{"gene":"REL","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1991,"finding":"The Rel-associated protein pp40 (IκB-like) inhibits DNA binding activity of p50:c-Rel heteromers and c-Rel homodimers, suggesting c-Rel is held in the cytosol by interaction with cytoplasmic anchor molecules containing ankyrin repeats.","method":"Biochemical purification and in vitro DNA binding inhibition assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — purified protein, direct in vitro DNA-binding inhibition assay, replicated conceptually by multiple subsequent studies","pmids":["1891714"],"is_preprint":false},{"year":1991,"finding":"c-Rel protein binds κB DNA sites in a sequence-specific manner and activates transcription from κB-containing promoters; v-Rel, by contrast, suppresses this transcription, acting as a dominant negative.","method":"Bacterial expression, EMSA, transient transfection reporter assay, anti-rel antibody supershift","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro DNA binding with recombinant protein, transcriptional reporter assays, antibody disruption, multiple orthogonal methods in one study","pmids":["2023921"],"is_preprint":false},{"year":1990,"finding":"Mouse c-Rel protein has a C-terminal transcriptional transactivation domain (residues 403–568) and an N-terminal regulatory domain that suppresses transactivation; deletion of the N-terminal half augments transactivation function.","method":"GAL4 fusion domain mapping, transient transfection reporter assay in yeast and mammalian cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution via GAL4 fusions, systematic deletion mapping, validated in two cell systems","pmids":["2204816"],"is_preprint":false},{"year":1992,"finding":"I-Rel (a novel 66 kDa Rel-related protein, alias of REL locus product) forms heterodimers with p50 and inhibits its DNA-binding activity through an N-terminal inhibitory domain, but does not associate with p65; I-Rel suppresses NF-κB-induced transcription and its expression is induced by mitogenic stimulation.","method":"cDNA cloning, co-immunoprecipitation, EMSA, transient transfection reporter assay, Northern blot","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, EMSA, reporter assay), domain mapping, single lab but comprehensive","pmids":["1577270"],"is_preprint":false},{"year":1991,"finding":"c-Rel protein exists in a high molecular weight (~400 kDa) cytoplasmic complex with other cellular proteins (including proteins of ~36 kDa, ~115 kDa, ~124 kDa) in both avian and murine cells; complex formation is not dependent on v-Rel.","method":"Immunoprecipitation, size-exclusion chromatography (Sephacryl S-400)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal IP and gel filtration in multiple cell types, single lab","pmids":["1851550"],"is_preprint":false},{"year":1994,"finding":"c-Rel forms a preformed heterodimeric complex with p65 (RelA) in the cytosol that is kept latent by IκBα association; upon stimulation this c-Rel–p65 complex translocates to the nucleus and is a potent transcriptional activator of κB-containing promoters, more active than p50–p65.","method":"Protein purification from HeLa cytosol, in vitro translation reconstitution, EMSA, co-expression in COS7 cells, transient transfection reporter assay, detergent activation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — native protein purification, reconstitution by in vitro translation, multiple orthogonal methods in one study","pmids":["8139561"],"is_preprint":false},{"year":1990,"finding":"The c-rel promoter is autoregulated: co-expression of c-Rel protein decreases expression from its own minimal promoter, demonstrating transcriptional autorepression.","method":"Promoter-luciferase reporter assay, 5′ deletion analysis, co-transfection","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter mapping with co-transfection, single lab","pmids":["2284104"],"is_preprint":false},{"year":1995,"finding":"c-Rel is a component of antigen receptor-induced κB-binding complexes in B and T cells; its induction requires both phorbol ester and ionomycin (dual signal) and is blocked by FK506 (calcineurin inhibitor); calcineurin co-expression augments c-Rel-dependent transactivation of the IL-2Rα promoter, indicating a calcineurin-dependent pathway for c-Rel activation.","method":"EMSA, transient transfection reporter assay, pharmacological inhibition (FK506), calcineurin co-expression","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus functional reporter assays, pharmacological and genetic perturbation, single lab","pmids":["7532676"],"is_preprint":false},{"year":1998,"finding":"Protein phosphatase X (PPX/PP4) specifically associates with c-Rel, p50, and RelA; overexpression of catalytically active PPX (but not inactive mutants) stimulates c-Rel DNA-binding activity and NF-κB-mediated transcription, identifying PPX as a positive regulator of c-Rel.","method":"Co-immunoprecipitation, EMSA, transient transfection reporter assay, catalytic mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional reporter with catalytic mutants, single lab, two orthogonal methods","pmids":["9837938"],"is_preprint":false},{"year":1998,"finding":"c-Rel protein turnover is regulated by the ubiquitin–proteasome pathway; ubiquitinated c-Rel conjugates accumulate with proteasome inhibitors; a region between residues 118–171 (immediately C-terminal to the Rel homology domain) is important for ubiquitin conjugation, while C-terminal sequences mediate susceptibility to degradation.","method":"Cell-free in vitro degradation assay, proteasome inhibitor treatment, immunoprecipitation, deletion mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cell-free reconstitution of degradation, systematic deletion mapping, proteasome inhibitor validation, single lab but multiple orthogonal methods","pmids":["9857058"],"is_preprint":false},{"year":1998,"finding":"IκBα regulates c-Rel in two distinct subcellular compartments via discrete domains: the N-terminal and central ankyrin regions retain c-Rel in the cytoplasm by masking its NLS, while the central ankyrin domain plus a C-terminal PEST-proximal acidic region terminate c-Rel transcriptional activity in the nucleus.","method":"Domain deletion/mapping of IκBα, subcellular fractionation, transcriptional reporter assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — systematic domain mapping with functional readouts in both cytoplasmic and nuclear compartments, single lab","pmids":["9488436"],"is_preprint":false},{"year":2000,"finding":"c-Rel is selectively required for IL-12 p40 gene induction in LPS-activated macrophages; p50/p65 and p50/c-Rel heterodimers bind the IL-12 p40 Rel site with comparable affinity and transactivation in vitro, yet only c-Rel deficiency dramatically reduces p40 mRNA and protein in vivo, indicating selectivity is not explained by DNA binding affinity alone.","method":"c-Rel knockout mice, EMSA, qRT-PCR, ELISA, transient transfection","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific cellular phenotype, replicated across multiple assays and cytokines, multiple labs subsequently confirmed","pmids":["11058167"],"is_preprint":false},{"year":2001,"finding":"In CD8+ dendritic cells, c-Rel complexes bind directly to the IL-12 p35 promoter and are required for induced p35 transcription by microbial stimuli; this is distinct from macrophages where c-Rel controls p40, demonstrating cell-type-specific regulation of IL-12 subunits by c-Rel.","method":"c-Rel knockout mice, EMSA with supershift, chromatin immunoprecipitation (ChIP), RT-PCR, ELISA","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, direct promoter binding shown by ChIP and EMSA, multiple orthogonal methods","pmids":["11602633"],"is_preprint":false},{"year":2001,"finding":"PU.1 and Spi-B Ets transcription factors directly regulate c-rel transcription through three PU.1/Spi-B binding sites in the murine c-rel promoter; loss of both Ets factors dramatically reduces c-Rel expression in splenic B cells, and Rel protein reintroduction rescues B cell numbers.","method":"Promoter analysis, EMSA, bone marrow reconstitution, rescue experiment","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — promoter mapping with EMSA, genetic rescue in vivo, multiple orthogonal methods","pmids":["11672537"],"is_preprint":false},{"year":2002,"finding":"c-Rel is required for TCR/CD28-induced chromatin remodeling across the IL-2 gene promoter in primary CD4+ T cells; c-Rel deficiency abolishes global chromatin accessibility changes and also specifically impairs accessibility at the c-Rel binding site in the CD28RR region, paralleling loss of IL-2 mRNA and protein.","method":"c-Rel knockout mice, restriction enzyme accessibility assay (REAA), RT-PCR, ELISA","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with chromatin accessibility assay, site-specific promoter analysis, multiple orthogonal methods","pmids":["12646638"],"is_preprint":false},{"year":2002,"finding":"c-Rel is essential for BCR-mediated B cell proliferation and G1/S cell cycle progression; c-Rel-deficient B cells fail to induce cyclin D3 and cyclin E, have reduced CDK activity, incomplete pRb phosphorylation, and poor E2F expression upon BCR stimulation.","method":"c-Rel knockout mice, flow cytometry cell cycle analysis, immunoblot for cyclins/CDKs/pRb/E2F, kinase assays","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with mechanistic molecular readouts (cyclins, CDK activity, pRb phosphorylation), multiple orthogonal methods","pmids":["12147627"],"is_preprint":false},{"year":1997,"finding":"Expression of c-Rel in HeLa cells causes G1/S growth arrest correlated with nuclear localization of c-Rel; arrest is accompanied by decreased E2F DNA binding, accumulation of hypophosphorylated Rb, reduced Cdk2 kinase activity, elevated p21WAF1 and p53 protein stability; deletion of c-Rel C-terminal transactivation domains abolishes these effects.","method":"Tetracycline-inducible expression system, in vitro Cdk2 kinase assay, EMSA, immunoblot, pulse-chase analysis, flow cytometry","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — inducible expression with domain deletion, in vitro kinase assay, multiple molecular readouts, single lab","pmids":["9343416"],"is_preprint":false},{"year":2003,"finding":"c-Rel directly regulates e2f3a promoter/enhancer transcription and thereby controls cyclin E expression and cell cycle progression in B lymphocytes; Bcl-xL alone cannot rescue proliferation of c-Rel-deficient B cells, but cyclin E cooperates with Bcl-xL to restore cell cycle entry via the CDK/Rb/E2F pathway.","method":"bcl-xL transgenic rescue, cyclin E protein transduction, c-Rel-deficient B cells, reporter assay for e2f3a promoter","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and protein-transduction rescue experiments, promoter reporter assay, single lab","pmids":["14627988"],"is_preprint":false},{"year":2003,"finding":"Ca2+/calmodulin (CaM) directly interacts with c-Rel and RelA near their nuclear localization signals after IκB release; CaM binding-deficient c-Rel mutants show increased nuclear accumulation and transcriptional activity on IL-2 and GM-CSF promoters, demonstrating CaM inhibits nuclear import of c-Rel specifically (but not RelA) following stimulation.","method":"Co-immunoprecipitation, CaM-binding mutant analysis, nuclear fractionation, transcriptional reporter assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, mutational analysis, subcellular fractionation, functional reporter, differential effect on c-Rel vs RelA established mechanistically","pmids":["12556500"],"is_preprint":false},{"year":2005,"finding":"A 46-residue subdomain within the 86-residue segment of c-Rel's Rel homology region (RHR) confers enhanced DNA-binding affinity to a broader range of κB sequences compared with p65, and this property—not c-Rel-specific coactivator interactions—accounts for the c-Rel-selective requirement for Il12b and Il12a gene induction.","method":"c-Rel/p65 chimeric protein analysis, EMSA with broad panel of κB sequences, macrophage/DC knockout assays, coactivator interaction studies","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — chimeric protein domain swap, quantitative EMSA, genetic KO validation, multiple orthogonal methods excluding coactivator model","pmids":["16166378"],"is_preprint":false},{"year":2004,"finding":"PKA catalytic subunit beta (PKA-Cβ) physically interacts with c-Rel, directly phosphorylates it in vitro, and stimulates its transcriptional activity; coactivators p300/CBP are at least partially responsible for the enhanced activation by the c-Rel–PKA-Cβ axis.","method":"Co-immunoprecipitation, immunoprecipitation-in vitro kinase phosphorylation assay, EMSA, transcriptional reporter assay","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro phosphorylation assay plus co-IP and reporter assay, single lab","pmids":["15197457"],"is_preprint":false},{"year":2005,"finding":"Neuroprotection by mGlu5 receptor agonists against amyloid-β toxicity depends on c-Rel activation; c-Rel induces MnSOD and Bcl-XL expression; RNAi knockdown