{"gene":"RELT","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"RELT is a type I transmembrane glycoprotein with a cysteine-rich extracellular domain that activates the NF-κB pathway and selectively binds TRAF1 (but not other TRAFs). Immobilized RELT costimulates T-cell proliferation in the presence of CD3 signaling.","method":"Cloning, transfection/overexpression in cells, NF-κB reporter assay, co-immunoprecipitation/binding assay, mixed lymphocyte reaction","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assay and functional reporter assay in a single lab with two orthogonal methods","pmids":["11313261"],"is_preprint":false},{"year":2006,"finding":"RELT activates p38 and JNK but does not activate NF-κB in 293 cells upon overexpression. RELT does not bind TRAF1, 2, 3, 5, or 6. Instead, RELT binds SPAK (Ste20-related proline-alanine-rich kinase) via a 349RFRV motif in its intracellular domain; disruption of this motif or expression of kinase-dead SPAK inhibits RELT-mediated p38 and JNK activation.","method":"Yeast two-hybrid screen, co-immunoprecipitation, site-directed mutagenesis of RELT binding motif, kinase-dead dominant-negative SPAK, NF-κB reporter assay, MAPK activation assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid identification followed by mutagenesis of binding motif, dominant-negative kinase, and MAPK assays in single lab with multiple orthogonal methods","pmids":["16530727"],"is_preprint":false},{"year":2005,"finding":"RELT homologues RELL1 and RELL2 physically interact with RELT and co-localize with RELT at the plasma membrane. OSR1 kinase, identified via yeast two-hybrid screen, binds all three RELT family members and phosphorylates them in vitro.","method":"Yeast two-hybrid screen, in vitro co-immunoprecipitation, subcellular co-localization (fluorescence microscopy), in vitro kinase assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid identification, co-IP, localization imaging, and direct in vitro kinase assay in a single study with multiple orthogonal methods","pmids":["16389068"],"is_preprint":false},{"year":2009,"finding":"Overexpression of RELT in HEK 293 epithelial cells induces cell death with DNA fragmentation consistent with apoptosis; overexpression in COS-7 cells causes cell rounding and lifting without DNA fragmentation, indicating cell-type-dependent outcomes.","method":"Transient transfection/overexpression, cell death assay (morphology, DNA fragmentation)","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression phenotype replicated across two cell lines in single lab; mechanistic pathway not fully defined","pmids":["19969290"],"is_preprint":false},{"year":2011,"finding":"PLSCR1 (Phospholipid Scramblase 1) interacts physically with all RELT family members (RELT, RELL1, RELL2), co-localizes with RELT in intracellular regions of HEK-293 cells, and RELT overexpression alters PLSCR1 localization. OSR1 phosphorylates PLSCR1 in vitro only in the presence of RELT, indicating formation of a functional RELT–OSR1–PLSCR1 multiprotein complex.","method":"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence co-localization, in vitro kinase assay","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid identification, co-IP, localization imaging, and in vitro kinase assay in single lab with multiple orthogonal methods","pmids":["22052202"],"is_preprint":false},{"year":2017,"finding":"RELT family members activate p38 MAPK upon overexpression in HEK-293 cells; this activation is blocked by dominant-negative forms of OSR1 or TRAF2, implicating both in RELT signaling. RELT-induced apoptosis is not prevented by blocking FADD or Caspase-8, indicating a pathway distinct from death-domain-containing TNFRs such as TNFR1. Deletion mutagenesis suggests the apoptotic function requires the full intracellular domain, consistent with a novel death domain at the carboxyl-terminus.","method":"Overexpression, dominant-negative mutants of OSR1 and TRAF2, deletion mutagenesis of RELT intracellular domain, FADD/Caspase-8 blockade, MAPK activation assay, apoptosis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutants and pathway inhibitors used in single lab with several orthogonal approaches","pmids":["28688764"],"is_preprint":false},{"year":2018,"finding":"In RELT knockout mice, loss of RELT selectively promotes homeostatic proliferation of CD4+ T cells and enhances anti-tumor CD8+ T-cell responses, demonstrating that RELT acts as a negative regulator of the early phase of T-cell activation, likely by promoting T-cell apoptosis.","method":"RELT knockout (RELT-/- mice), adoptive transfer model, in vivo tumor model, T-cell proliferation and response assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO mouse model with defined cellular phenotype, single lab","pmids":["30138536"],"is_preprint":false},{"year":2018,"finding":"Loss-of-function mutations in RELT cause autosomal recessive amelogenesis imperfecta. Relt-/- mice (generated by CRISPR/Cas9) exhibit enamel malformations with rough surface, rapid attrition, and abnormal hypermineralization at the dentino-enamel junction; Relt mRNA is expressed specifically by secretory-stage ameloblasts and odontoblasts.","method":"Human genetics (homozygosity