glucocorticoid-induced leucine zipper (GILZ) in immuno suppression: master regulator or bystander?","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26498359","citation_count":23,"is_preprint":false},{"pmid":"22396737","id":"PMC_22396737","title":"Glucocorticoid-induced leucine zipper (GILZ) antagonizes TNF-α inhibition of mesenchymal stem cell osteogenic differentiation.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22396737","citation_count":23,"is_preprint":false},{"pmid":"17574218","id":"PMC_17574218","title":"Localization of glucocorticoid-induced leucine zipper (GILZ) expressing neurons in the central nervous system and its relationship to the stress response.","date":"2007","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/17574218","citation_count":23,"is_preprint":false},{"pmid":"22571926","id":"PMC_22571926","title":"The Glucocorticoid-induced leucine zipper (GILZ) Is essential for spermatogonial survival and spermatogenesis.","date":"2012","source":"Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/22571926","citation_count":23,"is_preprint":false},{"pmid":"30522007","id":"PMC_30522007","title":"Temporal dynamics of cortisol-associated changes in mRNA expression of glucocorticoid responsive genes FKBP5, GILZ, SDPR, PER1, PER2 and PER3 in healthy humans.","date":"2018","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30522007","citation_count":22,"is_preprint":false},{"pmid":"31840802","id":"PMC_31840802","title":"Overexpression of GILZ in macrophages limits systemic inflammation while increasing bacterial clearance in sepsis in mice.","date":"2020","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31840802","citation_count":22,"is_preprint":false},{"pmid":"31572404","id":"PMC_31572404","title":"Glucocorticoids and Glucocorticoid-Induced-Leucine-Zipper (GILZ) in Psoriasis.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31572404","citation_count":20,"is_preprint":false},{"pmid":"31379872","id":"PMC_31379872","title":"Could GILZ Be the Answer to Glucocorticoid Toxicity in Lupus?","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31379872","citation_count":20,"is_preprint":false},{"pmid":"32150332","id":"PMC_32150332","title":"Glucocorticoid-transactivated TSC22D3 attenuates hypoxia- and diabetes-induced Müller glial galectin-1 expression via HIF-1α destabilization.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32150332","citation_count":19,"is_preprint":false},{"pmid":"8982256","id":"PMC_8982256","title":"hDIP--a potential transcriptional regulator related to murine TSC-22 and Drosophila shortsighted (shs)--is expressed in a large number of human tissues.","date":"1996","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8982256","citation_count":19,"is_preprint":false},{"pmid":"31055798","id":"PMC_31055798","title":"Cholesterol Starvation and Hypoxia Activate the FVII Gene via the SREBP1-GILZ Pathway in Ovarian Cancer Cells to Produce Procoagulant Microvesicles.","date":"2019","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/31055798","citation_count":18,"is_preprint":false},{"pmid":"20671745","id":"PMC_20671745","title":"Glucocorticoid-induced activation of caspase-8 protects the glucocorticoid-induced protein Gilz from proteasomal degradation and induces its binding to SUMO-1 in murine thymocytes.","date":"2010","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/20671745","citation_count":18,"is_preprint":false},{"pmid":"17383627","id":"PMC_17383627","title":"Notch signaling links interactions between the C/EBP homolog slow border cells and the GILZ homolog bunched during cell migration.","date":"2007","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17383627","citation_count":17,"is_preprint":false},{"pmid":"23665588","id":"PMC_23665588","title":"Zebrafish transforming growth factor-β-stimulated clone 22 domain 3 (TSC22D3) plays critical roles in Bmp-dependent dorsoventral patterning via two deubiquitylating enzymes Usp15 and Otud4.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23665588","citation_count":16,"is_preprint":false},{"pmid":"27934944","id":"PMC_27934944","title":"Overexpression of Glucocorticoid-induced Leucine Zipper (GILZ) increases susceptibility to Imiquimod-induced psoriasis and involves cutaneous activation of TGF-β1.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27934944","citation_count":16,"is_preprint":false},{"pmid":"35810690","id":"PMC_35810690","title":"GILZ regulates type I interferon release and sequesters STAT1.","date":"2022","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/35810690","citation_count":15,"is_preprint":false},{"pmid":"27178044","id":"PMC_27178044","title":"Low expression of the GILZ may contribute to adipose inflammation and altered adipokine production in human obesity.","date":"2016","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/27178044","citation_count":15,"is_preprint":false},{"pmid":"36768553","id":"PMC_36768553","title":"Association of GILZ with MUC2, TLR2, and TLR4 in Inflammatory Bowel Disease.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36768553","citation_count":14,"is_preprint":false},{"pmid":"29344311","id":"PMC_29344311","title":"Gilz-Activin A as a Novel Signaling Axis Orchestrating Mesenchymal Stem Cell and Th17 Cell Interplay.","date":"2018","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/29344311","citation_count":14,"is_preprint":false},{"pmid":"24993177","id":"PMC_24993177","title":"Recombinant long-glucocorticoid-induced leucine zipper (L-GILZ) protein restores the control of proliferation in gilz KO spermatogonia.","date":"2014","source":"European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24993177","citation_count":14,"is_preprint":false},{"pmid":"27416758","id":"PMC_27416758","title":"GILZ overexpression attenuates endoplasmic reticulum stress-mediated cell death via the activation of mitochondrial oxidative phosphorylation.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27416758","citation_count":14,"is_preprint":false},{"pmid":"31197018","id":"PMC_31197018","title":"Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part III: Estrous Cycle and Estrogen Receptor-Dependent Antagonism of Glucocorticoid-Induced Leucine Zipper (GILZ) Enhancement by Corticosteroids.","date":"2019","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31197018","citation_count":14,"is_preprint":false},{"pmid":"25146427","id":"PMC_25146427","title":"Glucocorticoid-induced leucine zipper (GILZ) controls inflammation and tissue damage after spinal cord injury.","date":"2014","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/25146427","citation_count":14,"is_preprint":false},{"pmid":"29146236","id":"PMC_29146236","title":"Infectious bursal disease virus protein VP4 suppresses type I interferon expression via inhibiting K48-linked ubiquitylation of glucocorticoid-induced leucine zipper (GILZ).","date":"2017","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29146236","citation_count":14,"is_preprint":false},{"pmid":"26697291","id":"PMC_26697291","title":"A focused Real Time PCR strategy to determine GILZ expression in mouse tissues.","date":"2015","source":"Results in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26697291","citation_count":13,"is_preprint":false},{"pmid":"31001916","id":"PMC_31001916","title":"The testicular soma of Tsc22d3 knockout mice supports spermatogenesis and germline transmission from spermatogonial stem cell lines upon