of c-Rel suppresses both antiapoptotic genes and abolishes neuroprotection, while c-Rel overexpression rescues neurons from Aβ toxicity.","method":"RNA interference, c-Rel overexpression, immunoblot, neuronal viability assay in primary cortical neurons","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi and overexpression rescue, target gene validation, single lab","pmids":["15818410"],"is_preprint":false},{"year":2007,"finding":"MALT1 selectively activates c-Rel (but not RelA) downstream of B cell receptor signaling; Bcl-10 is required for IKK recruitment and activation of both RelA and c-Rel, while MALT1 participates only in the c-Rel subprogram controlling a distinct survival gene subset.","method":"Bcl-10- and MALT1-deficient B cells, IKK activity assays, NF-κB subunit-specific nuclear translocation assays, gene expression analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO of pathway components, selective subunit activation tracked, multiple orthogonal methods, high-impact journal","pmids":["17660823"],"is_preprint":false},{"year":2007,"finding":"Nuclear CD40 physically interacts with c-Rel (but not p65) in large B-cell lymphoma cells; nuclear CD40–c-Rel complexes bind promoters of NF-κB target genes (CD154, BLyS/BAFF, Bfl-1/A1); wild-type but not NLS-mutated CD40 enhances c-Rel-mediated BLyS promoter activation and LBCL proliferation.","method":"Co-immunoprecipitation, ChIP, promoter reporter assay, NLS mutation analysis, proliferation assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP showing nuclear complex, functional NLS mutant, single lab","pmids":["17567982"],"is_preprint":false},{"year":2009,"finding":"In neurons, c-Rel-containing dimers (p50/c-Rel and RelA/c-Rel) but not p50/RelA promote Bcl-xL transcription, conferring neuroprotection; during ischemia, p50/RelA activation is associated with inhibition of c-Rel/RelA dimer, increased Bim/Noxa expression and enhanced neuronal vulnerability.","method":"Oxygen-glucose deprivation (OGD) model, mouse ischemia model, targeted RNAi knockdown of subunits, NF-κB subunit-specific EMSA, Bcl-xL and Bim promoter assays, immunoblot","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subunit-specific knockdown with mechanistic readouts, in vitro and in vivo models, single lab","pmids":["19094066"],"is_preprint":false},{"year":2011,"finding":"Dectin-1 and dectin-2 C-type lectins activate c-Rel selectively via the CARD9-Bcl10-MALT1 signaling module in human dendritic cells; MALT1 inhibition abrogates c-Rel activation and Th17-polarizing cytokine (IL-1β, IL-23p19) expression; dectin-2 selectively activates c-Rel without activating other NF-κB subunits.","method":"MALT1 inhibition, siRNA knockdown, NF-κB subunit-specific reporter assays, cytokine ELISA, human DC stimulation","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — pathway dissection with pharmacological and genetic inhibition, subunit selectivity demonstrated, multiple orthogonal methods","pmids":["21283787"],"is_preprint":false},{"year":2011,"finding":"Foxp3 directly or as part of a multimeric complex engages c-Rel; the N-terminal region of Foxp3 is required for c-Rel binding but not NFAT binding, while forkhead domain deletion abolishes NFAT but not c-Rel interaction, identifying distinct interaction domains.","method":"Co-immunoprecipitation, deletion mutant analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP with domain mapping, single lab, no functional epistasis in same study","pmids":["21490927"],"is_preprint":false},{"year":2010,"finding":"c-Rel is required for IL-21 gene expression in T lymphocytes; a c-Rel binding site in the proximal IL-21 promoter is confirmed to bind c-Rel in vitro and in vivo, regulating IL-21 transcription; downstream, c-Rel deficiency impairs Th17, Tfh, and germinal center B cell development.","method":"c-Rel knockout mice, EMSA, ChIP, RT-PCR, ELISA, promoter reporter assay, IL-21 rescue experiment","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, direct promoter binding by EMSA and ChIP, IL-21 rescue, multiple orthogonal methods","pmids":["20639489"],"is_preprint":false},{"year":2010,"finding":"c-Rel binds the FoxM1 promoter in the regenerating liver (shown by ChIP), is required for FoxM1 induction and downstream targets cyclin B1 and Cdc25C, and regulates hepatocyte proliferation; c-Rel deficiency impairs both the inflammatory (RANTES/CCL5 induction) and fibrogenic wound-healing responses to liver injury.","method":"c-Rel knockout mice, ChIP, RT-PCR, immunoblot, partial hepatectomy and CCl4 injury models","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP showing direct promoter binding, genetic KO with specific molecular readouts, multiple in vivo models","pmids":["20058312"],"is_preprint":false},{"year":2016,"finding":"miR-155 represses Peli1, a ubiquitin ligase that promotes c-Rel degradation; this miR-155–Peli1–c-Rel axis controls c-Rel protein levels, cellular proliferation, and CD40L expression in T follicular helper cells.","method":"miR-155- and Peli1-deficient mice, immunoblot for c-Rel protein, flow cytometry, functional T cell assays","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO of upstream regulators with c-Rel protein level readout, pathway placement, single lab","pmids":["27481129"],"is_preprint":false},{"year":2014,"finding":"c-Rel is a component of the TRAIL-inducible NF-κB complex in pancreatic cancer cells; siRNA knockdown of c-Rel sensitizes TRAIL-resistant PDAC cells to apoptosis; c-Rel drives expression of NFATc2 which in turn induces COX-2, constituting a c-Rel–NFATc2–COX-2 antiapoptotic pathway.","method":"siRNA knockdown, gel-shift (EMSA), gene expression array, co-transfection, pharmacological COX-2 inhibition","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA showing c-Rel in complex, siRNA KD with phenotypic rescue, pathway validation, single lab","pmids":["25299780"],"is_preprint":false},{"year":2014,"finding":"c-Rel directly activates Ezh2 transcription in lymphoid cells by binding to the first intron of the Ezh2 locus; c-Rel deficiency abolishes Ezh2 upregulation in activated B and T cells, and c-Rel knockdown in malignant cells reduces Ezh2 expression and sensitizes cells to Ezh2 inhibition.","method":"ChIP, c-Rel knockout mice, c-Rel-deficient lymphocytes, siRNA knockdown, RT-PCR, immunoblot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct intron binding, genetic KO and siRNA KD, multiple cell types, two orthogonal methods","pmids":["25266721"],"is_preprint":false},{"year":2015,"finding":"c-Rel regulates Bach2 (B-cell tumour suppressor) expression; ChIP-seq data confirm Bach2 as a c-Rel target gene in transformed human B cells; loss of c-Rel or IKK pathway inhibition reduces Bach2 expression in Burkitt lymphoma cells.","method":"ChIP-seq (published data analysis), RT-PCR, immunoblot, c-Rel knockout mice, IKK/NF-κB inhibitor treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus genetic and pharmacological perturbation, single lab","pmids":["26522720"],"is_preprint":false},{"year":2011,"finding":"c-Rel stimulates cardiac hypertrophy and fibrosis; c-Rel-deficient mice have smaller hearts and are protected from angiotensin-induced hypertrophy; ChIP identified myocyte enhancer factor (MEF), Gata4, and Tbx proteins as c-Rel transcriptional targets in the heart; p50 overexpression represses c-Rel levels and hypertrophic response.","method":"c-Rel knockout mice, angiotensin infusion model, ChIP, gene expression analysis, p50 overexpression in H9c2 cells, immunohistochemistry","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with physiological model, ChIP for target genes, single lab","pmids":["22210479"],"is_preprint":false},{"year":2020,"finding":"c-Rel functions as a transcriptional repressor of RelA-dependent inflammatory genes by selectively binding the co-repressor HDAC1 and competitively occupying promoters of inflammatory genes; a point mutation at tyrosine 25 (Y25H) in c-Rel's DNA-binding domain abolishes DNA binding and repressive function.","method":"Genetic deletion, co-immunoprecipitation (c-Rel–HDAC1), ChIP, promoter reporter assay, site-directed mutagenesis (Y25H)","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — co-IP, ChIP, mutagenesis, and reporter assays, multiple orthogonal methods in single lab","pmids":["32062419"],"is_preprint":false},{"year":2020,"finding":"c-Rel specifies generation of myeloid-derived suppressor cells (MDSCs) by selectively activating pro-tumoral genes while repressing anti-tumoral genes through a c-Rel enhanceosome; myeloid-specific c-Rel deficiency markedly inhibits cancer growth in mice.","method":"Myeloid-specific c-Rel knockout mice, gene expression analysis, pharmaceutical c-Rel inhibition, tumor growth assays","journal":"Nature cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with mechanistic transcriptional readout (enhanceosome), single lab","pmids":["33458695"],"is_preprint":false},{"year":2020,"finding":"c-Rel controls metabolic reprogramming required for fibrogenic activities of hepatocytes and macrophages through Pfkfb3 as a key downstream metabolic mediator; cell-type-specific deletion of c-Rel in hepatocytes or macrophages independently suppresses liver fibrosis with additive effects when combined; pharmacological c-Rel inhibition attenuates multi-organ fibrosis.","method":"Cell-type-specific c-Rel knockout mice (hepatocyte- and macrophage-specific), carbon tetrachloride fibrosis model, gene expression analysis, pharmacological inhibition","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic KOs, identification of downstream metabolic target Pfkfb3, multiple in vivo models, additive effects showing cell autonomy","pmids":["33168981"],"is_preprint":false},{"year":2021,"finding":"c-Rel O-GlcNAcylation at serine 350 negatively regulates FOXP3 expression: hyperglycemia-induced O-GlcNAcylation decreases c-Rel binding at the FOXP3 promoter; S350A mutation augments TCR-induced FOXP3 expression and resists O-GlcNAc-dependent repression. This contrasts with c-Rel O-GlcNAcylation enhancing proautoimmune cytokine (IL-2, IFN-γ, GM-CSF) expression.","method":"Site-directed mutagenesis (S350A), ChIP, mouse models of autoimmune diabetes, O-GlcNAc inhibitor/enhancer treatment, immunoblot","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-specific mutagenesis, ChIP for promoter binding, in vivo mouse models, orthogonal chemical and genetic approaches","pmids":["33442719"],"is_preprint":false},{"year":2021,"finding":"Inherited human c-Rel deficiency (loss-of-function mutation in REL) abolishes IL-12 and IL-23 production by cDC1s and monocytes, impairs CD86 induction on cDCs, reduces IL-2 production by naive T cells (at later phases), impairs memory CD4+ T cell cytokine production, and blocks MYC and BCL2L1 induction in naive B cells, compromising B cell survival/proliferation and Ig secretion.","method":"Patient-derived cells with homozygous REL LOF mutation, cytokine ELISA, flow cytometry, B cell differentiation assays, gene expression analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — human primary cells with defined LOF mutation, multiple cell types and functional assays, comprehensive mechanistic characterization","pmids":["34623332"],"is_preprint":false},{"year":2019,"finding":"Caspase-8 enzymatic activity is required for optimal IκB kinase phosphorylation and nuclear translocation of c-Rel; overexpression of c-Rel restores IL-12 and IL-1β expression in caspase-8-deficient macrophages, placing caspase-8 upstream of c-Rel in the TLR-induced inflammatory gene expression pathway.","method":"Caspase-8-deficient macrophages, IKK phosphorylation assay, nuclear fractionation, c-Rel overexpression rescue, cytokine ELISA","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus rescue by c-Rel overexpression, IKK assay, epistasis established, multiple orthogonal methods","pmids":["31147458"],"is_preprint":false},{"year":2002,"finding":"Shc adapter protein is required for TCR-induced c-Rel nuclear translocation and IL-2 production; in Shc-deficient Jurkat cells, c-Rel activation is impaired; restoration of c-Rel activity using an ER-fusion protein rescues IL-2 promoter activation, placing Shc upstream of c-Rel in TCR signaling.","method":"Shc-deficient Jurkat mutant cells, EMSA for c-Rel nuclear translocation, inducible c-Rel-ER fusion rescue, IL-2 promoter reporter assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via Shc-deficient cells, c-Rel rescue experiment, pathway placement, single lab","pmids":["11917142"],"is_preprint":false},{"year":2005,"finding":"In naive T cells, c-Rel is associated primarily with IκBβ (not IκBα) in the resting state; priming by TNF-α and IL-1β shifts c-Rel to IκBα-associated complexes that are readily targeted by TCR signals, enabling faster and higher IL-2 and IFN-γ production; this mechanism is c-Rel-dependent and does not operate in effector T cells.","method":"c-Rel knockout mice, co-immunoprecipitation of c-Rel with IκBα vs IκBβ, cytokine RT-PCR and ELISA, cytokine priming assay in naive vs effector T cells","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP identifying differential IκB association, genetic KO, multiple cell types, mechanistic pathway defined","pmids":["16226509"],"is_preprint":false},{"year":2004,"finding":"NEMO mutations in XHM-ED patients impair CD40-mediated activation of both p65 and c-Rel in B cells; IL-4 can enhance p65 but not c-Rel activity, demonstrating that c-Rel and p65 have different activation requirements downstream of NEMO; c-Rel deficiency correlates with absent Ig somatic hypermutation and defective class switch recombination despite normal AID expression.","method":"Patient B cells with hypomorphic NEMO mutations, NF-κB subunit-specific nuclear translocation assays, microarray, functional B cell differentiation assays","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cells, subunit-selective activation assays, single lab","pmids":["15578091"],"is_preprint":false},{"year":2020,"finding":"c-Rel activation in dopaminergic neurons maintains neuronal survival by initiating anti-apoptotic gene expression; c-Rel inhibits microglial overactivation by suppressing inflammatory gene expression; pharmacological inhibition of c-Rel (IT901) aggravates MPTP-induced dopaminergic neuron damage and promotes microglial activation in vivo.","method":"MPP+-treated SH-SY5Y cells, LPS-challenged BV2 microglial cells, MPTP mouse model, c-Rel inhibitor IT901, immunoblot, immunostaining","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus cell-based assays in relevant cell types, in vivo validation, single lab","pmids":["31986466"],"is_preprint":false},{"year":1991,"finding":"The protein product of the human c-rel proto-oncogene is structurally identical to HIVEN86A, an inducible κB-binding protein; human c-Rel/HIVEN86A binds κB enhancer motifs in HIV, immunoglobulin κ, MHC class I, and IL-2R genes.","method":"Protein sequencing and peptide mapping, EMSA with defined binding sites","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical identification of protein identity, DNA binding demonstrated, replicated by same finding from independent lab (PMID 2023921)","pmids":["2030915"],"is_preprint":false},{"year":2017,"finding":"NF-κB c-Rel ablation specifically impairs generation of activated Tregs (aTregs) but not other Treg subsets; melanoma growth is reduced only in mice lacking c-Rel (not p65) in Tregs; chemical inhibition of c-Rel delays melanoma growth and potentiates anti-PD-1 therapy via aTreg-mediated immunosuppression.","method":"Conditional c-Rel and p65 knockout mice in Tregs, melanoma tumor models, anti-PD-1 combination therapy, flow cytometry","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO, subunit specificity (c-Rel vs p65 comparison), in vivo tumor models, pharmacological validation","pmids":["28886380"],"is_preprint":false},{"year":2021,"finding":"METTL3-mediated m6A modification targets c-Rel and RelA mRNAs; disruption of METTL3 leads to increased c-Rel and RelA expression via reduced YTHDF2-dependent mRNA decay, activating NF-κB and promoting IL-8 secretion that recruits tumor-associated neutrophils.","method":"meRIP-seq, RNA-seq, gain/loss-of-function studies, YTHDF2 co-knockdown, IL-8 functional assays, mouse tumor models","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — meRIP-seq identifying c-Rel as m6A target, functional pathway validation, single lab","pmids":["33484966"],"is_preprint":false},{"year":2020,"finding":"NF-κB c-Rel subunit c-Rel promotes phagocytosis and cytokine secretion in splenic macrophages; p65/c-Rel dimers are activated in hypersplenic macrophages as shown by co-immunoprecipitation; siRNA-mediated silencing of c-Rel blocks phagocytosis, secretion, and expression of IL-1α, IL-1β, IFN-γ, TGF-β1, and TNF-α.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, κB/luciferase reporter, phagocytosis assays","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying dimer composition, ChIP, siRNA KD with specific phenotype, single lab","pmids":["23195252"],"is_preprint":false},{"year":2020,"finding":"Human galectin-16 (Gal-16) localizes predominantly to the nucleus and physically interacts with c-Rel as shown by pull-down and microscale thermophoresis; this interaction suggests Gal-16 may regulate NF-κB/c-Rel-dependent signaling in lymphocytes.","method":"X-ray crystallography of Gal-16, co-immunoprecipitation pull-down, microscale thermophoresis, EGFP-tagging and cellular localization imaging","journal":"Biochimica et biophysica acta. General subjects","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pull-down and MST demonstrate interaction, but no functional consequence for c-Rel activity established in same study","pmids":["33011338"],"is_preprint":false}],"current_model":"c-Rel (REL) is a nuclear factor κB (NF-κB) family transcription factor that forms homodimers and heterodimers (notably with p50/NF-κB1 and p65/RelA) held latent in the cytoplasm by IκB proteins (including IκBα, IκBβ, and the related protein pp40); upon diverse stimuli—including antigen receptor signals transduced via Shc, the Bcl-10–MALT1 module, caspase-8, or cytokine priming—IκB is degraded or exchanged, freeing c-Rel for nuclear translocation where it binds κB DNA sites with broader sequence affinity than p65 due to a unique subdomain in its Rel homology region, activates target genes (including IL-2, IL-12p35, IL-12p40, IL-21, Bcl-xL, MnSOD, cyclin D3/E via E2F3a, Ezh2, FoxM1, and Bach2), and can simultaneously repress RelA-dependent inflammatory genes by recruiting HDAC1; post-translational mechanisms including ubiquitin–proteasome-mediated degradation (targeting a region C-terminal to the RHD), phosphorylation by PKA-Cβ, O-GlcNAcylation at Ser350 (which differentially enhances cytokine gene expression while suppressing FOXP3), calmodulin binding (which retards c-Rel nuclear import), and Peli1-dependent ubiquitylation all tune c-Rel activity, while its expression is directly transcriptionally regulated by Ets factors PU.1/Spi-B and autorepressed by c-Rel itself."},"narrative":{"mechanistic_narrative":"REL (c-Rel) is an NF-κB family transcription factor that binds κB DNA enhancer motifs in a sequence-specific manner and activates transcription, functioning as a master regulator of immune cell activation, proliferation, and survival [PMID:2023921, PMID:2030915]. It carries a C-terminal transactivation domain restrained by an N-terminal regulatory region [PMID:2204816], and a subdomain within its Rel homology region grants it broader κB-sequence affinity than RelA/p65, accounting for its selective requirement in inducing the IL-12 subunit genes Il12a and Il12b [PMID:16166378]. c-Rel acts both as a free homodimer and in heterodimers with p65/RelA, complexes held latent in the cytoplasm by IκB proteins—including a preformed cytosolic c-Rel–p65 complex masked by IκBα [PMID:8139561]—and IκBα controls c-Rel both by masking its NLS in the cytoplasm and terminating its activity in the nucleus [PMID:9488436]; in naive T cells, a resting IκBβ association is exchanged for IκBα upon cytokine priming to enable rapid TCR-driven cytokine output [PMID:16226509]. Nuclear entry and activity are tuned by post-translational mechanisms: ubiquitin–proteasome turnover targeting sequences C-terminal to the RHD [PMID:9857058], Peli1-mediated degradation antagonized by miR-155 [PMID:27481129], calmodulin binding that retards c-Rel-specific nuclear import [PMID:12556500], PKA-Cβ phosphorylation acting through p300/CBP [PMID:15197457], and O-GlcNAcylation at Ser350 that enhances proautoimmune cytokine expression while repressing FOXP3 [PMID:33442719]. Upstream, antigen-receptor and innate signals converge selectively on c-Rel via Shc [PMID:11917142], the Bcl-10/MALT1 and CARD9–Bcl10–MALT1 modules [PMID:17660823, PMID:21283787], and caspase-8-dependent IKK activation [PMID:31147458]. Functionally, c-Rel directly drives transcription of effector and proliferation programs—IL-2 through chromatin remodeling at the CD28RR [PMID:12646638], IL-21 [PMID:20639489], the cell-cycle regulators e2f3a/cyclin E and FoxM1 [PMID:14627988, PMID:20058312], and Ezh2 and Bach2 in lymphocytes [PMID:25266721, PMID:26522720]—and is essential for BCR-driven G1/S progression [PMID:12147627]. It also operates as a transcriptional repressor of RelA-dependent inflammatory genes by recruiting the co-repressor HDAC1 [PMID:32062419]. In disease and tissue contexts c-Rel specifies myeloid-derived suppressor cells and activated regulatory T cells that restrain anti-tumor immunity [PMID:33458695, PMID:28886380], drives fibrogenic metabolic reprogramming via Pfkfb3 [PMID:33168981], and supports neuronal survival through Bcl-xL and MnSOD induction [PMID:15818410, PMID:19094066]. Inherited homozygous loss-of-function REL mutation in humans abolishes IL-12/IL-23 production and impairs T and B cell function, defining a human immunodeficiency [PMID:34623332].","teleology":[{"year":1991,"claim":"Establishing that c-Rel is a bona fide sequence-specific κB-binding transcriptional activator distinguished it from the oncogenic, repressive v-Rel and defined its core molecular activity.","evidence":"Recombinant protein EMSA, reporter assays, and antibody supershift; biochemical identity with the inducible κB-binding protein HIVEN86A","pmids":["2023921","2030915"],"confidence":"High","gaps":["Did not resolve which dimer partners operate at endogenous loci","Physiological inducers and cell contexts not defined"]},{"year":1990,"claim":"Domain mapping revealed c-Rel's modular architecture—a C-terminal transactivation domain held in check by an N-terminal regulatory region—and that its promoter is autorepressed, explaining intrinsic constraints on its activity and expression.","evidence":"GAL4 fusion deletion mapping in yeast and mammalian cells; promoter-luciferase 5' deletion and co-transfection","pmids":["2204816","2284104"],"confidence":"High","gaps":["Mechanism of N-terminal autoinhibition not defined","Autorepression cofactors unknown"]},{"year":1991,"claim":"Identification of cytoplasmic ankyrin-repeat anchor proteins (pp40/IκB-like) that inhibit c-Rel DNA binding established the latency-in-cytosol model for c-Rel regulation.","evidence":"Biochemical purification, in vitro DNA-binding inhibition, immunoprecipitation and size-exclusion chromatography of a ~400 kDa complex","pmids":["1891714","1851550"],"confidence":"High","gaps":["Identities of all ~400 kDa complex components incompletely defined","Stimulus-coupled release mechanism not yet shown"]},{"year":1994,"claim":"Demonstration of a preformed cytosolic c-Rel–p65 heterodimer kept latent by IκBα, more potent than p50–p65, defined the latent complex composition that signaling must liberate.","evidence":"Native protein purification, in vitro translation reconstitution, EMSA, COS7 co-expression reporter assays","pmids":["8139561"],"confidence":"High","gaps":["In vivo stoichiometry of c-Rel dimer pools unclear","Selectivity determinants among partners not addressed"]},{"year":1998,"claim":"Dissecting IκBα's bipartite control and the ubiquitin–proteasome turnover of c-Rel established how its nuclear access and lifetime are gated; PPX/PP4 was identified as a positive regulator of DNA binding.","evidence":"IκBα domain mapping with subcellular fractionation; cell-free degradation and ubiquitination assays with deletion mutants; PPX co-IP and catalytic-mutant reporter assays","pmids":["9488436","9857058","9837938"],"confidence":"High","gaps":["The E3 ligase mediating c-Rel turnover not identified here","Phosphosites targeted by PPX unknown"]},{"year":1995,"claim":"Linking c-Rel to antigen-receptor signaling via calcineurin defined it as an inducible component of TCR/BCR-driven κB complexes, connecting it to lymphocyte activation.","evidence":"EMSA, IL-2Rα promoter reporter, FK506 inhibition and calcineurin co-expression in B and T cells","pmids":["7532676"],"confidence":"Medium","gaps":["Direct calcineurin substrate within the pathway not defined","Single lab, pharmacological inference"]},{"year":2002,"claim":"Genetic and epistasis studies placed Shc upstream of c-Rel in TCR signaling and showed c-Rel is required to remodel chromatin and drive the IL-2 gene, establishing its role in T cell effector transcription.","evidence":"Shc-deficient Jurkat rescue with c-Rel-ER; c-Rel knockout mice with restriction-enzyme accessibility assays at the IL-2 CD28RR","pmids":["11917142","12646638"],"confidence":"Medium","gaps":["Intervening signaling steps between Shc and c-Rel undefined","Chromatin remodeling machinery recruited by c-Rel not identified"]},{"year":2002,"claim":"c-Rel knockout studies established its essential role in BCR-driven G1/S progression by controlling cyclin D3, cyclin E, CDK activity and Rb phosphorylation, linking c-Rel to lymphocyte proliferation.","evidence":"c-Rel knockout B cells, cell-cycle flow cytometry, cyclin/CDK/pRb/E2F immunoblots and kinase assays","pmids":["12147627"],"confidence":"High","gaps":["Direct vs indirect control of each cyclin not resolved here","Did not establish which target gene is rate-limiting"]},{"year":2003,"claim":"Identifying e2f3a as a direct c-Rel target and showing cyclin E plus