mapping, sequencing), CRISPR/Cas9 knockout mice, RNAscope in situ hybridization, micro-CT/histology of teeth","journal":"Clinical genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human disease genetics combined with CRISPR KO mouse model and direct in situ localization, independently supported by multiple families","pmids":["30506946"],"is_preprint":false},{"year":2019,"finding":"ADAM10 (but not ADAM17) cleaves the extracellular domain of RELT. ADAM10 is expressed by ameloblasts from the apical loop through the secretory stage, linking RELT ectodomain shedding to enamel development.","method":"PCR screen for ADAM expression in enamel organs, cell migration/invasion assay (Matrigel), proteolytic cleavage assay comparing ADAM10 and ADAM17 activity on RELT extracellular domain","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical cleavage assay distinguishing ADAM10 from ADAM17, combined with expression data in single lab","pmids":["31575895"],"is_preprint":false},{"year":2020,"finding":"MDFIC (MyoD family inhibitor domain-containing protein) physically interacts with RELT, RELL1, and RELL2. Co-IP deletion mutant analysis identified regions of MDFIC and RELT important for their physical association. MDFIC co-localizes with RELT family members at the plasma membrane.","method":"Yeast two-hybrid screen, co-immunoprecipitation with deletion mutants, immunofluorescence co-localization","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus co-IP with deletion mapping and co-localization in single lab","pmids":["33367115"],"is_preprint":false},{"year":2024,"finding":"Nuclear localization of RELT was detected in MDA-MB-231 breast cancer cells and HEK-293 cells. RELT overexpression induces apoptosis (phosphatidylserine externalization, Caspase-3/7 activation) in breast cancer cells; co-transfection of constructs predicted to block OXSR1-mediated phosphorylation of RELT did not abrogate RELT-induced apoptosis, indicating OXSR1 phosphorylation is not required for RELT-induced cell death.","method":"Immunofluorescence, western blotting (nuclear fractionation), flow cytometry (phosphatidylserine, Caspase-3/7), co-immunoprecipitation with OXSR1-binding mutant","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple orthogonal methods in single lab; nuclear localization finding is novel but not yet functionally linked","pmids":["39767574"],"is_preprint":false},{"year":2024,"finding":"LILRB4 on multiple myeloma cells promotes osteoclast differentiation and bone lesion by upregulating secreted RELT; exogenous or overexpressed RELT rescues bone damage in LILRB4-KO cells both in vitro and in vivo, placing RELT downstream of LILRB4 in a p-SHP2/NF-κB signaling axis.","method":"LILRB4 knockout, conditioned medium experiments, cytokine array, co-immunoprecipitation, luciferase reporter assay, xenograft/syngeneic/PDX mouse models, micro-CT","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo rescue experiments placing RELT downstream of LILRB4, single lab","pmids":["38951916"],"is_preprint":false}],"current_model":"RELT is a type I transmembrane TNF receptor superfamily member that signals through SPAK and OSR1 kinases (binding via a 349RFRV intracellular motif) to activate p38 and JNK MAPKs, interacts with TRAF1, PLSCR1, and MDFIC as binding partners, undergoes ectodomain shedding by ADAM10, can translocate to the nucleus, induces apoptosis through a FADD/Caspase-8-independent pathway requiring its full intracellular domain, negatively regulates T-cell activation in vivo (shown by KO mice), and is required for normal enamel formation during the secretory stage of amelogenesis (evidenced by human loss-of-function mutations and CRISPR KO mice causing amelogenesis imperfecta)."},"narrative":{"mechanistic_narrative":"RELT is a type I transmembrane TNF receptor superfamily member with a cysteine-rich extracellular domain that couples to the Ste20-related kinases SPAK and OSR1 to drive stress-MAPK signaling and apoptosis [PMID:11313261, PMID:16530727, PMID:16389068]. RELT binds SPAK through a 349RFRV motif in its intracellular domain to activate p38 and JNK, and disrupting this motif or using kinase-dead SPAK abolishes the response [PMID:16530727]; OSR1 binds and phosphorylates RELT and its homologues RELL1/RELL2, and assembles with RELT and the substrate PLSCR1 into a membrane-associated multiprotein complex [PMID:16389068, PMID:22052202]. RELT overexpression induces apoptosis in a cell-type-dependent manner through a FADD/Caspase-8-independent route that requires the full intracellular domain and does not depend on OXSR1-mediated phosphorylation [PMID:19969290, PMID:28688764, PMID:39767574]. The receptor is regulated by ADAM10-mediated ectodomain shedding [PMID:31575895] and additionally interacts with TRAF1 and MDFIC [PMID:11313261, PMID:33367115]. Physiologically, RELT negatively regulates the early phase of T-cell activation in vivo, restraining CD4+ homeostatic proliferation and CD8+ anti-tumor responses [PMID:30138536]. Loss-of-function mutations in RELT cause autosomal recessive amelogenesis imperfecta, and RELT is expressed by secretory-stage ameloblasts and odontoblasts where it is required for normal enamel formation [PMID:30506946].","teleology":[{"year":2001,"claim":"Establishing RELT as a TNFRSF member, the first study showed it engaged NF-κB signaling, bound TRAF1 selectively, and costimulated T cells, framing it as an immune-regulatory receptor.","evidence":"Cloning, NF-κB reporter, co-IP binding assay, and mixed lymphocyte reaction in transfected cells","pmids":["11313261"],"confidence":"Medium","gaps":["NF-κB activation not reproduced in later work","endogenous ligand unidentified","physiological TRAF1 dependence untested"]},{"year":2005,"claim":"Identifying OSR1 as a binding kinase that phosphorylates RELT, RELL1, and RELL2 defined the RELT family as substrates of a Ste20-related kinase at the plasma membrane.","evidence":"Yeast two-hybrid, co-IP, co-localization microscopy, and in vitro kinase assay","pmids":["16389068"],"confidence":"High","gaps":["functional consequence of OSR1 phosphorylation undefined","phosphorylation sites not mapped"]},{"year":2006,"claim":"Mapping the 349RFRV motif that recruits SPAK and showing it is required for p38/JNK activation pinpointed the structural determinant linking RELT to stress-MAPK signaling, while contradicting the earlier NF-κB/TRAF model.","evidence":"Yeast two-hybrid, co-IP, motif mutagenesis, dominant-negative kinase, and MAPK/NF-κB reporter assays in 293 cells","pmids":["16530727"],"confidence":"High","gaps":["discrepancy with 2001 NF-κB/TRAF1 findings unresolved","all data from overexpression","no endogenous-level validation"]},{"year":2009,"claim":"Demonstrating that RELT overexpression triggers apoptosis with cell-type-dependent outcomes established RELT as a death-inducing receptor.","evidence":"Transient overexpression with morphology and DNA-fragmentation assays in HEK-293 and COS-7 cells","pmids":["19969290"],"confidence":"Medium","gaps":["apoptotic pathway not defined","overexpression-only evidence","no link to physiological signaling"]},{"year":2011,"claim":"Showing OSR1 phosphorylates PLSCR1 only in the presence of RELT defined a functional RELT–OSR1–PLSCR1 complex, connecting the receptor to a phospholipid scramblase substrate.","evidence":"Yeast two-hybrid, co-IP, immunofluorescence, and RELT-dependent in vitro kinase assay","pmids":["22052202"],"confidence":"Medium","gaps":["downstream effect of PLSCR1 phosphorylation unknown","complex not validated endogenously"]},{"year":2017,"claim":"Defining RELT-induced apoptosis as FADD/Caspase-8-independent and requiring the full intracellular domain distinguished RELT from classical death-domain TNFRs and implicated OSR1/TRAF2 in its MAPK output.","evidence":"Deletion mutagenesis, OSR1/TRAF2 dominant-negatives, FADD/Caspase-8 blockade, MAPK and apoptosis assays in HEK-293","pmids":["28688764"],"confidence":"Medium","gaps":["the putative C-terminal death domain not structurally confirmed","effector caspases not identified","overexpression-based"]},{"year":2018,"claim":"A RELT knockout mouse revealed RELT as an in vivo negative regulator of early T-cell activation, providing the first physiological role linked to its apoptotic activity.","evidence":"RELT-/- mice, adoptive transfer, in vivo tumor model, T-cell proliferation/response assays","pmids":["30138536"],"confidence":"Medium","gaps":["molecular pathway in T cells not delineated","ligand and upstream activation signal unknown"]},{"year":2018,"claim":"Human loss-of-function mutations plus CRISPR KO mice established RELT as causative for autosomal recessive amelogenesis imperfacta, assigning it an unexpected role in enamel biology.","evidence":"Homozygosity mapping/sequencing, CRISPR/Cas9 mice, RNAscope, micro-CT/histology","pmids":["30506946"],"confidence":"High","gaps":["signaling mechanism in ameloblasts undefined","link between MAPK/apoptosis activity and enamel formation unestablished"]},{"year":2019,"claim":"Identifying ADAM10 as the specific sheddase of the RELT ectodomain in ameloblasts introduced post-translational regulation of RELT during enamel development.","evidence":"ADAM expression PCR in enamel organs and ADAM10-vs-ADAM17 proteolytic cleavage assay","pmids":["31575895"],"confidence":"Medium","gaps":["functional consequence of shedding for signaling not shown","fate of shed fragments unknown"]},{"year":2020,"claim":"Mapping a physical MDFIC–RELT interaction added a new membrane-associated binding partner to the RELT family interactome.","evidence":"Yeast two-hybrid, co-IP with deletion mapping, immunofluorescence co-localization","pmids":["33367115"],"confidence":"Medium","gaps":["functional role of MDFIC binding unknown","single-lab interaction"]},{"year":2024,"claim":"Detecting nuclear RELT and confirming OXSR1-phosphorylation-independent apoptosis in breast cancer cells extended RELT's death activity beyond immune cells and decoupled it from OSR1 phosphorylation.","evidence":"Nuclear fractionation/western, immunofluorescence, flow cytometry (PS, Caspase-3/7), co-IP with OXSR1-binding mutant in MDA-MB-231 and HEK-293","pmids":["39767574"],"confidence":"Medium","gaps":["function of nuclear RELT undefined","mechanism of nuclear translocation unknown"]},{"year":2024,"claim":"Placing secreted RELT downstream of LILRB4 in myeloma-driven osteoclastogenesis linked RELT to bone pathology via a p-SHP2/NF-κB