transplantation.","date":"2019","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/31001916","citation_count":13,"is_preprint":false},{"pmid":"27716396","id":"PMC_27716396","title":"Glucocorticoid-induced leucine zipper (GILZ) is involved in glucocorticoid-induced and mineralocorticoid-induced leptin production by osteoarthritis synovial fibroblasts.","date":"2016","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/27716396","citation_count":13,"is_preprint":false},{"pmid":"18073156","id":"PMC_18073156","title":"IL-2 induces and altered CD4/CD8 ratio of splenic T lymphocytes from transgenic mice overexpressing the glucocorticoid-induced protein GILZ.","date":"2007","source":"Journal of chemotherapy (Florence, Italy)","url":"https://pubmed.ncbi.nlm.nih.gov/18073156","citation_count":13,"is_preprint":false},{"pmid":"20701225","id":"PMC_20701225","title":"[GILZ (glucocorticoid-induced leucine zipper), a mediator of the anti-inflammatory and immunosuppressive activity of glucocorticoids].","date":"2010","source":"Annali di igiene : medicina preventiva e di comunita","url":"https://pubmed.ncbi.nlm.nih.gov/20701225","citation_count":13,"is_preprint":false},{"pmid":"36505447","id":"PMC_36505447","title":"Type 1 interferon suppresses expression and glucocorticoid induction of glucocorticoid-induced leucine zipper (GILZ).","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36505447","citation_count":12,"is_preprint":false},{"pmid":"22977521","id":"PMC_22977521","title":"High TSC22D3 and low GBP1 expression in the liver is a risk factor for early recurrence of hepatocellular carcinoma.","date":"2011","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22977521","citation_count":11,"is_preprint":false},{"pmid":"33889157","id":"PMC_33889157","title":"GILZ Regulates the Expression of Pro-Inflammatory Cytokines and Protects Against End-Organ Damage in a Model of Lupus.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33889157","citation_count":11,"is_preprint":false},{"pmid":"23090754","id":"PMC_23090754","title":"Expression of glucocorticoid-induced leucine zipper (GILZ) in cardiomyocytes.","date":"2013","source":"Cardiovascular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/23090754","citation_count":11,"is_preprint":false},{"pmid":"18309369","id":"PMC_18309369","title":"Energy Balance, Myostatin, and GILZ: Factors Regulating Adipocyte Differentiation in Belly and Bone.","date":"2007","source":"PPAR research","url":"https://pubmed.ncbi.nlm.nih.gov/18309369","citation_count":11,"is_preprint":false},{"pmid":"27807817","id":"PMC_27807817","title":"Neutrophil expression of glucocorticoid-induced leucine zipper (GILZ) anti-inflammatory protein is associated with acute respiratory distress syndrome severity.","date":"2016","source":"Annals of intensive care","url":"https://pubmed.ncbi.nlm.nih.gov/27807817","citation_count":11,"is_preprint":false},{"pmid":"36081527","id":"PMC_36081527","title":"SOCS3 Attenuates Dexamethasone-Induced M2 Polarization by Down-Regulation of GILZ via ROS- and p38 MAPK-Dependent Pathways.","date":"2022","source":"Immune network","url":"https://pubmed.ncbi.nlm.nih.gov/36081527","citation_count":11,"is_preprint":false},{"pmid":"28771604","id":"PMC_28771604","title":"Role of glucocorticoid-induced leucine zipper (GILZ) in inflammatory bone loss.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28771604","citation_count":11,"is_preprint":false},{"pmid":"28259749","id":"PMC_28259749","title":"Metabolic rewiring in cancer cells overexpressing the glucocorticoid-induced leucine zipper protein (GILZ): Activation of mitochondrial oxidative phosphorylation and sensitization to oxidative cell death induced by mitochondrial targeted drugs.","date":"2017","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28259749","citation_count":11,"is_preprint":false},{"pmid":"28499885","id":"PMC_28499885","title":"The role of GILZ in modulation of adaptive immunity in a murine model of myocardial infarction.","date":"2017","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28499885","citation_count":10,"is_preprint":false},{"pmid":"20970683","id":"PMC_20970683","title":"Role of glucocorticoid-induced leucine zipper (GILZ) expression by dendritic cells in tolerance induction.","date":"2010","source":"Transplantation proceedings","url":"https://pubmed.ncbi.nlm.nih.gov/20970683","citation_count":10,"is_preprint":false},{"pmid":"29278648","id":"PMC_29278648","title":"Clock represses preadipocytes adipogenesis via GILZ.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29278648","citation_count":9,"is_preprint":false},{"pmid":"28638383","id":"PMC_28638383","title":"Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response.","date":"2017","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28638383","citation_count":9,"is_preprint":false},{"pmid":"38036512","id":"PMC_38036512","title":"Dynamic RBM47 ISGylation confers broad immunoprotection against lung injury and tumorigenesis via TSC22D3 downregulation.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38036512","citation_count":8,"is_preprint":false},{"pmid":"22792400","id":"PMC_22792400","title":"Yersinia enterocolitica YopT and Clostridium difficile toxin B induce expression of GILZ in epithelial cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22792400","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50552,"output_tokens":9510,"usd":0.147153,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19803,"output_tokens":9288,"usd":0.165607,"stage2_stop_reason":"end_turn"},"total_usd":0.31276,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"GILZ directly interacts with c-Fos and c-Jun in vitro through its N-terminal 60-amino acid region, inhibiting AP-1 DNA binding; homodimerization of GILZ requires the leucine zipper domain. GILZ expression in Jurkat T cells blocks AP-1-driven, IL-2 promoter-driven, and FasL promoter-driven reporter constructs, and inhibits Egr-2/Egr-3-mediated FasL induction.\",\n      \"method\": \"Recombinant protein in vitro interaction assays, transient transfection reporter assays, domain-deletion mutants, anti-CD3-stimulated normal T cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, domain mutagenesis, and reporter assays in multiple cell types; replicated/extended in subsequent work\",\n      \"pmids\": [\"11397794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In THP-1 macrophage-like cells treated with glucocorticoids or IL-10, GILZ associates with the p65 subunit of NF-κB, and GILZ transfection inhibits NF-κB function and suppresses expression of CD80, CD86, CCL5, CCL3, and TLR2.\",\n      \"method\": \"Co-immunoprecipitation in THP-1 cells, transfection of GILZ gene, flow cytometry, RT-PCR\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP in cell line, multiple functional readouts, single lab\",\n      \"pmids\": [\"12393603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"FoxO3 binding to Forkhead-responsive elements in the GILZ promoter is necessary for induction of GILZ expression upon IL-2 withdrawal. GILZ overexpression protects T cells from IL-2 withdrawal-induced apoptosis and inhibits Bim expression, while GILZ silencing accelerates cell death and enhances Bim. GILZ also inhibits FoxO3 transcriptional activity, creating a negative feedback loop.