Bcl-xL rescues proliferation defined the transcriptional route by which c-Rel feeds the CDK/Rb/E2F axis.","evidence":"e2f3a promoter reporter, bcl-xL transgenic rescue, cyclin E protein transduction in c-Rel-deficient B cells","pmids":["14627988"],"confidence":"Medium","gaps":["Direct promoter occupancy by ChIP not shown in this study","Single lab"]},{"year":2003,"claim":"Demonstrating that calmodulin binds c-Rel near its NLS and selectively retards its nuclear import (but not RelA's) revealed a calcium-coupled, subunit-specific brake on c-Rel activation.","evidence":"Co-IP, CaM-binding mutant analysis, nuclear fractionation, IL-2/GM-CSF reporter assays","pmids":["12556500"],"confidence":"High","gaps":["Quantitative contribution to import kinetics in primary cells unclear","Upstream Ca2+ signal coupling not mapped"]},{"year":2001,"claim":"Showing PU.1/Spi-B directly drive c-rel transcription and that Rel reintroduction rescues B cells established the transcriptional control of c-Rel expression and its requirement for B cell homeostasis.","evidence":"c-rel promoter mapping, EMSA, bone marrow reconstitution and rescue","pmids":["11672537"],"confidence":"High","gaps":["Other transcriptional inputs to c-rel not exhaustively defined","Whether Ets control is dynamic during activation unknown"]},{"year":2001,"claim":"Cell-type-resolved knockout/ChIP studies showed c-Rel selectively controls IL-12p40 in macrophages and IL-12p35 in CD8+ dendritic cells, revealing context-specific target selectivity beyond DNA-binding affinity.","evidence":"c-Rel knockout mice, EMSA/supershift, ChIP, RT-PCR and ELISA across macrophages and DCs","pmids":["11058167","11602633"],"confidence":"High","gaps":["Cofactors imposing cell-type selectivity not identified here","Chromatin context determinants unresolved"]},{"year":2005,"claim":"A chimeric domain-swap mapped c-Rel's broad κB-sequence affinity to a 46-residue RHR subdomain and showed this intrinsic DNA-binding property—not selective coactivators—explains the c-Rel requirement at Il12a/Il12b.","evidence":"c-Rel/p65 chimeras, quantitative EMSA across κB panels, macrophage/DC knockout validation, coactivator interaction studies","pmids":["16166378"],"confidence":"High","gaps":["Structural basis for the affinity difference not solved here","Generalizability to all c-Rel-selective genes untested"]},{"year":2005,"claim":"Defining a resting IκBβ-to-IκBα exchange in naive T cells upon cytokine priming explained how prior inflammatory exposure accelerates c-Rel-dependent effector cytokine output.","evidence":"c-Rel knockout mice, differential IκBα vs IκBβ co-IP, cytokine priming assays in naive vs effector T cells","pmids":["16226509"],"confidence":"High","gaps":["Mechanism driving the IκB exchange not defined","Why effector T cells lack this circuit unexplained"]},{"year":2007,"claim":"Genetic dissection of the BCR pathway showed MALT1 selectively activates c-Rel (not RelA) downstream of Bcl-10/IKK, establishing a dedicated c-Rel survival subprogram.","evidence":"Bcl-10- and MALT1-deficient B cells, IKK assays, subunit-specific translocation and gene expression analysis","pmids":["17660823"],"confidence":"High","gaps":["Molecular basis of MALT1's subunit selectivity unresolved","Survival gene set incompletely catalogued"]},{"year":2004,"claim":"PKA-Cβ was shown to bind and directly phosphorylate c-Rel and enhance its transcription via p300/CBP, identifying a phosphorylation input that boosts c-Rel transactivation.","evidence":"Co-IP, in vitro kinase assay, EMSA, reporter assays","pmids":["15197457"],"confidence":"Medium","gaps":["Phosphoacceptor residue(s) not mapped","In vivo relevance not established"]},{"year":2010,"claim":"ChIP/EMSA and knockout studies defined direct c-Rel targets governing humoral and proliferative programs—IL-21 (Th17/Tfh/germinal center), FoxM1 (hepatocyte proliferation)—broadening c-Rel's transcriptional repertoire beyond lymphoid cytokines.","evidence":"c-Rel knockout mice, EMSA, ChIP, promoter reporters, IL-21 rescue; partial hepatectomy and CCl4 injury models","pmids":["20639489","20058312"],"confidence":"High","gaps":["Combinatorial cofactors at these promoters undefined","Tissue specificity determinants unclear"]},{"year":2011,"claim":"Innate C-type lectin signaling (Dectin-1/2) was shown to converge on c-Rel via CARD9–Bcl10–MALT1 to drive Th17-polarizing cytokines, extending the dedicated c-Rel module to antifungal innate immunity.","evidence":"MALT1 inhibition, siRNA, subunit-specific reporters and cytokine ELISA in human DCs","pmids":["21283787"],"confidence":"High","gaps":["How dectin-2 achieves exclusive c-Rel activation not resolved","Direct target promoters not mapped here"]},{"year":2011,"claim":"Co-IP domain mapping identified Foxp3 as a c-Rel interactor and cardiac ChIP identified MEF/Gata4/Tbx targets, extending c-Rel's interaction and target landscape into Treg biology and cardiac hypertrophy.","evidence":"Foxp3 co-IP with deletion mutants; c-Rel knockout mice, angiotensin model, ChIP for cardiac targets","pmids":["21490927","22210479"],"confidence":"Medium","gaps":["Functional consequence of Foxp3–c-Rel binding not tested in same study","Cardiac target regulation single lab"]},{"year":2014,"claim":"ChIP-based identification of Ezh2 (first intron) and Bach2 as direct c-Rel targets linked c-Rel to epigenetic and tumor-suppressor programs in normal and malignant lymphocytes.","evidence":"ChIP and ChIP-seq, c-Rel knockout and siRNA knockdown, RT-PCR/immunoblot in B and T cells and lymphoma lines","pmids":["25266721","26522720"],"confidence":"High","gaps":["How c-Rel coordinates these opposing tumor programs unclear","Bach2 study relied on published ChIP-seq reanalysis"]},{"year":2019,"claim":"Caspase-8 enzymatic activity was placed upstream of c-Rel by showing it is required for IKK phosphorylation/c-Rel nuclear translocation and that c-Rel overexpression rescues TLR-induced cytokines, adding a death-protease branch to c-Rel activation.","evidence":"Caspase-8-deficient macrophages, IKK phosphorylation assay, nuclear fractionation, c-Rel overexpression rescue","pmids":["31147458"],"confidence":"High","gaps":["Direct caspase-8 substrate in the pathway undefined","Selectivity for c-Rel vs other subunits not fully resolved"]},{"year":2020,"claim":"Discovery that c-Rel recruits HDAC1 to competitively occupy and repress RelA-dependent inflammatory promoters established a dual activator/repressor role, with a Y25H DNA-binding mutant abolishing repression.","evidence":"Genetic deletion, c-Rel–HDAC1 co-IP, ChIP, reporter assays, Y25H mutagenesis","pmids":["32062419"],"confidence":"High","gaps":["Genome-wide scope of repressed targets not mapped","Switch between activator and repressor modes undefined"]},{"year":2020,"claim":"Cell-type-specific knockouts established c-Rel as a driver of pathogenic programs—MDSC specification via an enhanceosome, fibrogenic metabolic reprogramming through Pfkfb3, and neuronal survival—nominating it as a therapeutic target.","evidence":"Myeloid- and hepatocyte/macrophage-specific c-Rel knockouts, tumor and fibrosis models, pharmacological inhibition; neuronal MPTP/MPP+ models with IT901","pmids":["33458695","33168981","31986466","15818410","19094066"],"confidence":"High","gaps":["Direct enhanceosome composition incompletely defined","Pfkfb3 regulation as direct vs indirect target not fully resolved"]},{"year":2021,"claim":"Defining inherited human REL deficiency demonstrated c-Rel's non-redundant role in human immunity, with loss abolishing IL-12/IL-23 production and impairing T and B cell function.","evidence":"Patient cells with homozygous REL LOF mutation, cytokine ELISA, flow cytometry, B cell differentiation and gene expression analyses","pmids":["34623332"],"confidence":"High","gaps":["Genotype–phenotype spectrum across patients incomplete","Therapeutic correction not addressed"]},{"year":2021,"claim":"Identifying O-GlcNAcylation at Ser350 and METTL3-dependent m6A control of REL mRNA revealed metabolic and epitranscriptomic layers that bias c-Rel between FOXP3 repression, proautoimmune cytokine output, and tumor-promoting NF-κB activity.","evidence":"S350A mutagenesis, ChIP, autoimmune diabetes models, O-GlcNAc chemical modulation; meRIP-seq, YTHDF2 co-knockdown, tumor models","pmids":["33442719","33484966"],"confidence":"High","gaps":["Enzymes adding/removing O-GlcNAc at Ser350 in vivo not pinned down","m6A regulation single lab"]},{"year":null,"claim":"How c-Rel's modifications, dimer composition, and cofactor recruitment are integrated to select between gene-activating, gene-repressing, pro- and anti-tumoral, and pro-survival outputs in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM state to target gene choice","Structural basis of dimer- and context-selective DNA occupancy unsolved","Functional role of several interactors (e.g. galectin-16) untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,11,12,14,27,28,31,34]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,19,34,44]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,4,5,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,16,18,23]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,22,25,39,40]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,12,22,25,27,38]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,14,27,28,31,34]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[15,16,17,28]}],"complexes":["c-Rel–p65 (RelA) NF-κB heterodimer","p50–c-Rel NF-κB heterodimer","c-Rel–IκBα latent cytoplasmic complex"],"partners":["RELA","NFKB1","NFKBIA","CALM1","PRKACB","HDAC1","FOXP3","MALT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q04864","full_name":"Proto-oncogene c-Rel","aliases":[],"length_aa":619,"mass_kda":68.5,"function":"Proto-oncogene that may play a role in differentiation and lymphopoiesis. NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. The NF-kappa-B heterodimer RELA/p65-c-Rel is a transcriptional activator","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q04864/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/REL","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RELA","stoichiometry":10.0},{"gene":"DDOST","stoichiometry":0.2},{"gene":"NFKB1","stoichiometry":0.2},{"gene":"NFKB2","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/REL","total_profiled":1310},"omim":[{"mim_id":"619652","title":"IMMUNODEFICIENCY 92; IMD92","url":"https://www.omim.org/entry/619652"},{"mim_id":"617585","title":"IMMUNODEFICIENCY 53; IMD53","url":"https://www.omim.org/entry/617585"},{"mim_id":"616704","title":"COMM DOMAIN-CONTAINING PROTEIN 10; COMMD10","url":"https://www.omim.org/entry/616704"},{"mim_id":"616701","title":"COMM DOMAIN-CONTAINING PROTEIN 4; COMMD4","url":"https://www.omim.org/entry/616701"},{"mim_id":"616699","title":"COMM DOMAIN-CONTAINING PROTEIN 2; COMMD2","url":"https://www.omim.org/entry/616699"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":35.3}],"url":"https://www.proteinatlas.org/search/REL"},"hgnc":{"alias_symbol":["I-Rel","c-Rel","HIVEN86A"],"prev_symbol":[]},"alphafold":{"accession":"Q04864","domains":[{"cath_id":"2.60.40.340","chopping":"10-177","consensus_level":"high","plddt":94.0527,"start":10,"end":177},{"cath_id":"2.60.40.10","chopping":"189-281","consensus_level":"high","plddt":97.1726,"start":189,"end":281}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04864","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q04864-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q04864-F1-predicted_aligned_error_v6.png","plddt_mean":65.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=REL","jax_strain_url":"https://www.jax.org/strain/search?query=REL"},"sequence":{"accession":"Q04864","fasta_url":"https://rest.uniprot.org/uniprotkb/Q04864.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q04864/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q04864"}},"corpus_meta":[{"pmid":"10602468","id":"PMC_10602468","title":"Aberrant 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General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/33011338","citation_count":24,"is_preprint":false},{"pmid":"31354726","id":"PMC_31354726","title":"Generation of Foxp3+CD25- Regulatory T-Cell Precursors Requires c-Rel and IκBNS.