axis.","evidence":"LILRB4 KO, conditioned medium, cytokine array, co-IP, luciferase reporter, xenograft/PDX models, micro-CT","pmids":["38951916"],"confidence":"Medium","gaps":["receptor mediating secreted RELT's osteoclast effect unidentified","relationship to ADAM10 shedding unclear"]},{"year":null,"claim":"How RELT's SPAK/OSR1-coupled MAPK signaling, its caspase-independent apoptotic activity, and its tissue roles in enamel formation, T-cell regulation, and bone remodeling are mechanistically unified — and what its physiological ligand is — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no identified endogenous ligand","C-terminal death domain unconfirmed structurally","mechanism connecting receptor signaling to enamel biology unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,5,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,6]}],"complexes":["RELT–OSR1–PLSCR1 complex"],"partners":["SPAK","OXSR1","PLSCR1","TRAF1","MDFIC","RELL1","RELL2","ADAM10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969Z4","full_name":"Tumor necrosis factor receptor superfamily member 19L","aliases":["Receptor expressed in lymphoid tissues"],"length_aa":430,"mass_kda":46.1,"function":"May play a role in apoptosis (PubMed:19969290, PubMed:28688764). Induces activation of MAPK14/p38 and MAPK8/JNK MAPK cascades, when overexpressed (PubMed:16530727). Involved in dental enamel formation (PubMed:30506946)","subcellular_location":"Cell membrane; Cytoplasm; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q969Z4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RELT","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RELT","total_profiled":1310},"omim":[{"mim_id":"618386","title":"AMELOGENESIS IMPERFECTA, TYPE IIIC; AI3C","url":"https://www.omim.org/entry/618386"},{"mim_id":"611213","title":"RELT-LIKE 2; RELL2","url":"https://www.omim.org/entry/611213"},{"mim_id":"611212","title":"RELT-LIKE 1; RELL1","url":"https://www.omim.org/entry/611212"},{"mim_id":"611211","title":"RECEPTOR EXPRESSED IN LYMPHOID TISSUES; RELT","url":"https://www.omim.org/entry/611211"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":146.0}],"url":"https://www.proteinatlas.org/search/RELT"},"hgnc":{"alias_symbol":["FLJ14993"],"prev_symbol":["TNFRSF19L"]},"alphafold":{"accession":"Q969Z4","domains":[{"cath_id":"1.20.5","chopping":"159-190","consensus_level":"medium","plddt":91.4847,"start":159,"end":190}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969Z4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969Z4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969Z4-F1-predicted_aligned_error_v6.png","plddt_mean":62.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RELT","jax_strain_url":"https://www.jax.org/strain/search?query=RELT"},"sequence":{"accession":"Q969Z4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969Z4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969Z4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969Z4"}},"corpus_meta":[{"pmid":"11313261","id":"PMC_11313261","title":"RELT, a new member of the tumor necrosis factor receptor superfamily, is selectively expressed in hematopoietic tissues and activates transcription factor NF-kappaB.","date":"2001","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11313261","citation_count":62,"is_preprint":false},{"pmid":"30506946","id":"PMC_30506946","title":"Mutations in RELT cause autosomal recessive amelogenesis imperfecta.","date":"2018","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30506946","citation_count":48,"is_preprint":false},{"pmid":"16530727","id":"PMC_16530727","title":"The TNF receptor, RELT, binds SPAK and uses it to mediate p38 and JNK activation.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16530727","citation_count":40,"is_preprint":false},{"pmid":"19969290","id":"PMC_19969290","title":"RELT induces cellular death in HEK 293 epithelial cells.","date":"2009","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19969290","citation_count":39,"is_preprint":false},{"pmid":"28688764","id":"PMC_28688764","title":"RELT family members activate p38 and induce apoptosis by a mechanism distinct from TNFR1.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28688764","citation_count":38,"is_preprint":false},{"pmid":"16389068","id":"PMC_16389068","title":"Identification of RELT homologues that associate with RELT and are phosphorylated by OSR1.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16389068","citation_count":31,"is_preprint":false},{"pmid":"32052416","id":"PMC_32052416","title":"New missense variants in RELT causing hypomineralised amelogenesis imperfecta.","date":"2020","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32052416","citation_count":18,"is_preprint":false},{"pmid":"30138536","id":"PMC_30138536","title":"RELT negatively regulates the early phase of the T-cell response in mice.","date":"2018","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30138536","citation_count":17,"is_preprint":false},{"pmid":"38951916","id":"PMC_38951916","title":"LILRB4 on multiple myeloma cells promotes bone lesion by p-SHP2/NF-κB/RELT signal pathway.