\",\n      \"method\": \"GILZ promoter characterization, FHRE mutagenesis, GILZ overexpression and siRNA knockdown in CTLL-2 cells, apoptosis assays, Western blot for Bim\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — promoter mutagenesis establishing FoxO3 binding site, combined with gain/loss-of-function and defined molecular phenotype (Bim regulation)\",\n      \"pmids\": [\"15031210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"GILZ binds directly to tandem CCAAT/enhancer-binding protein (C/EBP) binding sites in the PPARγ2 promoter and acts as a sequence-specific transcriptional repressor, inhibiting PPARγ2 transcription and blocking glucocorticoid-induced adipocyte differentiation.\",\n      \"method\": \"Promoter binding assays, ectopic GILZ expression in mesenchymal cells, adipogenic differentiation assays, marker gene expression analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct promoter binding established, gain-of-function with defined molecular and cellular phenotype\",\n      \"pmids\": [\"12671681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GILZ interacts directly with Ras in vitro and in vivo (co-immunoprecipitation and colocalization in primary T cells); interaction is mediated through the TSC box domain. GILZ forms a trimeric complex with Ras and Raf. These interactions reduce ERK1/2, AKT/PKB phosphorylation, Rb phosphorylation, and cyclin D1 expression, inhibiting Ras/Raf-dependent proliferation and NIH-3T3 transformation. GILZ silencing abrogates dexamethasone antiproliferative effects.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation, colocalization imaging, GILZ domain mutants, siRNA knockdown, cell proliferation/transformation assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution combined with co-IP in primary cells, domain mutant analysis, and loss-of-function phenotype\",\n      \"pmids\": [\"17492054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GILZ homo-dimerization via the leucine zipper domain and the C-terminal PER domain (particularly residues 121–123) are both required for GILZ/p65 NF-κB interaction and inhibition of NF-κB transcriptional activity and IL-2 synthesis, as shown by in vitro and in vivo co-immunoprecipitation with multiple GILZ mutants.\",\n      \"method\": \"In vitro and in vivo co-immunoprecipitation, GILZ domain deletion/point mutants, NF-κB transcriptional reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain mutagenesis combined with co-IP and functional reporter assays in a single rigorous study\",\n      \"pmids\": [\"17169985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GILZ and its isoform L-GILZ are expressed in skeletal muscle and C2C12 myoblasts; GILZ/L-GILZ overexpression inhibits myotube formation and reduces MyoD function and myogenin expression by binding and regulating MyoD/HDAC1 transcriptional activity. GILZ/L-GILZ silencing dampens glucocorticoid anti-myogenic effects.\",\n      \"method\": \"C2C12 myoblast differentiation assays, GILZ/L-GILZ overexpression and siRNA knockdown, co-immunoprecipitation of GILZ with MyoD/HDAC1, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying binding partner plus gain/loss-of-function with functional phenotype; single lab\",\n      \"pmids\": [\"20124407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GILZ overexpression in mouse mesenchymal stem cells increases alkaline phosphatase activity, mineralized nodule formation, and expression of Runx2/Cbfa1, alkaline phosphatase, type I collagen, and osteocalcin, while reducing PPARγ2 and C/EBPα. Gilz knockdown reduces MSC osteogenic differentiation capacity, indicating GILZ shifts MSC commitment from adipogenic to osteogenic.\",\n      \"method\": \"GILZ overexpression and siRNA knockdown in mouse MSCs, alkaline phosphatase activity assay, mineralized nodule formation, RT-PCR for lineage markers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss-of-function with multiple differentiation markers; single lab\",\n      \"pmids\": [\"18084007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GILZ inhibits inflammatory cytokine (TNF-α and IL-1β)-induced COX-2 mRNA and protein expression in bone marrow mesenchymal stem cells by blocking NF-κB nuclear translocation and NF-κB-mediated COX-2 promoter activity. Knockdown of GILZ by shRNA reduces glucocorticoid inhibition of cytokine-induced COX-2.\",\n      \"method\": \"Retroviral GILZ overexpression, shRNA knockdown, COX-2 reporter assay, NF-κB nuclear translocation (fractionation/immunofluorescence), RT-PCR, Western blot\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with mechanistic pathway readout (NF-κB translocation), single lab\",\n      \"pmids\": [\"17910039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GILZ promotes nuclear exclusion of FOXO3 in a Crm1-dependent manner: GILZ expression (exclusively cytoplasmic) causes FOXO3 to relocalize from nucleus to cytoplasm, suppressing FOXO1/3/4 transcriptional activity and downregulating FOXO targets p27KIP1 and Bim. GILZ does not physically interact with FOXO3 and does not hinder FOXO3 DNA-binding directly.\",\n      \"method\": \"Fluorescence microscopy, Crm1 inhibitor (leptomycin B) treatment, FOXO-responsive reporter assays in HL-60 and CTLL-2 cells, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging of localization tied to functional consequence, multiple cell lines, negative interaction result mechanistically informative; single lab\",\n      \"pmids\": [\"20018851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Glucocorticoid-induced caspase-8 activation protects GILZ from proteasomal degradation and induces GILZ binding to SUMO-1; GILZ contains a SUMO-binding site, binds the SUMO E2-conjugating enzyme Ubc9 in vitro and in vivo, and co-immunoprecipitates with SUMO-1 in a caspase-8-dependent manner in thymocytes.\",\n      \"method\": \"In vitro binding assays (GILZ–Ubc9, GILZ–SUMO-1), co-immunoprecipitation, caspase-8 inhibition, proteasome inhibition, caspase-8-deficient thymocytes\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding plus in vivo co-IP, proteasome inhibitor corroboration; single lab\",\n      \"pmids\": [\"20671745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"GILZ binds to and inhibits mTORC2 (but not mTORC1) in mouse and human BCR-ABL+ cells, suppressing Ser473-AKT phosphorylation and activating FoxO3a-mediated Bim transcription, thereby inducing apoptosis and reducing imatinib/dasatinib resistance.\",\n      \"method\": \"Co-immunoprecipitation of GILZ with mTORC2 components, AKT phosphorylation (Western blot), FoxO3a reporter assays, apoptosis assays, CD34+ CML stem cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP distinguishing mTORC1 vs mTORC2, multiple functional readouts; single lab\",\n      \"pmids\": [\"21804606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"L-GILZ (long isoform of GILZ) is highly expressed in spermatogonia and primary spermatocytes; Gilz knockout mice develop complete loss of germ cells and male sterility. GILZ deficiency leads to increased ERK and Akt phosphorylation (Ras pathway hyperactivation) and aberrant spermatogonial differentiation.