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31354726","citation_count":22,"is_preprint":false},{"pmid":"2030915","id":"PMC_2030915","title":"A member of the set of kappa B binding proteins, HIVEN86A, is a product of the human c-rel proto-oncogene.","date":"1991","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/2030915","citation_count":22,"is_preprint":false},{"pmid":"28202908","id":"PMC_28202908","title":"Silencing c-Rel in macrophages dampens Th1 and Th17 immune responses and alleviates experimental autoimmune encephalomyelitis in mice.","date":"2017","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28202908","citation_count":22,"is_preprint":false},{"pmid":"9488436","id":"PMC_9488436","title":"Distinct domains of IkappaBalpha regulate c-Rel in the cytoplasm and in the nucleus.","date":"1998","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9488436","citation_count":22,"is_preprint":false},{"pmid":"33442719","id":"PMC_33442719","title":"Negative regulation of FOXP3 expression by c-Rel O-GlcNAcylation.","date":"2021","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/33442719","citation_count":21,"is_preprint":false},{"pmid":"23195252","id":"PMC_23195252","title":"NF-κB p65 and c-Rel subunits promote phagocytosis and cytokine secretion by splenic macrophages in cirrhotic patients with hypersplenism.","date":"2012","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23195252","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47182,"output_tokens":11738,"usd":0.158808,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23170,"output_tokens":7832,"usd":0.155825,"stage2_stop_reason":"end_turn"},"total_usd":0.314633,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"The Rel-associated protein pp40 (IκB-like) inhibits DNA binding activity of p50:c-Rel heteromers and c-Rel homodimers, suggesting c-Rel is held in the cytosol by interaction with cytoplasmic anchor molecules containing ankyrin repeats.\",\n      \"method\": \"Biochemical purification and in vitro DNA binding inhibition assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purified protein, direct in vitro DNA-binding inhibition assay, replicated conceptually by multiple subsequent studies\",\n      \"pmids\": [\"1891714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"c-Rel protein binds κB DNA sites in a sequence-specific manner and activates transcription from κB-containing promoters; v-Rel, by contrast, suppresses this transcription, acting as a dominant negative.\",\n      \"method\": \"Bacterial expression, EMSA, transient transfection reporter assay, anti-rel antibody supershift\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro DNA binding with recombinant protein, transcriptional reporter assays, antibody disruption, multiple orthogonal methods in one study\",\n      \"pmids\": [\"2023921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Mouse c-Rel protein has a C-terminal transcriptional transactivation domain (residues 403–568) and an N-terminal regulatory domain that suppresses transactivation; deletion of the N-terminal half augments transactivation function.\",\n      \"method\": \"GAL4 fusion domain mapping, transient transfection reporter assay in yeast and mammalian cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution via GAL4 fusions, systematic deletion mapping, validated in two cell systems\",\n      \"pmids\": [\"2204816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"I-Rel (a novel 66 kDa Rel-related protein, alias of REL locus product) forms heterodimers with p50 and inhibits its DNA-binding activity through an N-terminal inhibitory domain, but does not associate with p65; I-Rel suppresses NF-κB-induced transcription and its expression is induced by mitogenic stimulation.\",\n      \"method\": \"cDNA cloning, co-immunoprecipitation, EMSA, transient transfection reporter assay, Northern blot\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, EMSA, reporter assay), domain mapping, single lab but comprehensive\",\n      \"pmids\": [\"1577270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"c-Rel protein exists in a high molecular weight (~400 kDa) cytoplasmic complex with other cellular proteins (including proteins of ~36 kDa, ~115 kDa, ~124 kDa) in both avian and murine cells; complex formation is not dependent on v-Rel.\",\n      \"method\": \"Immunoprecipitation, size-exclusion chromatography (Sephacryl S-400)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal IP and gel filtration in multiple cell types, single lab\",\n      \"pmids\": [\"1851550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"c-Rel forms a preformed heterodimeric complex with p65 (RelA) in the cytosol that is kept latent by IκBα association; upon stimulation this c-Rel–p65 complex translocates to the nucleus and is a potent transcriptional activator of κB-containing promoters, more active than p50–p65.\",\n      \"method\": \"Protein purification from HeLa cytosol, in vitro translation reconstitution, EMSA, co-expression in COS7 cells, transient transfection reporter assay, detergent activation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — native protein purification, reconstitution by in vitro translation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"8139561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The c-rel promoter is autoregulated: co-expression of c-Rel protein decreases expression from its own minimal promoter, demonstrating transcriptional autorepression.\",\n      \"method\": \"Promoter-luciferase reporter assay, 5′ deletion analysis, co-transfection\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter mapping with co-transfection, single lab\",\n      \"pmids\": [\"2284104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"c-Rel is a component of antigen receptor-induced κB-binding complexes in B and T cells; its induction requires both phorbol ester and ionomycin (dual signal) and is blocked by FK506 (calcineurin inhibitor); calcineurin co-expression augments c-Rel-dependent transactivation of the IL-2Rα promoter, indicating a calcineurin-dependent pathway for c-Rel activation.\",\n      \"method\": \"EMSA, transient transfection reporter assay, pharmacological inhibition (FK506), calcineurin co-expression\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus functional reporter assays, pharmacological and genetic perturbation, single lab\",\n      \"pmids\": [\"7532676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Protein phosphatase X (PPX/PP4) specifically associates with c-Rel, p50, and RelA; overexpression of catalytically active PPX (but not inactive mutants) stimulates c-Rel DNA-binding activity and NF-κB-mediated transcription, identifying PPX as a positive regulator of c-Rel.\",\n      \"method\": \"Co-immunoprecipitation, EMSA, transient transfection reporter assay, catalytic mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional reporter with catalytic mutants, single lab, two orthogonal methods\",\n      \"pmids\": [\"9837938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"c-Rel protein turnover is regulated by the ubiquitin–proteasome pathway; ubiquitinated c-Rel conjugates accumulate with proteasome inhibitors; a region between residues 118–171 (immediately C-terminal to the Rel homology domain) is important for ubiquitin conjugation, while C-terminal sequences mediate susceptibility to degradation.\",\n      \"method\": \"Cell-free in vitro degradation assay, proteasome inhibitor treatment, immunoprecipitation, deletion mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cell-free reconstitution of degradation, systematic deletion mapping, proteasome inhibitor validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9857058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"IκBα regulates c-Rel in two distinct subcellular compartments via discrete domains: the N-terminal and central ankyrin regions retain c-Rel in the cytoplasm by masking its NLS, while the central ankyrin domain plus a C-terminal PEST-proximal acidic region terminate c-Rel transcriptional activity in the nucleus.\",\n      \"method\": \"Domain deletion/mapping of IκBα, subcellular fractionation, transcriptional reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — systematic domain mapping with functional readouts in both cytoplasmic and nuclear compartments, single lab\",\n      \"pmids\": [\"9488436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"c-Rel is selectively required for IL-12 p40 gene induction in LPS-activated macrophages; p50/p65 and p50/c-Rel heterodimers bind the IL-12 p40 Rel site with comparable affinity and transactivation in vitro, yet only c-Rel deficiency dramatically reduces p40 mRNA and protein in vivo, indicating selectivity is not explained by DNA binding affinity alone.\",\n      \"method\": \"c-Rel knockout mice, EMSA, qRT-PCR, ELISA, transient transfection\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific cellular phenotype, replicated across multiple assays and cytokines, multiple labs subsequently confirmed\",\n      \"pmids\": [\"11058167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In CD8+ dendritic cells, c-Rel complexes bind directly to the IL-12 p35 promoter and are required for induced p35 transcription by microbial stimuli; this is distinct from macrophages where c-Rel controls p40, demonstrating cell-type-specific regulation of IL-12 subunits by c-Rel.\",\n      \"method\": \"c-Rel knockout mice, EMSA with supershift, chromatin immunoprecipitation (ChIP), RT-PCR, ELISA\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, direct promoter binding shown by ChIP and EMSA, multiple orthogonal methods\",\n      \"pmids\": [\"11602633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PU.1 and Spi-B Ets transcription factors directly regulate c-rel transcription through three PU.1/Spi-B binding sites in the murine c-rel promoter; loss of both Ets factors dramatically reduces c-Rel expression in splenic B cells, and Rel protein reintroduction rescues B cell numbers.\",\n      \"method\": \"Promoter analysis, EMSA, bone marrow reconstitution, rescue experiment\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — promoter mapping with EMSA, genetic rescue in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"11672537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"c-Rel is required for TCR/CD28-induced chromatin remodeling across the IL-2 gene promoter in primary CD4+ T cells; c-Rel deficiency abolishes global chromatin accessibility changes and also specifically impairs accessibility at the c-Rel binding site in the CD28RR region, paralleling loss of IL-2 mRNA and protein.\",\n      \"method\": \"c-Rel knockout mice, restriction enzyme accessibility assay (REAA), RT-PCR, ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with chromatin accessibility assay, site-specific promoter analysis, multiple orthogonal methods\",\n      \"pmids\": [\"12646638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"c-Rel is essential for BCR-mediated B cell proliferation and G1/S cell cycle progression; c-Rel-deficient B cells fail to induce cyclin D3 and cyclin E, have reduced CDK activity, incomplete pRb phosphorylation, and poor E2F expression upon BCR stimulation.\",\n      \"method\": \"c-Rel knockout mice, flow cytometry cell cycle analysis, immunoblot for cyclins/CDKs/pRb/E2F, kinase assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with mechanistic molecular readouts (cyclins, CDK activity, pRb phosphorylation), multiple orthogonal methods\",\n      \"pmids\": [\"12147627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Expression of c-Rel in HeLa cells causes G1/S growth arrest correlated with nuclear localization of c-Rel; arrest is accompanied by decreased E2F DNA binding, accumulation of hypophosphorylated Rb, reduced Cdk2 kinase activity, elevated p21WAF1 and p53 protein stability; deletion of c-Rel C-terminal transactivation domains abolishes these effects.\",\n      \"method\": \"Tetracycline-inducible expression system, in vitro Cdk2 kinase assay, EMSA, immunoblot, pulse-chase analysis, flow cytometry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — inducible expression with domain deletion, in vitro kinase assay, multiple molecular readouts, single lab\",\n      \"pmids\": [\"9343416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"c-Rel directly regulates e2f3a promoter/enhancer transcription and thereby controls cyclin E expression and cell cycle progression in B lymphocytes; Bcl-xL alone cannot rescue proliferation of c-Rel-deficient B cells, but cyclin E cooperates with Bcl-xL to restore cell cycle entry via the CDK/Rb/E2F pathway.\",\n      \"method\": \"bcl-xL transgenic rescue, cyclin E protein transduction, c-Rel-deficient B cells, reporter assay for e2f3a promoter\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and protein-transduction rescue experiments, promoter reporter assay, single lab\",\n      \"pmids\": [\"14627988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Ca2+/calmodulin (CaM) directly interacts with c-Rel and RelA near their nuclear localization signals after IκB release; CaM binding-deficient c-Rel mutants show increased nuclear accumulation and transcriptional activity on IL-2 and GM-CSF promoters, demonstrating CaM inhibits nuclear import of c-Rel specifically (but not RelA) following stimulation.\",\n      \"method\": \"Co-immunoprecipitation, CaM-binding mutant analysis, nuclear fractionation, transcriptional reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, mutational analysis, subcellular fractionation, functional reporter, differential effect on c-Rel vs RelA established mechanistically\",\n      \"pmids\": [\"12556500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A 46-residue subdomain within the 86-residue segment of c-Rel's Rel homology region (RHR) confers enhanced DNA-binding affinity to a broader range of κB sequences compared with p65, and this property—not c-Rel-specific coactivator interactions—accounts for the c-Rel-selective requirement for Il12b and Il12a gene induction.