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38951916","citation_count":16,"is_preprint":false},{"pmid":"31575895","id":"PMC_31575895","title":"ADAM10 is Expressed by Ameloblasts, Cleaves the RELT TNF Receptor Extracellular Domain and Facilitates Enamel Development.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31575895","citation_count":16,"is_preprint":false},{"pmid":"22052202","id":"PMC_22052202","title":"Identification of PLSCR1 as a protein that interacts with RELT family members.","date":"2011","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22052202","citation_count":16,"is_preprint":false},{"pmid":"37893069","id":"PMC_37893069","title":"The RELT Family of Proteins: An Increasing Awareness of Their Importance for Cancer, the Immune System, and Development.","date":"2023","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/37893069","citation_count":12,"is_preprint":false},{"pmid":"34121605","id":"PMC_34121605","title":"RELT promotes the growth of esophageal squamous cell carcinoma by activating the NF-κB pathway.","date":"2021","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/34121605","citation_count":8,"is_preprint":false},{"pmid":"33367115","id":"PMC_33367115","title":"RELT stains prominently in B-cell lymphomas and binds the hematopoietic transcription factor MDFIC.","date":"2020","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/33367115","citation_count":6,"is_preprint":false},{"pmid":"37670079","id":"PMC_37670079","title":"Oro-dental phenotyping and report of three families with RELT-associated amelogenesis imperfecta.","date":"2023","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/37670079","citation_count":5,"is_preprint":false},{"pmid":"28508139","id":"PMC_28508139","title":"Functional annotation of a novel toxin-antitoxin system Xn-RelT of Xenorhabdus nematophila; a combined in silico and in vitro approach.","date":"2017","source":"Journal of molecular modeling","url":"https://pubmed.ncbi.nlm.nih.gov/28508139","citation_count":4,"is_preprint":false},{"pmid":"39767574","id":"PMC_39767574","title":"RELT Is Upregulated in Breast Cancer and Induces Death in Breast Cancer Cells.","date":"2024","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/39767574","citation_count":1,"is_preprint":false},{"pmid":"38996888","id":"PMC_38996888","title":"Recombinant human protein TCFL5-activated NRSN2-AS1 promotes esophageal cancer progression via the microRNA-874-5p/RELT regulatory axis.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38996888","citation_count":1,"is_preprint":false},{"pmid":"41376629","id":"PMC_41376629","title":"Immune-related RELT drives clear cell renal cell carcinoma progression through JAK/STAT signaling pathway activation.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41376629","citation_count":0,"is_preprint":false},{"pmid":"39856501","id":"PMC_39856501","title":"[Frameshift mutation in RELT gene causes amelogenesis imperfecta].","date":"2025","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39856501","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11553,"output_tokens":3247,"usd":0.041682,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10608,"output_tokens":3824,"usd":0.07432,"stage2_stop_reason":"end_turn"},"total_usd":0.116002,"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\": 2001,\n      \"finding\": \"RELT is a type I transmembrane glycoprotein with a cysteine-rich extracellular domain that activates the NF-κB pathway and selectively binds TRAF1 (but not other TRAFs). Immobilized RELT costimulates T-cell proliferation in the presence of CD3 signaling.\",\n      \"method\": \"Cloning, transfection/overexpression in cells, NF-κB reporter assay, co-immunoprecipitation/binding assay, mixed lymphocyte reaction\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assay and functional reporter assay in a single lab with two orthogonal methods\",\n      \"pmids\": [\"11313261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RELT activates p38 and JNK but does not activate NF-κB in 293 cells upon overexpression. RELT does not bind TRAF1, 2, 3, 5, or 6. Instead, RELT binds SPAK (Ste20-related proline-alanine-rich kinase) via a 349RFRV motif in its intracellular domain; disruption of this motif or expression of kinase-dead SPAK inhibits RELT-mediated p38 and JNK activation.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, site-directed mutagenesis of RELT binding motif, kinase-dead dominant-negative SPAK, NF-κB reporter assay, MAPK activation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid identification followed by mutagenesis of binding motif, dominant-negative kinase, and MAPK assays in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16530727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RELT homologues RELL1 and RELL2 physically interact with RELT and co-localize with RELT at the plasma membrane. OSR1 kinase, identified via yeast two-hybrid screen, binds all three RELT family members and phosphorylates them in vitro.