\",\n      \"method\": \"Gilz knockout mice, immunohistochemistry, Western blot for ERK/Akt phosphorylation, apoptosis assays, spermatogenesis phenotyping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive KO with clear cellular and molecular phenotype, replicated by multiple independent KO papers\",\n      \"pmids\": [\"22110132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Estradiol (E2) antagonizes glucocorticoid-induced GILZ gene expression through the estrogen receptor (ERα and ERβ): both GR and ERα are recruited to GRE-containing regions of the GILZ promoter, and E2 treatment decreases GR binding there. ER antagonist ICI 182,780 and ERα siRNA block E2-mediated GILZ repression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for GR and ERα at GILZ promoter, siRNA knockdown of ERα, ER antagonist treatment, nascent RNA assay, in vivo mouse uterus model\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP establishing promoter occupancy, multiple genetic and pharmacological interventions in vitro and in vivo; single lab\",\n      \"pmids\": [\"23183181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GILZ overexpression in HUVECs inhibits TNF-induced NF-κB p65 DNA binding (without affecting p65 nuclear translocation), and suppresses p38, ERK, and JNK MAPK activation while increasing MKP-1. This reduces leukocyte rolling, adhesion, and transmigration, and decreases E-selectin, ICAM-1, CCL2, CXCL8, and IL-6.\",\n      \"method\": \"Transient transfection of GILZ in HUVECs, NF-κB reporter/DNA binding assays, p65 nuclear translocation imaging, MAPK phosphorylation (Western blot), leukocyte adhesion assays, MKP-1 quantification\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal readouts distinguishing p65 translocation from DNA binding; single lab, transfection system\",\n      \"pmids\": [\"23729444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DC-SCRIPT coexists with GR in protein complexes and functions as a corepressor of GR-mediated transcription; DC-SCRIPT knockdown enhances GR-dependent upregulation of GILZ mRNA in dendritic cells.\",\n      \"method\": \"Co-immunoprecipitation of DC-SCRIPT with GR, DC-SCRIPT knockdown (siRNA), GILZ mRNA quantification in monocyte-derived DCs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying complex, loss-of-function confirming functional relevance; single lab\",\n      \"pmids\": [\"23440419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GILZ inhibits dexamethasone-suppressed airway epithelial repair by suppressing Raf-1, MEK1/2, and ERK1/2 phosphorylation (MAPK-ERK pathway), thereby inhibiting proliferation and migration. Silencing GILZ with siRNA reverses DEX-mediated inhibition of these pathway components and restores cell repair.\",\n      \"method\": \"siRNA knockdown, Western blot for pRaf/pMEK/pERK, wound-healing/migration assays, MTT proliferation assay, CFSE labeling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with defined pathway and phenotypic readout; single lab\",\n      \"pmids\": [\"23573276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"L-GILZ (long isoform) binds preferentially to MDM2 (in the presence of both p53 and MDM2) and interferes with p53/MDM2 complex formation, stabilizing p53 by decreasing its ubiquitination and increasing MDM2 ubiquitination, leading to p21 and PUMA induction and tumor growth suppression.\",\n      \"method\": \"Co-immunoprecipitation of L-GILZ with p53 and MDM2, ubiquitination assays, p53-proficient vs -deficient cell lines, xenograft tumor growth, siRNA knockdown of L-GILZ\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-IP, ubiquitination assay, isogenic p53+/+ vs p53-/- cells establishing pathway dependence, in vivo xenograft; single lab\",\n      \"pmids\": [\"25168242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GILZ promotes TGF-β signaling by binding to Smad2 and promoting its phosphorylation, thereby activating FoxP3 expression and enabling GCs to cooperate with TGF-β in peripheral regulatory T cell (pTreg) generation. GILZ-deficient mice show impaired pTreg generation and increased intestinal inflammation.\",\n      \"method\": \"GILZ overexpression transgenic mice, Gilz knockout mice, co-immunoprecipitation of GILZ with Smad2, Smad2 phosphorylation assay, FoxP3 reporter, intestinal inflammation model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — co-IP with Smad2, phosphorylation assay, combined gain (transgenic) and loss (KO) of function, in vivo model; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24703841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GILZ physically interacts with C/EBPs and disrupts C/EBP-mediated PPARγ gene transcription, enhancing osteogenic while suppressing adipogenic differentiation. Transgenic mice expressing GILZ under a collagen promoter show increased bone mass, bone formation rate, and osteoblast numbers.\",\n      \"method\": \"Co-immunoprecipitation of GILZ with C/EBPs, PPARγ promoter reporter assays, transgenic mice, bone histomorphometry, MSC differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus promoter assay plus in vivo transgenic phenotype; single lab\",\n      \"pmids\": [\"24860090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Curcumin induces GILZ protein expression post-transcriptionally via HuR: HuR binds GILZ mRNA (confirmed by RNA immunoprecipitation), and HuR overexpression increases GILZ protein but not mRNA. GILZ induction by curcumin mediates its anti-inflammatory effects (NF-κB/ERK inhibition, TNF-α reduction) in macrophages, as shown in GILZ KO macrophages.\",\n      \"method\": \"RNA immunoprecipitation (RIP) of HuR–GILZ mRNA, HuR overexpression, GILZ KO bone marrow-derived macrophages, NF-κB/ERK activity assays, TNF-α ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP establishing direct RNA–protein interaction, KO macrophage validation, multiple readouts; single lab\",\n      \"pmids\": [\"27629417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In immunoregulatory MSC (primed with IFN-γ and TNF-α), GILZ translocates to the nucleus and binds the promoters of iNOS and Activin βA to induce their expression. Activin A produced downstream of GILZ directly represses Th17 cell differentiation via Smad3/2 activation.\",\n      \"method\": \"ChIP of GILZ at iNOS and Activin βA promoters, nuclear translocation imaging, Activin A ELISA, Smad2/3 phosphorylation, adoptive transfer experiments\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing promoter binding with functional consequence, localization experiment; single lab\",\n      \"pmids\": [\"29344311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GILZ deletion in adults causes exhaustion of GFRα1+ spermatogonial stem cells and germline degeneration associated with mTORC1 activation and reduced USP9X (a deubiquitylase required for spermatogenesis). mTOR inhibitor treatment rescues GFRα1+ spermatogonial failure. GILZ interacts with TSC22D family proteins (forming GILZ-TSC22D complexes) and controls ERK MAPK upstream of mTORC1.\",\n      \"method\": \"Adult conditional Gilz knockout, mTOR inhibitor rescue, USP9X expression analysis, co-immunoprecipitation of GILZ with TSC22D proteins, ERK phosphorylation analysis in cultured spermatogonia\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with pharmacological rescue establishing pathway, co-IP identifying complex, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"30126904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GILZ restrains neutrophil activation by reducing ERK and p38 MAPK phosphorylation as well as NOX2 and p47phox activation; GILZ-KO neutrophils show enhanced phagocytosis, oxidative burst, and bacterial killing.