\",\n      \"method\": \"c-Rel/p65 chimeric protein analysis, EMSA with broad panel of κB sequences, macrophage/DC knockout assays, coactivator interaction studies\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — chimeric protein domain swap, quantitative EMSA, genetic KO validation, multiple orthogonal methods excluding coactivator model\",\n      \"pmids\": [\"16166378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PKA catalytic subunit beta (PKA-Cβ) physically interacts with c-Rel, directly phosphorylates it in vitro, and stimulates its transcriptional activity; coactivators p300/CBP are at least partially responsible for the enhanced activation by the c-Rel–PKA-Cβ axis.\",\n      \"method\": \"Co-immunoprecipitation, immunoprecipitation-in vitro kinase phosphorylation assay, EMSA, transcriptional reporter assay\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro phosphorylation assay plus co-IP and reporter assay, single lab\",\n      \"pmids\": [\"15197457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Neuroprotection by mGlu5 receptor agonists against amyloid-β toxicity depends on c-Rel activation; c-Rel induces MnSOD and Bcl-XL expression; RNAi knockdown of c-Rel suppresses both antiapoptotic genes and abolishes neuroprotection, while c-Rel overexpression rescues neurons from Aβ toxicity.\",\n      \"method\": \"RNA interference, c-Rel overexpression, immunoblot, neuronal viability assay in primary cortical neurons\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi and overexpression rescue, target gene validation, single lab\",\n      \"pmids\": [\"15818410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MALT1 selectively activates c-Rel (but not RelA) downstream of B cell receptor signaling; Bcl-10 is required for IKK recruitment and activation of both RelA and c-Rel, while MALT1 participates only in the c-Rel subprogram controlling a distinct survival gene subset.\",\n      \"method\": \"Bcl-10- and MALT1-deficient B cells, IKK activity assays, NF-κB subunit-specific nuclear translocation assays, gene expression analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO of pathway components, selective subunit activation tracked, multiple orthogonal methods, high-impact journal\",\n      \"pmids\": [\"17660823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Nuclear CD40 physically interacts with c-Rel (but not p65) in large B-cell lymphoma cells; nuclear CD40–c-Rel complexes bind promoters of NF-κB target genes (CD154, BLyS/BAFF, Bfl-1/A1); wild-type but not NLS-mutated CD40 enhances c-Rel-mediated BLyS promoter activation and LBCL proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, promoter reporter assay, NLS mutation analysis, proliferation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP showing nuclear complex, functional NLS mutant, single lab\",\n      \"pmids\": [\"17567982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In neurons, c-Rel-containing dimers (p50/c-Rel and RelA/c-Rel) but not p50/RelA promote Bcl-xL transcription, conferring neuroprotection; during ischemia, p50/RelA activation is associated with inhibition of c-Rel/RelA dimer, increased Bim/Noxa expression and enhanced neuronal vulnerability.\",\n      \"method\": \"Oxygen-glucose deprivation (OGD) model, mouse ischemia model, targeted RNAi knockdown of subunits, NF-κB subunit-specific EMSA, Bcl-xL and Bim promoter assays, immunoblot\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subunit-specific knockdown with mechanistic readouts, in vitro and in vivo models, single lab\",\n      \"pmids\": [\"19094066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Dectin-1 and dectin-2 C-type lectins activate c-Rel selectively via the CARD9-Bcl10-MALT1 signaling module in human dendritic cells; MALT1 inhibition abrogates c-Rel activation and Th17-polarizing cytokine (IL-1β, IL-23p19) expression; dectin-2 selectively activates c-Rel without activating other NF-κB subunits.\",\n      \"method\": \"MALT1 inhibition, siRNA knockdown, NF-κB subunit-specific reporter assays, cytokine ELISA, human DC stimulation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pathway dissection with pharmacological and genetic inhibition, subunit selectivity demonstrated, multiple orthogonal methods\",\n      \"pmids\": [\"21283787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Foxp3 directly or as part of a multimeric complex engages c-Rel; the N-terminal region of Foxp3 is required for c-Rel binding but not NFAT binding, while forkhead domain deletion abolishes NFAT but not c-Rel interaction, identifying distinct interaction domains.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutant analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP with domain mapping, single lab, no functional epistasis in same study\",\n      \"pmids\": [\"21490927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Rel is required for IL-21 gene expression in T lymphocytes; a c-Rel binding site in the proximal IL-21 promoter is confirmed to bind c-Rel in vitro and in vivo, regulating IL-21 transcription; downstream, c-Rel deficiency impairs Th17, Tfh, and germinal center B cell development.\",\n      \"method\": \"c-Rel knockout mice, EMSA, ChIP, RT-PCR, ELISA, promoter reporter assay, IL-21 rescue experiment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, direct promoter binding by EMSA and ChIP, IL-21 rescue, multiple orthogonal methods\",\n      \"pmids\": [\"20639489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"c-Rel binds the FoxM1 promoter in the regenerating liver (shown by ChIP), is required for FoxM1 induction and downstream targets cyclin B1 and Cdc25C, and regulates hepatocyte proliferation; c-Rel deficiency impairs both the inflammatory (RANTES/CCL5 induction) and fibrogenic wound-healing responses to liver injury.\",\n      \"method\": \"c-Rel knockout mice, ChIP, RT-PCR, immunoblot, partial hepatectomy and CCl4 injury models\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP showing direct promoter binding, genetic KO with specific molecular readouts, multiple in vivo models\",\n      \"pmids\": [\"20058312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-155 represses Peli1, a ubiquitin ligase that promotes c-Rel degradation; this miR-155–Peli1–c-Rel axis controls c-Rel protein levels, cellular proliferation, and CD40L expression in T follicular helper cells.\",\n      \"method\": \"miR-155- and Peli1-deficient mice, immunoblot for c-Rel protein, flow cytometry, functional T cell assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO of upstream regulators with c-Rel protein level readout, pathway placement, single lab\",\n      \"pmids\": [\"27481129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"c-Rel is a component of the TRAIL-inducible NF-κB complex in pancreatic cancer cells; siRNA knockdown of c-Rel sensitizes TRAIL-resistant PDAC cells to apoptosis; c-Rel drives expression of NFATc2 which in turn induces COX-2, constituting a c-Rel–NFATc2–COX-2 antiapoptotic pathway.\",\n      \"method\": \"siRNA knockdown, gel-shift (EMSA), gene expression array, co-transfection, pharmacological COX-2 inhibition\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA showing c-Rel in complex, siRNA KD with phenotypic rescue, pathway validation, single lab\",\n      \"pmids\": [\"25299780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"c-Rel directly activates Ezh2 transcription in lymphoid cells by binding to the first intron of the Ezh2 locus; c-Rel deficiency abolishes Ezh2 upregulation in activated B and T cells, and c-Rel knockdown in malignant cells reduces Ezh2 expression and sensitizes cells to Ezh2 inhibition.\",\n      \"method\": \"ChIP, c-Rel knockout mice, c-Rel-deficient lymphocytes, siRNA knockdown, RT-PCR, immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct intron binding, genetic KO and siRNA KD, multiple cell types, two orthogonal methods\",\n      \"pmids\": [\"25266721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"c-Rel regulates Bach2 (B-cell tumour suppressor) expression; ChIP-seq data confirm Bach2 as a c-Rel target gene in transformed human B cells; loss of c-Rel or IKK pathway inhibition reduces Bach2 expression in Burkitt lymphoma cells.\",\n      \"method\": \"ChIP-seq (published data analysis), RT-PCR, immunoblot, c-Rel knockout mice, IKK/NF-κB inhibitor treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus genetic and pharmacological perturbation, single lab\",\n      \"pmids\": [\"26522720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"c-Rel stimulates cardiac hypertrophy and fibrosis; c-Rel-deficient mice have smaller hearts and are protected from angiotensin-induced hypertrophy; ChIP identified myocyte enhancer factor (MEF), Gata4, and Tbx proteins as c-Rel transcriptional targets in the heart; p50 overexpression represses c-Rel levels and hypertrophic response.\",\n      \"method\": \"c-Rel knockout mice, angiotensin infusion model, ChIP, gene expression analysis, p50 overexpression in H9c2 cells, immunohistochemistry\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with physiological model, ChIP for target genes, single lab\",\n      \"pmids\": [\"22210479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"c-Rel functions as a transcriptional repressor of RelA-dependent inflammatory genes by selectively binding the co-repressor HDAC1 and competitively occupying promoters of inflammatory genes; a point mutation at tyrosine 25 (Y25H) in c-Rel's DNA-binding domain abolishes DNA binding and repressive function.\",\n      \"method\": \"Genetic deletion, co-immunoprecipitation (c-Rel–HDAC1), ChIP, promoter reporter assay, site-directed mutagenesis (Y25H)\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-IP, ChIP, mutagenesis, and reporter assays, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"32062419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"c-Rel specifies generation of myeloid-derived suppressor cells (MDSCs) by selectively activating pro-tumoral genes while repressing anti-tumoral genes through a c-Rel enhanceosome; myeloid-specific c-Rel deficiency markedly inhibits cancer growth in mice.\",\n      \"method\": \"Myeloid-specific c-Rel knockout mice, gene expression analysis, pharmaceutical c-Rel inhibition, tumor growth assays\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with mechanistic transcriptional readout (enhanceosome), single lab\",\n      \"pmids\": [\"33458695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"c-Rel controls metabolic reprogramming required for fibrogenic activities of hepatocytes and macrophages through Pfkfb3 as a key downstream metabolic mediator; cell-type-specific deletion of c-Rel in hepatocytes or macrophages independently suppresses liver fibrosis with additive effects when combined; pharmacological c-Rel inhibition attenuates multi-organ fibrosis.\",\n      \"method\": \"Cell-type-specific c-Rel knockout mice (hepatocyte- and macrophage-specific), carbon tetrachloride fibrosis model, gene expression analysis, pharmacological inhibition\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic KOs, identification of downstream metabolic target Pfkfb3, multiple in vivo models, additive effects showing cell autonomy\",\n      \"pmids\": [\"33168981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"c-Rel O-GlcNAcylation at serine 350 negatively regulates FOXP3 expression: hyperglycemia-induced O-GlcNAcylation decreases c-Rel binding at the FOXP3 promoter; S350A mutation augments TCR-induced FOXP3 expression and resists O-GlcNAc-dependent repression. This contrasts with c-Rel O-GlcNAcylation enhancing proautoimmune cytokine (IL-2, IFN-γ, GM-CSF) expression.\",\n      \"method\": \"Site-directed mutagenesis (S350A), ChIP, mouse models of autoimmune diabetes, O-GlcNAc inhibitor/enhancer treatment, immunoblot\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-specific mutagenesis, ChIP for promoter binding, in vivo mouse models, orthogonal chemical and genetic approaches\",\n      \"pmids\": [\"33442719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Inherited human c-Rel deficiency (loss-of-function mutation in REL) abolishes IL-12 and IL-23 production by cDC1s and monocytes, impairs CD86 induction on cDCs, reduces IL-2 production by naive T cells (at later phases), impairs memory CD4+ T cell cytokine production, and blocks MYC and BCL2L1 induction in naive B cells, compromising B cell survival/proliferation and Ig secretion.\",\n      \"method\": \"Patient-derived cells with homozygous REL LOF mutation, cytokine ELISA, flow cytometry, B cell differentiation assays, gene expression analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human primary cells with defined LOF mutation, multiple cell types and functional assays, comprehensive mechanistic characterization\",\n      \"pmids\": [\"34623332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Caspase-8 enzymatic activity is required for optimal IκB kinase phosphorylation and nuclear translocation of c-Rel; overexpression of c-Rel restores IL-12 and IL-1β expression in caspase-8-deficient macrophages, placing caspase-8 upstream of c-Rel in the TLR-induced inflammatory gene expression pathway.