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro co-immunoprecipitation, subcellular co-localization (fluorescence microscopy), in vitro kinase assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid identification, co-IP, localization imaging, and direct in vitro kinase assay in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"16389068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Overexpression of RELT in HEK 293 epithelial cells induces cell death with DNA fragmentation consistent with apoptosis; overexpression in COS-7 cells causes cell rounding and lifting without DNA fragmentation, indicating cell-type-dependent outcomes.\",\n      \"method\": \"Transient transfection/overexpression, cell death assay (morphology, DNA fragmentation)\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression phenotype replicated across two cell lines in single lab; mechanistic pathway not fully defined\",\n      \"pmids\": [\"19969290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PLSCR1 (Phospholipid Scramblase 1) interacts physically with all RELT family members (RELT, RELL1, RELL2), co-localizes with RELT in intracellular regions of HEK-293 cells, and RELT overexpression alters PLSCR1 localization. OSR1 phosphorylates PLSCR1 in vitro only in the presence of RELT, indicating formation of a functional RELT–OSR1–PLSCR1 multiprotein complex.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence co-localization, in vitro kinase assay\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid identification, co-IP, localization imaging, and in vitro kinase assay in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22052202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RELT family members activate p38 MAPK upon overexpression in HEK-293 cells; this activation is blocked by dominant-negative forms of OSR1 or TRAF2, implicating both in RELT signaling. RELT-induced apoptosis is not prevented by blocking FADD or Caspase-8, indicating a pathway distinct from death-domain-containing TNFRs such as TNFR1. Deletion mutagenesis suggests the apoptotic function requires the full intracellular domain, consistent with a novel death domain at the carboxyl-terminus.\",\n      \"method\": \"Overexpression, dominant-negative mutants of OSR1 and TRAF2, deletion mutagenesis of RELT intracellular domain, FADD/Caspase-8 blockade, MAPK activation assay, apoptosis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutants and pathway inhibitors used in single lab with several orthogonal approaches\",\n      \"pmids\": [\"28688764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In RELT knockout mice, loss of RELT selectively promotes homeostatic proliferation of CD4+ T cells and enhances anti-tumor CD8+ T-cell responses, demonstrating that RELT acts as a negative regulator of the early phase of T-cell activation, likely by promoting T-cell apoptosis.\",\n      \"method\": \"RELT knockout (RELT-/- mice), adoptive transfer model, in vivo tumor model, T-cell proliferation and response assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO mouse model with defined cellular phenotype, single lab\",\n      \"pmids\": [\"30138536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss-of-function mutations in RELT cause autosomal recessive amelogenesis imperfecta. Relt-/- mice (generated by CRISPR/Cas9) exhibit enamel malformations with rough surface, rapid attrition, and abnormal hypermineralization at the dentino-enamel junction; Relt mRNA is expressed specifically by secretory-stage ameloblasts and odontoblasts.\",\n      \"method\": \"Human genetics (homozygosity mapping, sequencing), CRISPR/Cas9 knockout mice, RNAscope in situ hybridization, micro-CT/histology of teeth\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human disease genetics combined with CRISPR KO mouse model and direct in situ localization, independently supported by multiple families\",\n      \"pmids\": [\"30506946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM10 (but not ADAM17) cleaves the extracellular domain of RELT. ADAM10 is expressed by ameloblasts from the apical loop through the secretory stage, linking RELT ectodomain shedding to enamel development.\",\n      \"method\": \"PCR screen for ADAM expression in enamel organs, cell migration/invasion assay (Matrigel), proteolytic cleavage assay comparing ADAM10 and ADAM17 activity on RELT extracellular domain\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical cleavage assay distinguishing ADAM10 from ADAM17, combined with expression data in single lab\",\n      \"pmids\": [\"31575895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MDFIC (MyoD family inhibitor domain-containing protein) physically interacts with RELT, RELL1, and RELL2. Co-IP deletion mutant analysis identified regions of MDFIC and RELT important for their physical association. MDFIC co-localizes with RELT family members at the plasma membrane.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation with deletion mutants, immunofluorescence co-localization\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus co-IP with deletion mapping and co-localization in single lab\",\n      \"pmids\": [\"33367115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nuclear localization of RELT was detected in MDA-MB-231 breast cancer cells and HEK-293 cells. RELT overexpression induces apoptosis (phosphatidylserine externalization, Caspase-3/7 activation) in breast cancer cells; co-transfection of constructs predicted to block OXSR1-mediated phosphorylation of RELT did not abrogate RELT-induced apoptosis, indicating OXSR1 phosphorylation is not required for RELT-induced cell death.