\",\n      \"method\": \"GILZ-KO neutrophils, Candida albicans infection model, DNBS colitis model, MAPK phosphorylation (Western blot), oxidative burst assay, phagocytosis assay\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined signaling and functional phenotype in two in vivo models; single lab\",\n      \"pmids\": [\"30371949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Stress-induced elevation of corticosterone upregulates Tsc22d3 (GILZ) in dendritic cells, which blocks type I IFN responses in DCs and IFN-γ+ T cell activation. Enforced DC-specific Tsc22d3 expression is sufficient to abolish therapeutic tumor control, and DC-specific Tsc22d3 deletion reverses the negative impact of stress/glucocorticoid on therapy outcomes.\",\n      \"method\": \"Social defeat stress mouse model, DC-specific Tsc22d3 transgenic and conditional KO mice, glucocorticoid receptor antagonist treatment, IFN response assays, tumor challenge models\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific gain and loss of function in vivo, pharmacological rescue, multiple independent approaches establishing DC-intrinsic mechanism\",\n      \"pmids\": [\"31501614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cholesterol deficiency under hypoxia activates SREBP1, which induces GILZ expression; GILZ in turn binds the FVII gene locus (confirmed by chromatin immunoprecipitation in xenograft tumors) and activates FVII transcription. GILZ expression is also induced by HIF1α. Reciprocal regulation between SREBP1 and GILZ was observed.\",\n      \"method\": \"ChIP in xenograft tumor samples (HIF1α at TSC22D3 locus; GILZ at FVII locus), GILZ siRNA knockdown, SREBP1 manipulation, luciferase reporter assays\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP in vivo confirming GILZ genomic binding, siRNA functional validation; single lab\",\n      \"pmids\": [\"31055798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Glucocorticoid-transactivated TSC22D3 (GILZ) interacts with HIF-1α (shown by co-immunoprecipitation) and promotes degradation of hypoxia-stabilized HIF-1α via the ubiquitin-proteasome pathway. TSC22D3 silencing reverses glucocorticoid-mediated HIF-1α ubiquitination and galectin-1 downregulation.\",\n      \"method\": \"Co-immunoprecipitation of TSC22D3 with HIF-1α, ubiquitination assay, TSC22D3 siRNA knockdown, HIF-1α protein stability assay, in vivo diabetic mouse retina model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay plus siRNA validation in vitro and in vivo; single lab\",\n      \"pmids\": [\"32150332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GILZ directly binds STAT1 and prevents its nuclear translocation, thereby suppressing IFN-stimulated gene (ISG) expression and the type I IFN auto-amplification loop. GILZ deficiency permits a type I IFN signature, and GILZ overexpression prevents ISG upregulation in response to IFNα.\",\n      \"method\": \"Co-immunoprecipitation of GILZ with STAT1, nuclear translocation assay, GILZ overexpression and knockout in human PBMC, ISG reporter assays, TLR7/9 stimulation\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing direct GILZ–STAT1 interaction, gain/loss-of-function, defined molecular phenotype (STAT1 nuclear exclusion); single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35810690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Type I IFN suppresses GILZ expression and glucocorticoid induction of GILZ in a JAK1/Tyk2-dependent manner; IFN activation of this pathway reduces GR binding at key regulatory regions of the GILZ locus, as shown by ChIP.\",\n      \"method\": \"ChIP for GR at GILZ locus, JAK inhibitor treatment (tofacitinib/tosylate salt), in vitro IFN treatment of human PBMCs, large SLE patient dataset correlation\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing mechanism of GR displacement, pharmacological JAK inhibitor reversal; single lab\",\n      \"pmids\": [\"36505447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GILZ overexpression in T-cell lineage transgenic mice decreases CD4+CD8+ thymocyte number, increases thymocyte apoptosis via reduced Bcl-xL expression and activated caspase-8 and caspase-3. TAT-GILZ fusion protein delivered into wild-type thymocytes decreases Bcl-xL and promotes apoptosis.\",\n      \"method\": \"Transgenic mice overexpressing GILZ in T cells, ex vivo thymocyte apoptosis assays, caspase activity assays, Bcl-xL Western blot, TAT-GILZ protein delivery\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic gain-of-function plus direct protein delivery, multiple apoptotic pathway readouts; single lab\",\n      \"pmids\": [\"15319285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Gilz knockout male mice develop severe testis dysplasia from postnatal day 10, increased apoptosis in seminiferous tubules, increased Leydig cells, and elevated FSH and testosterone; males are infertile. Additionally, Tsc22d3-2 KO mice display subtle renal sodium/water handling deficiency but no major immunological defects under unstressed conditions.\",\n      \"method\": \"Cre/loxP conditional KO (Tsc22d3-2), testis histology, TUNEL apoptosis, hormone quantification (FSH, testosterone), renal electrolyte measurement, immune challenges\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with well-defined tissue phenotype replicated across multiple independent Gilz KO studies\",\n      \"pmids\": [\"22556341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GILZ-deficient mice develop progressive B-cell lymphocytosis with expansion of B220+ cells dependent on increased B-cell survival; decreased B-cell apoptosis in gilz KO mice correlates with increased NF-κB transcriptional activity and Bcl-2 expression. B-cell-specific gilz KO confirms the effect is B-cell intrinsic.\",\n      \"method\": \"Global and B-cell-specific gilz KO mice, flow cytometry, apoptosis assays, NF-κB reporter, Bcl-2 Western blot\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO confirming intrinsic mechanism, defined molecular pathway (NF-κB/Bcl-2); single lab\",\n      \"pmids\": [\"26276664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In alcohol-treated cells, unliganded GR binds GREs in the GILZ proximal promoter (shown by gel mobility shift assay) and transactivates gilz expression independent of glucocorticoids; GR knockout (CRISPR/Cas9) or GILZ depletion (siRNA) diminishes alcohol-mediated suppression of the LPS inflammatory response.\",\n      \"method\": \"Gel mobility shift assay (EMSA) for GR–GRE interaction, GRE deletion/mutation luciferase reporters, CRISPR/Cas9 GR knockout, siRNA GILZ knockdown, GR nuclear translocation, alcohol dehydrogenase inhibitor (fomepizole)\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus reporter mutagenesis plus loss-of-function; single lab\",\n      \"pmids\": [\"28638383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IBDV VP4 suppresses GILZ K48-linked ubiquitylation, protecting GILZ from degradation and thereby inhibiting IFN-β expression. Mutation of VP4 residue R41G abolishes both VP4's inhibitory effect on IFN-β and on GILZ ubiquitylation. IBDV infection also markedly inhibits endogenous GILZ ubiquitylation.\",\n      \"method\": \"Ubiquitylation assays (K48-linkage specific), VP4 R41G point mutant, IBDV infection of cells, IFN-β reporter assays\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — linkage-specific ubiquitylation assay plus mutagenesis of viral effector; single lab\",\n      \"pmids\": [\"29146236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Bacterial toxins YopT and Clostridium difficile toxin B induce GILZ expression in epithelial cells by inactivating Rho GTPases; MAPK activation is required. USF-1 and USF-2 bind a canonical E-box (c-Myc binding site) in the GILZ promoter, which is essential for both basal and toxin-B-induced GILZ transcription.