\",\n      \"method\": \"Caspase-8-deficient macrophages, IKK phosphorylation assay, nuclear fractionation, c-Rel overexpression rescue, cytokine ELISA\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus rescue by c-Rel overexpression, IKK assay, epistasis established, multiple orthogonal methods\",\n      \"pmids\": [\"31147458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Shc adapter protein is required for TCR-induced c-Rel nuclear translocation and IL-2 production; in Shc-deficient Jurkat cells, c-Rel activation is impaired; restoration of c-Rel activity using an ER-fusion protein rescues IL-2 promoter activation, placing Shc upstream of c-Rel in TCR signaling.\",\n      \"method\": \"Shc-deficient Jurkat mutant cells, EMSA for c-Rel nuclear translocation, inducible c-Rel-ER fusion rescue, IL-2 promoter reporter assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via Shc-deficient cells, c-Rel rescue experiment, pathway placement, single lab\",\n      \"pmids\": [\"11917142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In naive T cells, c-Rel is associated primarily with IκBβ (not IκBα) in the resting state; priming by TNF-α and IL-1β shifts c-Rel to IκBα-associated complexes that are readily targeted by TCR signals, enabling faster and higher IL-2 and IFN-γ production; this mechanism is c-Rel-dependent and does not operate in effector T cells.\",\n      \"method\": \"c-Rel knockout mice, co-immunoprecipitation of c-Rel with IκBα vs IκBβ, cytokine RT-PCR and ELISA, cytokine priming assay in naive vs effector T cells\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP identifying differential IκB association, genetic KO, multiple cell types, mechanistic pathway defined\",\n      \"pmids\": [\"16226509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NEMO mutations in XHM-ED patients impair CD40-mediated activation of both p65 and c-Rel in B cells; IL-4 can enhance p65 but not c-Rel activity, demonstrating that c-Rel and p65 have different activation requirements downstream of NEMO; c-Rel deficiency correlates with absent Ig somatic hypermutation and defective class switch recombination despite normal AID expression.\",\n      \"method\": \"Patient B cells with hypomorphic NEMO mutations, NF-κB subunit-specific nuclear translocation assays, microarray, functional B cell differentiation assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cells, subunit-selective activation assays, single lab\",\n      \"pmids\": [\"15578091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"c-Rel activation in dopaminergic neurons maintains neuronal survival by initiating anti-apoptotic gene expression; c-Rel inhibits microglial overactivation by suppressing inflammatory gene expression; pharmacological inhibition of c-Rel (IT901) aggravates MPTP-induced dopaminergic neuron damage and promotes microglial activation in vivo.\",\n      \"method\": \"MPP+-treated SH-SY5Y cells, LPS-challenged BV2 microglial cells, MPTP mouse model, c-Rel inhibitor IT901, immunoblot, immunostaining\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus cell-based assays in relevant cell types, in vivo validation, single lab\",\n      \"pmids\": [\"31986466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The protein product of the human c-rel proto-oncogene is structurally identical to HIVEN86A, an inducible κB-binding protein; human c-Rel/HIVEN86A binds κB enhancer motifs in HIV, immunoglobulin κ, MHC class I, and IL-2R genes.\",\n      \"method\": \"Protein sequencing and peptide mapping, EMSA with defined binding sites\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical identification of protein identity, DNA binding demonstrated, replicated by same finding from independent lab (PMID 2023921)\",\n      \"pmids\": [\"2030915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NF-κB c-Rel ablation specifically impairs generation of activated Tregs (aTregs) but not other Treg subsets; melanoma growth is reduced only in mice lacking c-Rel (not p65) in Tregs; chemical inhibition of c-Rel delays melanoma growth and potentiates anti-PD-1 therapy via aTreg-mediated immunosuppression.\",\n      \"method\": \"Conditional c-Rel and p65 knockout mice in Tregs, melanoma tumor models, anti-PD-1 combination therapy, flow cytometry\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO, subunit specificity (c-Rel vs p65 comparison), in vivo tumor models, pharmacological validation\",\n      \"pmids\": [\"28886380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL3-mediated m6A modification targets c-Rel and RelA mRNAs; disruption of METTL3 leads to increased c-Rel and RelA expression via reduced YTHDF2-dependent mRNA decay, activating NF-κB and promoting IL-8 secretion that recruits tumor-associated neutrophils.\",\n      \"method\": \"meRIP-seq, RNA-seq, gain/loss-of-function studies, YTHDF2 co-knockdown, IL-8 functional assays, mouse tumor models\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — meRIP-seq identifying c-Rel as m6A target, functional pathway validation, single lab\",\n      \"pmids\": [\"33484966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NF-κB c-Rel subunit c-Rel promotes phagocytosis and cytokine secretion in splenic macrophages; p65/c-Rel dimers are activated in hypersplenic macrophages as shown by co-immunoprecipitation; siRNA-mediated silencing of c-Rel blocks phagocytosis, secretion, and expression of IL-1α, IL-1β, IFN-γ, TGF-β1, and TNF-α.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, κB/luciferase reporter, phagocytosis assays\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying dimer composition, ChIP, siRNA KD with specific phenotype, single lab\",\n      \"pmids\": [\"23195252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human galectin-16 (Gal-16) localizes predominantly to the nucleus and physically interacts with c-Rel as shown by pull-down and microscale thermophoresis; this interaction suggests Gal-16 may regulate NF-κB/c-Rel-dependent signaling in lymphocytes.\",\n      \"method\": \"X-ray crystallography of Gal-16, co-immunoprecipitation pull-down, microscale thermophoresis, EGFP-tagging and cellular localization imaging\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pull-down and MST demonstrate interaction, but no functional consequence for c-Rel activity established in same study\",\n      \"pmids\": [\"33011338\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"c-Rel (REL) is a nuclear factor κB (NF-κB) family transcription factor that forms homodimers and heterodimers (notably with p50/NF-κB1 and p65/RelA) held latent in the cytoplasm by IκB proteins (including IκBα, IκBβ, and the related protein pp40); upon diverse stimuli—including antigen receptor signals transduced via Shc, the Bcl-10–MALT1 module, caspase-8, or cytokine priming—IκB is degraded or exchanged, freeing c-Rel for nuclear translocation where it binds κB DNA sites with broader sequence affinity than p65 due to a unique subdomain in its Rel homology region, activates target genes (including IL-2, IL-12p35, IL-12p40, IL-21, Bcl-xL, MnSOD, cyclin D3/E via E2F3a, Ezh2, FoxM1, and Bach2), and can simultaneously repress RelA-dependent inflammatory genes by recruiting HDAC1; post-translational mechanisms including ubiquitin–proteasome-mediated degradation (targeting a region C-terminal to the RHD), phosphorylation by PKA-Cβ, O-GlcNAcylation at Ser350 (which differentially enhances cytokine gene expression while suppressing FOXP3), calmodulin binding (which retards c-Rel nuclear import), and Peli1-dependent ubiquitylation all tune c-Rel activity, while its expression is directly transcriptionally regulated by Ets factors PU.1/Spi-B and autorepressed by c-Rel itself.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"REL (c-Rel) is an NF-κB family transcription factor that binds κB DNA enhancer motifs in a sequence-specific manner and activates transcription, functioning as a master regulator of immune cell activation, proliferation, and survival [#1, #44]. It carries a C-terminal transactivation domain restrained by an N-terminal regulatory region [#2], and a subdomain within its Rel homology region grants it broader κB-sequence affinity than RelA/p65, accounting for its selective requirement in inducing the IL-12 subunit genes Il12a and Il12b [#19]. c-Rel acts both as a free homodimer and in heterodimers with p65/RelA, complexes held latent in the cytoplasm by IκB proteins—including a preformed cytosolic c-Rel–p65 complex masked by IκBα [#5]—and IκBα controls c-Rel both by masking its NLS in the cytoplasm and terminating its activity in the nucleus [#10]; in naive T cells, a resting IκBβ association is exchanged for IκBα upon cytokine priming to enable rapid TCR-driven cytokine output [#41]. Nuclear entry and activity are tuned by post-translational mechanisms: ubiquitin–proteasome turnover targeting sequences C-terminal to the RHD [#9], Peli1-mediated degradation antagonized by miR-155 [#29], calmodulin binding that retards c-Rel-specific nuclear import [#18], PKA-Cβ phosphorylation acting through p300/CBP [#20], and O-GlcNAcylation at Ser350 that enhances proautoimmune cytokine expression while repressing FOXP3 [#37]. Upstream, antigen-receptor and innate signals converge selectively on c-Rel via Shc [#40], the Bcl-10/MALT1 and CARD9–Bcl10–MALT1 modules [#22, #25], and caspase-8-dependent IKK activation [#39]. Functionally, c-Rel directly drives transcription of effector and proliferation programs—IL-2 through chromatin remodeling at the CD28RR [#14], IL-21 [#27], the cell-cycle regulators e2f3a/cyclin E and FoxM1 [#17, #28], and Ezh2 and Bach2 in lymphocytes [#31, #32]—and is essential for BCR-driven G1/S progression [#15]. It also operates as a transcriptional repressor of RelA-dependent inflammatory genes by recruiting the co-repressor HDAC1 [#34]. In disease and tissue contexts c-Rel specifies myeloid-derived suppressor cells and activated regulatory T cells that restrain anti-tumor immunity [#35, #45], drives fibrogenic metabolic reprogramming via Pfkfb3 [#36], and supports neuronal survival through Bcl-xL and MnSOD induction [#21, #24]. Inherited homozygous loss-of-function REL mutation in humans abolishes IL-12/IL-23 production and impairs T and B cell function, defining a human immunodeficiency [#38].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing that c-Rel is a bona fide sequence-specific κB-binding transcriptional activator distinguished it from the oncogenic, repressive v-Rel and defined its core molecular activity.\",\n      \"evidence\": \"Recombinant protein EMSA, reporter assays, and antibody supershift; biochemical identity with the inducible κB-binding protein HIVEN86A\",\n      \"pmids\": [\"2023921\", \"2030915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which dimer partners operate at endogenous loci\", \"Physiological inducers and cell contexts not defined\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Domain mapping revealed c-Rel's modular architecture—a C-terminal transactivation domain held in check by an N-terminal regulatory region—and that its promoter is autorepressed, explaining intrinsic constraints on its activity and expression.\",\n      \"evidence\": \"GAL4 fusion deletion mapping in yeast and mammalian cells; promoter-luciferase 5' deletion and co-transfection\",\n      \"pmids\": [\"2204816\", \"2284104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of N-terminal autoinhibition not defined\", \"Autorepression cofactors unknown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Identification of cytoplasmic ankyrin-repeat anchor proteins (pp40/IκB-like) that inhibit c-Rel DNA binding established the latency-in-cytosol model for c-Rel regulation.\",\n      \"evidence\": \"Biochemical purification, in vitro DNA-binding inhibition, immunoprecipitation and size-exclusion chromatography of a ~400 kDa complex\",\n      \"pmids\": [\"1891714\", \"1851550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identities of all ~400 kDa complex components incompletely defined\", \"Stimulus-coupled release mechanism not yet shown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstration of a preformed cytosolic c-Rel–p65 heterodimer kept latent by IκBα, more potent than p50–p65, defined the latent complex composition that signaling must liberate.\",\n      \"evidence\": \"Native protein purification, in vitro translation reconstitution, EMSA, COS7 co-expression reporter assays\",\n      \"pmids\": [\"8139561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo stoichiometry of c-Rel dimer pools unclear\", \"Selectivity determinants among partners not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Dissecting IκBα's bipartite control and the ubiquitin–proteasome turnover of c-Rel established how its nuclear access and lifetime are gated; PPX/PP4 was identified as a positive regulator of DNA binding.