\",\n      \"method\": \"Immunofluorescence, western blotting (nuclear fractionation), flow cytometry (phosphatidylserine, Caspase-3/7), co-immunoprecipitation with OXSR1-binding mutant\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple orthogonal methods in single lab; nuclear localization finding is novel but not yet functionally linked\",\n      \"pmids\": [\"39767574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LILRB4 on multiple myeloma cells promotes osteoclast differentiation and bone lesion by upregulating secreted RELT; exogenous or overexpressed RELT rescues bone damage in LILRB4-KO cells both in vitro and in vivo, placing RELT downstream of LILRB4 in a p-SHP2/NF-κB signaling axis.\",\n      \"method\": \"LILRB4 knockout, conditioned medium experiments, cytokine array, co-immunoprecipitation, luciferase reporter assay, xenograft/syngeneic/PDX mouse models, micro-CT\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo rescue experiments placing RELT downstream of LILRB4, single lab\",\n      \"pmids\": [\"38951916\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RELT is a type I transmembrane TNF receptor superfamily member that signals through SPAK and OSR1 kinases (binding via a 349RFRV intracellular motif) to activate p38 and JNK MAPKs, interacts with TRAF1, PLSCR1, and MDFIC as binding partners, undergoes ectodomain shedding by ADAM10, can translocate to the nucleus, induces apoptosis through a FADD/Caspase-8-independent pathway requiring its full intracellular domain, negatively regulates T-cell activation in vivo (shown by KO mice), and is required for normal enamel formation during the secretory stage of amelogenesis (evidenced by human loss-of-function mutations and CRISPR KO mice causing amelogenesis imperfecta).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RELT is a type I transmembrane TNF receptor superfamily member with a cysteine-rich extracellular domain that couples to the Ste20-related kinases SPAK and OSR1 to drive stress-MAPK signaling and apoptosis [#0, #1, #2]. RELT binds SPAK through a 349RFRV motif in its intracellular domain to activate p38 and JNK, and disrupting this motif or using kinase-dead SPAK abolishes the response [#1]; OSR1 binds and phosphorylates RELT and its homologues RELL1/RELL2, and assembles with RELT and the substrate PLSCR1 into a membrane-associated multiprotein complex [#2, #4]. RELT overexpression induces apoptosis in a cell-type-dependent manner through a FADD/Caspase-8-independent route that requires the full intracellular domain and does not depend on OXSR1-mediated phosphorylation [#3, #5, #10]. The receptor is regulated by ADAM10-mediated ectodomain shedding [#8] and additionally interacts with TRAF1 and MDFIC [#0, #9]. Physiologically, RELT negatively regulates the early phase of T-cell activation in vivo, restraining CD4+ homeostatic proliferation and CD8+ anti-tumor responses [#6]. Loss-of-function mutations in RELT cause autosomal recessive amelogenesis imperfecta, and RELT is expressed by secretory-stage ameloblasts and odontoblasts where it is required for normal enamel formation [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing RELT as a TNFRSF member, the first study showed it engaged NF-\\u03baB signaling, bound TRAF1 selectively, and costimulated T cells, framing it as an immune-regulatory receptor.\",\n      \"evidence\": \"Cloning, NF-\\u03baB reporter, co-IP binding assay, and mixed lymphocyte reaction in transfected cells\",\n      \"pmids\": [\"11313261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NF-\\u03baB activation not reproduced in later work\", \"endogenous ligand unidentified\", \"physiological TRAF1 dependence untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying OSR1 as a binding kinase that phosphorylates RELT, RELL1, and RELL2 defined the RELT family as substrates of a Ste20-related kinase at the plasma membrane.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, co-localization microscopy, and in vitro kinase assay\",\n      \"pmids\": [\"16389068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"functional consequence of OSR1 phosphorylation undefined\", \"phosphorylation sites not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapping the 349RFRV motif that recruits SPAK and showing it is required for p38/JNK activation pinpointed the structural determinant linking RELT to stress-MAPK signaling, while contradicting the earlier NF-\\u03baB/TRAF model.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, motif mutagenesis, dominant-negative kinase, and MAPK/NF-\\u03baB reporter assays in 293 cells\",\n      \"pmids\": [\"16530727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"discrepancy with 2001 NF-\\u03baB/TRAF1 findings unresolved\", \"all data from overexpression\", \"no endogenous-level validation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that RELT overexpression triggers apoptosis with cell-type-dependent outcomes established RELT as a death-inducing receptor.