\",\n      \"method\": \"GILZ promoter reporter assays, gel shift analysis (EMSA for USF1/2 binding), USF-1/2 siRNA knockdown, MAPK inhibitors, Yersinia mutant strains, RhoA/RhoB overexpression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus promoter mutagenesis plus siRNA establishing USF pathway; single lab\",\n      \"pmids\": [\"22792400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM47-ISGylation (at K329) negatively regulates TSC22D3 mRNA expression; K329R knockin mice with defective RBM47 ISGylation show elevated TSC22D3 and broad immunosuppression. A nanobody-targeted E3 ligase inducing site-specific RBM47 ISGylation in human cells directly inhibits TSC22D3 expression.\",\n      \"method\": \"K329R knockin mice, nanobody-targeted site-specific ISGylation in human cells, TSC22D3 mRNA quantification, LPS-induced lung injury and tumor models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockin mouse plus orthogonal site-specific ISGylation tool in human cells; single lab\",\n      \"pmids\": [\"38036512\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TSC22D3/GILZ is a glucocorticoid-inducible transcriptional regulator that mediates anti-inflammatory and immunosuppressive effects of glucocorticoids by directly binding and inhibiting multiple signaling nodes: it physically associates with NF-κB p65 (requiring LZ-mediated homodimerization and the C-terminal PER domain), AP-1 components c-Fos and c-Jun (via its N-terminal 60 aa), Ras and Raf (via its TSC box), mTORC2, Smad2, STAT1, MDM2, MyoD/HDAC1, C/EBPs, HIF-1α, and USP9X; promotes nuclear exclusion of FOXO3 in a Crm1-dependent manner; is itself transcriptionally induced by GR binding to GREs and by FoxO3 (upon IL-2 withdrawal), and is post-translationally regulated by caspase-8-dependent SUMO-1 conjugation and by K48-ubiquitylation; in spermatogonia its TSC22D complex form controls mTORC1 activity to maintain stem cell homeostasis; and GILZ-mediated suppression of type I IFN signaling occurs through direct STAT1 sequestration that prevents its nuclear translocation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TSC22D3 (GILZ) is a glucocorticoid-inducible leucine-zipper protein that executes the anti-inflammatory and immunosuppressive program of glucocorticoids by physically intercepting multiple pro-inflammatory and proliferative signaling nodes [#0, #5, #4]. It transcriptionally couples to upstream hormonal control: glucocorticoid receptor binding to GREs drives GILZ induction (including ligand-independent GR activation), and additional inputs—FoxO3 upon IL-2 withdrawal, SREBP1/HIF1\\u03b1, and USF1/2 at an E-box—tune its expression, while estradiol/ER\\u03b1 and type I IFN (JAK1/Tyk2-dependent) displace GR to repress it [#2, #25, #34, #13, #28]. Mechanistically, GILZ acts largely by sequestration and direct binding: homodimerization via its leucine zipper plus the C-terminal PER domain is required for binding NF-\\u03baB p65 and inhibiting NF-\\u03baB-driven transcription, its N-terminal 60 residues bind c-Fos/c-Jun to block AP-1, and its TSC box engages Ras and Raf to form a trimeric complex that dampens ERK/AKT signaling and proliferation [#5, #0, #4]. It further binds STAT1 to block its nuclear translocation and suppress type I IFN/ISG responses, promotes Crm1-dependent nuclear exclusion of FOXO3, binds Smad2 to promote TGF-\\u03b2/FoxP3-driven regulatory T cell generation, and represses adipogenic lineage genes (PPAR\\u03b32) through C/EBP sites while favoring osteogenic commitment [#27, #9, #18, #3, #19]. The long isoform L-GILZ binds MDM2 to stabilize p53, and in spermatogonia GILZ forms TSC22D-family complexes that restrain ERK and mTORC1 to maintain stem-cell homeostasis—Gilz loss causes germ-cell exhaustion and male sterility [#17, #22, #12]. Genetic loss-of-function across tissues establishes GILZ as a brake on immune and proliferative output, including B-cell survival via NF-\\u03baB/Bcl-2 and neutrophil oxidative activation, and as a stress/glucocorticoid-driven suppressor of antitumor immunity in dendritic cells [#31, #23, #24]. GILZ stability is itself controlled post-translationally through caspase-8-linked SUMO-1 conjugation and K48-ubiquitylation [#10, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the first direct molecular mechanism for GILZ as a transcriptional brake, showing it binds AP-1 components and requires leucine-zipper-mediated dimerization, defining its mode of action on immune gene promoters.\",\n      \"evidence\": \"Recombinant in vitro interaction assays, domain-deletion mutants, and reporter assays in Jurkat/primary T cells\",\n      \"pmids\": [\"11397794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address NF-\\u03baB or other transcription factor targets\", \"No in vivo validation of AP-1 inhibition\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended GILZ's inhibitory repertoire to NF-\\u03baB, linking glucocorticoid/IL-10 signaling to suppression of macrophage costimulatory and chemokine genes.\",\n      \"evidence\": \"Co-immunoprecipitation and GILZ transfection in THP-1 macrophage-like cells with flow cytometry/RT-PCR readouts\",\n      \"pmids\": [\"12393603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain requirements for p65 binding not defined here\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated GILZ acts as a sequence-specific transcriptional repressor at C/EBP sites, mechanistically explaining glucocorticoid inhibition of adipocyte differentiation.\",\n      \"evidence\": \"Promoter binding assays and ectopic expression in mesenchymal cells with adipogenic differentiation readouts\",\n      \"pmids\": [\"12671681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for promoter recognition\", \"Direct DNA-binding versus C/EBP tethering not fully resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed GILZ in a FoxO3-driven survival circuit, showing reciprocal regulation (FoxO3 induces GILZ; GILZ inhibits FoxO3) controlling Bim and T-cell apoptosis.\",\n      \"evidence\": \"GILZ promoter FHRE mutagenesis with gain/loss-of-function in CTLL-2 cells and apoptosis assays\",\n      \"pmids\": [\"15031210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of FoxO3 inhibition not defined at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established GILZ as a pro-apoptotic regulator of thymocyte selection in vivo through Bcl-xL downregulation and caspase activation.\",\n      \"evidence\": \"T-cell GILZ transgenic mice and TAT-GILZ protein delivery with caspase/Bcl-xL readouts\",\n      \"pmids\": [\"15319285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target driving Bcl-xL loss not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the bipartite structural requirement (leucine zipper plus PER domain) for GILZ/p65 binding, mechanistically dissecting NF-\\u03baB inhibition.\",\n      \"evidence\": \"In vitro and in vivo co-IP with multiple GILZ deletion/point mutants and NF-\\u03baB reporters\",\n      \"pmids\": [\"17169985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of GILZ/p65\", \"Stoichiometry of the inhibitory complex unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the TSC box as the Ras-binding module and showed GILZ forms a Ras/Raf trimeric complex, connecting GILZ to glucocorticoid antiproliferative effects.