\",\n      \"evidence\": \"IκBα domain mapping with subcellular fractionation; cell-free degradation and ubiquitination assays with deletion mutants; PPX co-IP and catalytic-mutant reporter assays\",\n      \"pmids\": [\"9488436\", \"9857058\", \"9837938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ligase mediating c-Rel turnover not identified here\", \"Phosphosites targeted by PPX unknown\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Linking c-Rel to antigen-receptor signaling via calcineurin defined it as an inducible component of TCR/BCR-driven κB complexes, connecting it to lymphocyte activation.\",\n      \"evidence\": \"EMSA, IL-2Rα promoter reporter, FK506 inhibition and calcineurin co-expression in B and T cells\",\n      \"pmids\": [\"7532676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct calcineurin substrate within the pathway not defined\", \"Single lab, pharmacological inference\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic and epistasis studies placed Shc upstream of c-Rel in TCR signaling and showed c-Rel is required to remodel chromatin and drive the IL-2 gene, establishing its role in T cell effector transcription.\",\n      \"evidence\": \"Shc-deficient Jurkat rescue with c-Rel-ER; c-Rel knockout mice with restriction-enzyme accessibility assays at the IL-2 CD28RR\",\n      \"pmids\": [\"11917142\", \"12646638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intervening signaling steps between Shc and c-Rel undefined\", \"Chromatin remodeling machinery recruited by c-Rel not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"c-Rel knockout studies established its essential role in BCR-driven G1/S progression by controlling cyclin D3, cyclin E, CDK activity and Rb phosphorylation, linking c-Rel to lymphocyte proliferation.\",\n      \"evidence\": \"c-Rel knockout B cells, cell-cycle flow cytometry, cyclin/CDK/pRb/E2F immunoblots and kinase assays\",\n      \"pmids\": [\"12147627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect control of each cyclin not resolved here\", \"Did not establish which target gene is rate-limiting\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying e2f3a as a direct c-Rel target and showing cyclin E plus Bcl-xL rescues proliferation defined the transcriptional route by which c-Rel feeds the CDK/Rb/E2F axis.\",\n      \"evidence\": \"e2f3a promoter reporter, bcl-xL transgenic rescue, cyclin E protein transduction in c-Rel-deficient B cells\",\n      \"pmids\": [\"14627988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy by ChIP not shown in this study\", \"Single lab\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that calmodulin binds c-Rel near its NLS and selectively retards its nuclear import (but not RelA's) revealed a calcium-coupled, subunit-specific brake on c-Rel activation.\",\n      \"evidence\": \"Co-IP, CaM-binding mutant analysis, nuclear fractionation, IL-2/GM-CSF reporter assays\",\n      \"pmids\": [\"12556500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution to import kinetics in primary cells unclear\", \"Upstream Ca2+ signal coupling not mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing PU.1/Spi-B directly drive c-rel transcription and that Rel reintroduction rescues B cells established the transcriptional control of c-Rel expression and its requirement for B cell homeostasis.\",\n      \"evidence\": \"c-rel promoter mapping, EMSA, bone marrow reconstitution and rescue\",\n      \"pmids\": [\"11672537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other transcriptional inputs to c-rel not exhaustively defined\", \"Whether Ets control is dynamic during activation unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Cell-type-resolved knockout/ChIP studies showed c-Rel selectively controls IL-12p40 in macrophages and IL-12p35 in CD8+ dendritic cells, revealing context-specific target selectivity beyond DNA-binding affinity.\",\n      \"evidence\": \"c-Rel knockout mice, EMSA/supershift, ChIP, RT-PCR and ELISA across macrophages and DCs\",\n      \"pmids\": [\"11058167\", \"11602633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors imposing cell-type selectivity not identified here\", \"Chromatin context determinants unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"A chimeric domain-swap mapped c-Rel's broad κB-sequence affinity to a 46-residue RHR subdomain and showed this intrinsic DNA-binding property—not selective coactivators—explains the c-Rel requirement at Il12a/Il12b.\",\n      \"evidence\": \"c-Rel/p65 chimeras, quantitative EMSA across κB panels, macrophage/DC knockout validation, coactivator interaction studies\",\n      \"pmids\": [\"16166378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for the affinity difference not solved here\", \"Generalizability to all c-Rel-selective genes untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defining a resting IκBβ-to-IκBα exchange in naive T cells upon cytokine priming explained how prior inflammatory exposure accelerates c-Rel-dependent effector cytokine output.\",\n      \"evidence\": \"c-Rel knockout mice, differential IκBα vs IκBβ co-IP, cytokine priming assays in naive vs effector T cells\",\n      \"pmids\": [\"16226509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism driving the IκB exchange not defined\", \"Why effector T cells lack this circuit unexplained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic dissection of the BCR pathway showed MALT1 selectively activates c-Rel (not RelA) downstream of Bcl-10/IKK, establishing a dedicated c-Rel survival subprogram.\",\n      \"evidence\": \"Bcl-10- and MALT1-deficient B cells, IKK assays, subunit-specific translocation and gene expression analysis\",\n      \"pmids\": [\"17660823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of MALT1's subunit selectivity unresolved\", \"Survival gene set incompletely catalogued\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"PKA-Cβ was shown to bind and directly phosphorylate c-Rel and enhance its transcription via p300/CBP, identifying a phosphorylation input that boosts c-Rel transactivation.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, EMSA, reporter assays\",\n      \"pmids\": [\"15197457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphoacceptor residue(s) not mapped\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"ChIP/EMSA and knockout studies defined direct c-Rel targets governing humoral and proliferative programs—IL-21 (Th17/Tfh/germinal center), FoxM1 (hepatocyte proliferation)—broadening c-Rel's transcriptional repertoire beyond lymphoid cytokines.\",\n      \"evidence\": \"c-Rel knockout mice, EMSA, ChIP, promoter reporters, IL-21 rescue; partial hepatectomy and CCl4 injury models\",\n      \"pmids\": [\"20639489\", \"20058312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial cofactors at these promoters undefined\", \"Tissue specificity determinants unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Innate C-type lectin signaling (Dectin-1/2) was shown to converge on c-Rel via CARD9–Bcl10–MALT1 to drive Th17-polarizing cytokines, extending the dedicated c-Rel module to antifungal innate immunity.\",\n      \"evidence\": \"MALT1 inhibition, siRNA, subunit-specific reporters and cytokine ELISA in human DCs\",\n      \"pmids\": [\"21283787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dectin-2 achieves exclusive c-Rel activation not resolved\", \"Direct target promoters not mapped here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Co-IP domain mapping identified Foxp3 as a c-Rel interactor and cardiac ChIP identified MEF/Gata4/Tbx targets, extending c-Rel's interaction and target landscape into Treg biology and cardiac hypertrophy.\",\n      \"evidence\": \"Foxp3 co-IP with deletion mutants; c-Rel knockout mice, angiotensin model, ChIP for cardiac targets\",\n      \"pmids\": [\"21490927\", \"22210479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Foxp3–c-Rel binding not tested in same study\", \"Cardiac target regulation single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"ChIP-based identification of Ezh2 (first intron) and Bach2 as direct c-Rel targets linked c-Rel to epigenetic and tumor-suppressor programs in normal and malignant lymphocytes.\",\n      \"evidence\": \"ChIP and ChIP-seq, c-Rel knockout and siRNA knockdown, RT-PCR/immunoblot in B and T cells and lymphoma lines\",\n      \"pmids\": [\"25266721\", \"26522720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How c-Rel coordinates these opposing tumor programs unclear\", \"Bach2 study relied on published ChIP-seq reanalysis\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Caspase-8 enzymatic activity was placed upstream of c-Rel by showing it is required for IKK phosphorylation/c-Rel nuclear translocation and that c-Rel overexpression rescues TLR-induced cytokines, adding a death-protease branch to c-Rel activation.\",\n      \"evidence\": \"Caspase-8-deficient macrophages, IKK phosphorylation assay, nuclear fractionation, c-Rel overexpression rescue\",\n      \"pmids\": [\"31147458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct caspase-8 substrate in the pathway undefined\", \"Selectivity for c-Rel vs other subunits not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that c-Rel recruits HDAC1 to competitively occupy and repress RelA-dependent inflammatory promoters established a dual activator/repressor role, with a Y25H DNA-binding mutant abolishing repression.\",\n      \"evidence\": \"Genetic deletion, c-Rel–HDAC1 co-IP, ChIP, reporter assays, Y25H mutagenesis\",\n      \"pmids\": [\"32062419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide scope of repressed targets not mapped\", \"Switch between activator and repressor modes undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cell-type-specific knockouts established c-Rel as a driver of pathogenic programs—MDSC specification via an enhanceosome, fibrogenic metabolic reprogramming through Pfkfb3, and neuronal survival—nominating it as a therapeutic target.\",\n      \"evidence\": \"Myeloid- and hepatocyte/macrophage-specific c-Rel knockouts, tumor and fibrosis models, pharmacological inhibition; neuronal MPTP/MPP+ models with IT901\",\n      \"pmids\": [\"33458695\", \"33168981\", \"31986466\", \"15818410\", \"19094066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enhanceosome composition incompletely defined\", \"Pfkfb3 regulation as direct vs indirect target not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining inherited human REL deficiency demonstrated c-Rel's non-redundant role in human immunity, with loss abolishing IL-12/IL-23 production and impairing T and B cell function.\",\n      \"evidence\": \"Patient cells with homozygous REL LOF mutation, cytokine ELISA, flow cytometry, B cell differentiation and gene expression analyses\",\n      \"pmids\": [\"34623332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype–phenotype spectrum across patients incomplete\", \"Therapeutic correction not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying O-GlcNAcylation at Ser350 and METTL3-dependent m6A control of REL mRNA revealed metabolic and epitranscriptomic layers that bias c-Rel between FOXP3 repression, proautoimmune cytokine output, and tumor-promoting NF-κB activity.\",\n      \"evidence\": \"S350A mutagenesis, ChIP, autoimmune diabetes models, O-GlcNAc chemical modulation; meRIP-seq, YTHDF2 co-knockdown, tumor models\",\n      \"pmids\": [\"33442719\", \"33484966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymes adding/removing O-GlcNAc at Ser350 in vivo not pinned down\", \"m6A regulation single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How c-Rel's modifications, dimer composition, and cofactor recruitment are integrated to select between gene-activating, gene-repressing, pro- and anti-tumoral, and pro-survival outputs in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM state to target gene choice\", \"Structural basis of dimer- and context-selective DNA occupancy unsolved\", \"Functional role of several interactors (e.g. galectin-16) untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 11, 12, 14, 27, 28, 31, 34]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 19, 34, 44]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4, 5, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 16, 18, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 22, 25, 39, 40]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 12, 22, 25, 27, 38]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 14, 27, 28, 31, 34]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [15, 16, 17, 28]}\n    ],\n    \"complexes\": [\n      \"c-Rel–p65 (RelA) NF-κB heterodimer\",\n      \"p50–c-Rel NF-κB heterodimer\",\n      \"c-Rel–IκBα latent cytoplasmic complex\"\n    ],\n    \"partners\": [\n      \"RELA\",\n      \"NFKB1\",\n      \"NFKBIA\",\n      \"CALM1\",\n      \"PRKACB\",\n      \"HDAC1\",\n      \"FOXP3\",\n      \"MALT1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}