\",\n      \"evidence\": \"Transient overexpression with morphology and DNA-fragmentation assays in HEK-293 and COS-7 cells\",\n      \"pmids\": [\"19969290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"apoptotic pathway not defined\", \"overexpression-only evidence\", \"no link to physiological signaling\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing OSR1 phosphorylates PLSCR1 only in the presence of RELT defined a functional RELT\\u2013OSR1\\u2013PLSCR1 complex, connecting the receptor to a phospholipid scramblase substrate.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, immunofluorescence, and RELT-dependent in vitro kinase assay\",\n      \"pmids\": [\"22052202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"downstream effect of PLSCR1 phosphorylation unknown\", \"complex not validated endogenously\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining RELT-induced apoptosis as FADD/Caspase-8-independent and requiring the full intracellular domain distinguished RELT from classical death-domain TNFRs and implicated OSR1/TRAF2 in its MAPK output.\",\n      \"evidence\": \"Deletion mutagenesis, OSR1/TRAF2 dominant-negatives, FADD/Caspase-8 blockade, MAPK and apoptosis assays in HEK-293\",\n      \"pmids\": [\"28688764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"the putative C-terminal death domain not structurally confirmed\", \"effector caspases not identified\", \"overexpression-based\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A RELT knockout mouse revealed RELT as an in vivo negative regulator of early T-cell activation, providing the first physiological role linked to its apoptotic activity.\",\n      \"evidence\": \"RELT-/- mice, adoptive transfer, in vivo tumor model, T-cell proliferation/response assays\",\n      \"pmids\": [\"30138536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular pathway in T cells not delineated\", \"ligand and upstream activation signal unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Human loss-of-function mutations plus CRISPR KO mice established RELT as causative for autosomal recessive amelogenesis imperfacta, assigning it an unexpected role in enamel biology.\",\n      \"evidence\": \"Homozygosity mapping/sequencing, CRISPR/Cas9 mice, RNAscope, micro-CT/histology\",\n      \"pmids\": [\"30506946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"signaling mechanism in ameloblasts undefined\", \"link between MAPK/apoptosis activity and enamel formation unestablished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying ADAM10 as the specific sheddase of the RELT ectodomain in ameloblasts introduced post-translational regulation of RELT during enamel development.\",\n      \"evidence\": \"ADAM expression PCR in enamel organs and ADAM10-vs-ADAM17 proteolytic cleavage assay\",\n      \"pmids\": [\"31575895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequence of shedding for signaling not shown\", \"fate of shed fragments unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping a physical MDFIC\\u2013RELT interaction added a new membrane-associated binding partner to the RELT family interactome.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP with deletion mapping, immunofluorescence co-localization\",\n      \"pmids\": [\"33367115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional role of MDFIC binding unknown\", \"single-lab interaction\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Detecting nuclear RELT and confirming OXSR1-phosphorylation-independent apoptosis in breast cancer cells extended RELT's death activity beyond immune cells and decoupled it from OSR1 phosphorylation.\",\n      \"evidence\": \"Nuclear fractionation/western, immunofluorescence, flow cytometry (PS, Caspase-3/7), co-IP with OXSR1-binding mutant in MDA-MB-231 and HEK-293\",\n      \"pmids\": [\"39767574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"function of nuclear RELT undefined\", \"mechanism of nuclear translocation unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing secreted RELT downstream of LILRB4 in myeloma-driven osteoclastogenesis linked RELT to bone pathology via a p-SHP2/NF-\\u03baB axis.\",\n      \"evidence\": \"LILRB4 KO, conditioned medium, cytokine array, co-IP, luciferase reporter, xenograft/PDX models, micro-CT\",\n      \"pmids\": [\"38951916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"receptor mediating secreted RELT's osteoclast effect unidentified\", \"relationship to ADAM10 shedding unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RELT's SPAK/OSR1-coupled MAPK signaling, its caspase-independent apoptotic activity, and its tissue roles in enamel formation, T-cell regulation, and bone remodeling are mechanistically unified \\u2014 and what its physiological ligand is \\u2014 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no identified endogenous ligand\", \"C-terminal death domain unconfirmed structurally\", \"mechanism connecting receptor signaling to enamel biology unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 5, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [\"RELT\\u2013OSR1\\u2013PLSCR1 complex\"],\n    \"partners\": [\"SPAK\", \"OXSR1\", \"PLSCR1\", \"TRAF1\", \"MDFIC\", \"RELL1\", \"RELL2\", \"ADAM10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}