\",\n      \"evidence\": \"In vitro binding, co-IP and colocalization in primary T cells, domain mutants, siRNA, and transformation assays\",\n      \"pmids\": [\"17492054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GILZ blocks Ras GTPase activity or only effector coupling not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed GILZ governs mesenchymal lineage choice, promoting osteogenesis at the expense of adipogenesis via lineage marker reprogramming.\",\n      \"evidence\": \"GILZ overexpression and knockdown in mouse MSCs with differentiation assays and lineage marker RT-PCR\",\n      \"pmids\": [\"18084007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets in osteogenic program not mapped here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended GILZ transcriptional inhibition to the myogenic program through MyoD/HDAC1 regulation, explaining glucocorticoid anti-myogenic effects.\",\n      \"evidence\": \"C2C12 differentiation with GILZ/L-GILZ gain/loss-of-function and co-IP with MyoD/HDAC1\",\n      \"pmids\": [\"20124407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect binding to MyoD not fully separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Refined GILZ's NF-\\u03baB inhibition mechanism in MSCs, showing it blocks p65 nuclear translocation to suppress COX-2.\",\n      \"evidence\": \"Retroviral overexpression/shRNA, NF-\\u03baB translocation imaging/fractionation, COX-2 reporters\",\n      \"pmids\": [\"17910039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent discrepancy with later reports that GILZ does not affect p65 translocation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved how GILZ inhibits FOXO3 without binding it, identifying Crm1-dependent nuclear exclusion as the mechanism.\",\n      \"evidence\": \"Live-cell imaging, leptomycin B treatment, FOXO reporters and fractionation in HL-60/CTLL-2\",\n      \"pmids\": [\"20018851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intermediate kinase/adaptor linking cytoplasmic GILZ to FOXO3 export unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined post-translational control of GILZ stability, linking glucocorticoid-induced caspase-8 to SUMO-1 conjugation via Ubc9 and protection from proteasomal degradation.\",\n      \"evidence\": \"In vitro GILZ\\u2013Ubc9/SUMO-1 binding, co-IP, caspase-8-deficient thymocytes, proteasome inhibition\",\n      \"pmids\": [\"20671745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of GILZ SUMOylation on activity not established\", \"SUMO acceptor lysine not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Distinguished GILZ inhibition of mTORC2 (not mTORC1), connecting it to AKT-S473/FoxO3a/Bim-driven apoptosis and drug sensitization in BCR-ABL+ cells.\",\n      \"evidence\": \"Reciprocal co-IP with mTOR complex components, AKT phosphorylation, FoxO3a reporters in CML cells\",\n      \"pmids\": [\"21804606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface with mTORC2 not mapped\", \"Apparent contrast with later spermatogonial mTORC1 control\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established GILZ as essential for spermatogenesis in vivo, with KO germline loss linked to Ras pathway (ERK/Akt) hyperactivation.\",\n      \"evidence\": \"Gilz knockout mice with IHC, ERK/Akt phosphorylation, and spermatogenesis phenotyping\",\n      \"pmids\": [\"22110132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether germline defect is cell-intrinsic versus somatic not resolved here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Confirmed and elaborated the Gilz-null testis phenotype while showing minimal baseline immune deficit, distinguishing tissue-specific essentiality.\",\n      \"evidence\": \"Conditional Tsc22d3-2 KO with testis histology, TUNEL, hormone and renal electrolyte measurements\",\n      \"pmids\": [\"22556341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Renal sodium/water handling mechanism not defined\", \"Immune phenotypes emerge mainly under challenge\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed ligand-independent GR can transactivate GILZ at GREs, broadening the upstream control of GILZ to non-glucocorticoid (alcohol) contexts.\",\n      \"evidence\": \"EMSA for GR\\u2013GRE, GRE reporter mutagenesis, CRISPR GR KO, GILZ siRNA\",\n      \"pmids\": [\"28638383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How unliganded GR is activated by alcohol not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a Rho-GTPase/MAPK/USF input controlling GILZ, showing bacterial toxins induce GILZ through an E-box bound by USF1/2.\",\n      \"evidence\": \"GILZ promoter reporters, EMSA for USF binding, USF siRNA, MAPK inhibitors, Rho manipulation\",\n      \"pmids\": [\"22792400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of toxin-induced GILZ for host defense not defined here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified estradiol/ER\\u03b1 as a repressor of GILZ that reduces GR occupancy at the promoter, defining cross-talk between estrogen and glucocorticoid control.\",\n      \"evidence\": \"ChIP for GR/ER\\u03b1 at GILZ promoter, ER\\u03b1 siRNA, ER antagonist, in vivo uterus model\",\n      \"pmids\": [\"23183181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ER\\u03b1 displaces GR not structurally defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Clarified that GILZ can inhibit NF-\\u03baB at the level of p65 DNA binding (not translocation) and broadly dampens MAPK signaling to limit endothelial leukocyte recruitment.\",\n      \"evidence\": \"GILZ transfection in HUVECs, NF-\\u03baB DNA-binding versus translocation assays, MAPK and MKP-1 readouts, adhesion assays\",\n      \"pmids\": [\"23729444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with translocation-blocking reports unresolved\", \"Transfection system only\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed GILZ induction under corepressor control, showing DC-SCRIPT restrains GR-driven GILZ expression in dendritic cells.\",\n      \"evidence\": \"Co-IP of DC-SCRIPT with GR and DC-SCRIPT knockdown in monocyte-derived DCs\",\n      \"pmids\": [\"23440419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect effect on GILZ locus not separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed GILZ mediates glucocorticoid suppression of airway epithelial repair via Raf-1/MEK/ERK inhibition, linking GILZ to tissue regeneration outcomes.\",\n      \"evidence\": \"GILZ siRNA, pRaf/pMEK/pERK Western blot, wound-healing and proliferation assays\",\n      \"pmids\": [\"23573276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GILZ acts via direct Raf binding here not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a p53-stabilizing function for L-GILZ via MDM2 binding, connecting GILZ to tumor suppression.\",\n      \"evidence\": \"Co-IP with p53/MDM2, ubiquitination assays, isogenic p53+/+ vs p53-/- cells, xenografts, L-GILZ siRNA\",\n      \"pmids\": [\"25168242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform specificity (L-GILZ vs GILZ) for MDM2 binding interface not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified GILZ as a positive regulator of TGF-\\u03b2/Smad2 signaling driving FoxP3+ regulatory T-cell generation, defining a pro-tolerogenic axis.\",\n      \"evidence\": \"GILZ transgenic and KO mice, co-IP with Smad2, Smad2 phosphorylation, FoxP3 reporter, intestinal inflammation model\",\n      \"pmids\": [\"24703841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GILZ promotes Smad2 phosphorylation mechanistically not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed in vivo that GILZ drives osteogenic over adipogenic commitment through C/EBP-mediated PPAR\\u03b3 repression, with transgenic mice showing increased bone mass.\",\n      \"evidence\": \"Co-IP with C/EBPs, PPAR\\u03b3 reporters, collagen-promoter GILZ transgenic mice, bone histomorphometry\",\n      \"pmids\": [\"24860090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA contact versus C/EBP tethering at PPAR\\u03b3 not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established a B-cell-intrinsic role for GILZ in restraining survival, with KO lymphocytosis tied to elevated NF-\\u03baB activity and Bcl-2.\",\n      \"evidence\": \"Global and B-cell-specific gilz KO, flow cytometry, apoptosis assays, NF-\\u03baB reporter, Bcl-2 Western blot\",\n      \"pmids\": [\"26276664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link from GILZ loss to Bcl-2 induction not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified post-transcriptional control of GILZ by HuR, explaining curcumin-driven anti-inflammatory GILZ induction independent of transcription.\",\n      \"evidence\": \"RNA immunoprecipitation of HuR\\u2013GILZ mRNA, HuR overexpression, GILZ KO macrophages, inflammatory readouts\",\n      \"pmids\": [\"27629417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HuR binding element on GILZ mRNA not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a nuclear, transcription-activating mode for GILZ in primed MSCs, binding iNOS and Activin \\u03b2A promoters to repress Th17 differentiation.\",\n      \"evidence\": \"ChIP at iNOS/Activin \\u03b2A promoters, nuclear translocation imaging, Activin A ELISA, Smad2/3 readouts, adoptive transfer\",\n      \"pmids\": [\"29344311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals controlling cytoplasmic-to-nuclear GILZ shift not defined\", \"Direct versus cofactor-dependent DNA binding unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed viral immune evasion converges on GILZ stability, with IBDV VP4 suppressing GILZ K48-ubiquitylation to limit IFN-\\u03b2.\",\n      \"evidence\": \"K48-linkage-specific ubiquitylation assays, VP4 R41G mutant, IBDV infection, IFN-\\u03b2 reporters\",\n      \"pmids\": [\"29146236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase and deubiquitylase acting on GILZ not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the spermatogonial stem-cell mechanism, showing GILZ forms TSC22D-family complexes and restrains ERK/mTORC1, with mTOR inhibition rescuing germline failure.\",\n      \"evidence\": \"Adult conditional Gilz KO, mTOR inhibitor rescue, USP9X analysis, co-IP with TSC22D proteins, ERK phosphorylation\",\n      \"pmids\": [\"30126904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GILZ\\u2013mTORC1 regulatory link versus ERK-mediated effect not separated\", \"Role of USP9X mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established GILZ as a brake on neutrophil effector function through MAPK and NOX2/p47phox suppression.\",\n      \"evidence\": \"GILZ-KO neutrophils, Candida and DNBS colitis models, MAPK and oxidative burst/phagocytosis assays\",\n      \"pmids\": [\"30371949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GILZ target controlling NOX2 not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected psychological stress to immunosuppression via DC-intrinsic GILZ, showing corticosterone-induced GILZ blocks type I IFN and abolishes antitumor therapy control.\",\n      \"evidence\": \"Social-defeat stress model, DC-specific Tsc22d3 transgenic and conditional KO mice, GR antagonist, tumor challenge\",\n      \"pmids\": [\"31501614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of GILZ in the DC IFN block not defined in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a metabolic/hypoxic transcriptional circuit, with SREBP1 and HIF1\\u03b1 inducing GILZ, which in turn binds and activates the FVII locus.\",\n      \"evidence\": \"ChIP for HIF1\\u03b1 at TSC22D3 and GILZ at FVII in xenografts, GILZ siRNA, SREBP1 manipulation, reporters\",\n      \"pmids\": [\"31055798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GILZ DNA-binding mode at FVII versus cofactor dependence unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed GILZ promotes ubiquitin-proteasomal degradation of HIF-1\\u03b1, defining a glucocorticoid mechanism for HIF-1\\u03b1 turnover in disease tissue.\",\n      \"evidence\": \"Co-IP with HIF-1\\u03b1, ubiquitination assays, TSC22D3 siRNA, in vivo diabetic retina model\",\n      \"pmids\": [\"32150332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GILZ recruits a specific E3 ligase to HIF-1\\u03b1 not established\", \"Apparent contrast with HIF1\\u03b1-induced GILZ expression\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the molecular basis of GILZ suppression of type I IFN, showing direct STAT1 binding that blocks STAT1 nuclear translocation and ISG induction.\",\n      \"evidence\": \"Co-IP with STAT1, nuclear translocation assays, GILZ overexpression/KO in human PBMC, ISG reporters\",\n      \"pmids\": [\"35810690\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"STAT1-binding domain on GILZ not mapped\", \"Effect on STAT2/STAT3 not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a feedback antagonism whereby type I IFN suppresses GILZ via JAK1/Tyk2 by reducing GR occupancy at the GILZ locus.\",\n      \"evidence\": \"ChIP for GR at GILZ locus, JAK inhibitors, IFN treatment of human PBMCs, SLE patient correlation\",\n      \"pmids\": [\"36505447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which JAK signaling displaces GR not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an ISGylation-dependent RNA-binding control of TSC22D3 mRNA, where RBM47 ISGylation at K329 negatively regulates GILZ expression.\",\n      \"evidence\": \"K329R knockin mice, nanobody-targeted site-specific RBM47 ISGylation in human cells, mRNA quantification, injury/tumor models\",\n      \"pmids\": [\"38036512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RBM47 binds TSC22D3 mRNA directly not established\", \"Mechanism of ISGylation-driven repression unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying structural and mechanistic account of how a single small leucine-zipper protein selects among its many binding partners (NF-\\u03baB, AP-1, Ras/Raf, STAT1, Smad2, MDM2, mTORC2, C/EBPs, HIF-1\\u03b1) in a context-dependent manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-structure of GILZ with any partner\", \"Determinants of partner selectivity across cell types unknown\", \"Cytoplasmic-sequestration versus nuclear-DNA-binding switch not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3, 5, 19, 21, 25]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 21, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5, 11, 17, 27]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [9, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 18, 24, 27, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 11, 14, 18, 27]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 5, 19, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 12, 19, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 29, 31]}\n    ],\n    \"complexes\": [\"GILZ-TSC22D complex\"],\n    \"partners\": [\"RELA\", \"JUN\", \"FOS\", \"RAF1\", \"SMAD2\", \"STAT1\", \"MDM2\", \"HIF1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}