{"gene":"MEX3B","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2018,"finding":"MEX3B binds to the 3' UTR of HLA-A mRNA and destabilizes it, leading to reduced HLA-A surface expression on tumor cells and decreased susceptibility to T-cell killing. This was demonstrated by RNA-binding protein immunoprecipitation and luciferase reporter assays.","method":"RNA-binding protein immunoprecipitation, luciferase reporter assay, ORF overexpression screen, exogenous HLA-A2 rescue experiment","journal":"Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal RIP and luciferase reporter assay in a single lab, two orthogonal methods with functional rescue","pmids":["29496759"],"is_preprint":false},{"year":2018,"finding":"MEX3B (Mex3b) acts as an E3 ubiquitin ligase that, in conjunction with the lncRNA HOTAIR, mediates ubiquitination and proteasomal degradation of the tumor suppressor Runx3, promoting gastric cancer cell invasion.","method":"Immunoprecipitation (ubiquitination assay), RNA immunoprecipitation, RNA pull-down, siRNA knockdown of Mex3b/HOTAIR","journal":"Gastric Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, RIP, RNA pulldown, functional rescue) in a single lab","pmids":["29417297"],"is_preprint":false},{"year":2016,"finding":"Mex3B physically associates with TLR3 in endosomes, binds dsRNA to enhance TLR3 dsRNA-binding activity, and promotes proteolytic processing of TLR3, functioning as a coreceptor required for TLR3-mediated IFN-β induction. RNA-binding-deficient Mex3B mutants lost this activity. Mex3b-/- mice showed reduced IFN-β in response to poly(I:C) but not RNA virus infection.","method":"Expression cloning screen, co-immunoprecipitation (TLR3-Mex3B), dsRNA binding assay, domain mutagenesis, Mex3b knockout mice, endosomal colocalization","journal":"Cell Research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, binding assay, mutagenesis, KO mouse phenotype), consistent findings across experiments","pmids":["26823206"],"is_preprint":false},{"year":2016,"finding":"Mex-3B post-transcriptionally upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33 mRNA. Mex3b-/- mice develop significantly less allergic airway inflammation due to reduced IL-33 induction.","method":"Mex3b knockout mice (allergic airway inflammation model), molecular interaction/reporter assays, antisense oligonucleotide treatment","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cellular phenotype, miR-competition mechanism established in single lab","pmids":["27545879"],"is_preprint":false},{"year":2009,"finding":"Xenopus Mex3b (RKHD3) binds the 3' long conserved UTR (3'LCU) of its own mRNA to promote destabilization, forming a negative autoregulatory loop. It also destabilizes mRNAs for FGF signaling components Syndecan 2 and Ets1b through their 3' UTRs, thereby attenuating FGF signaling and contributing to anteroposterior neural patterning.","method":"In vivo mRNA stability assays in Xenopus embryos, RNA binding experiments, 3'UTR reporter assays, gain/loss-of-function embryology","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in Xenopus model system, single lab, ortholog","pmids":["19542354"],"is_preprint":false},{"year":2014,"finding":"Mex3b regulates the spatial organization of the Rap1 pathway in Sertoli cells by controlling activation and transport of Rap1GAP, thereby maintaining cortical Rap1-GTP at physiological levels. Loss of Mex3b leads to excess membrane-cortical Rap1-GTP, disrupting phagocytosis and cell-cell adhesion (N-cadherin/connexin 43 mislocalization). Chemical restoration of Rap1-GTP levels rescues phagocytic and adhesion defects in Mex3b-deficient Sertoli cells.","method":"Mex3b knockout mice, Sertoli cell functional assays (phagocytosis, adhesion), Rap1-GTP pull-down/measurement, chemical rescue, immunofluorescence localization","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cellular phenotype, chemical rescue, multiple readouts, single lab","pmids":["24803656"],"is_preprint":false},{"year":2018,"finding":"Mex-3B binds the 3' UTR of Bim mRNA and blocks access of the Argonaute-miR-92a complex to a miR-92a target site within Bim mRNA, thereby post-transcriptionally upregulating Bim and promoting DNA stress-induced apoptosis.","method":"RNA immunoprecipitation, 3'UTR reporter assays, miRNA competition assay, knockdown/overexpression, apoptosis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, reporter assay, functional apoptosis readout) in single lab","pmids":["29849121"],"is_preprint":false},{"year":2019,"finding":"Mex-3B post-transcriptionally upregulates CXCL2 (a neutrophil chemokine) expression, and Mex3b-deficient mice show significantly reduced neutrophil infiltration in a steroid-resistant neutrophilic airway inflammation model.","method":"Mex3b knockout mice (neutrophilic airway inflammation model), anti-CXCL2 antibody and antisense oligonucleotide treatments, measurement of CXCL2 post-transcriptional regulation","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotype with defined molecular target (CXCL2), single lab","pmids":["31493864"],"is_preprint":false},{"year":2023,"finding":"MEX3B binds to the 3' UTR of TGFBR3 mRNA in human nasal epithelial cells and reduces its stability, leading to decreased TGF-βR3 expression, impaired TGF-β2-induced SMAD2 phosphorylation, and reduced collagen production.","method":"RNA immunoprecipitation (MEX3B binding to TGFBR3 3'UTR), MEX3B knockdown/overexpression, SMAD2 phosphorylation assay, collagen production assay","journal":"JCI Insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus gain/loss-of-function with defined downstream signaling readouts, single lab","pmids":["36976645"],"is_preprint":false},{"year":2022,"finding":"MEX3B (Mex3b) down-regulates DC-STAMP mRNA levels, inhibiting osteoclast cell fusion and osteoclastogenesis. During osteoclast differentiation, RANKL and TNFα cytokines reduce Mex3b expression, relieving suppression of DC-STAMP.","method":"Mex3b gain/loss-of-function experiments in osteoclast differentiation assay, DC-STAMP mRNA level measurement","journal":"Cell Insight","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, no explicit 3'UTR or binding assay described","pmids":["37192984"],"is_preprint":false},{"year":2023,"finding":"Grass carp (ortholog) CiMex3B promotes K63-linked ubiquitination of TLR3, co-localizes with TLR3 in late endosomes after poly(I:C) stimulation, and potentiates IRF3 phosphorylation-mediated antiviral innate immune responses. Both KH domains (N-terminal, aa 1-220) and RING domain region (aa 221-525) are individually insufficient to support K63-linked ubiquitination of TLR3, requiring the full-length protein.","method":"Truncation mutant analysis, co-immunoprecipitation, ubiquitination assay (K63-linkage), fluorescence colocalization, IRF3 phosphorylation assay","journal":"Fish & Shellfish Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (truncation mutants, ubiquitination assay, Co-IP, colocalization), fish ortholog","pmids":["37625735"],"is_preprint":false},{"year":2025,"finding":"MEX3B interacts with Rest mRNA and the lncRNA Hotair to form a tripartite complex in the presence of bFGF, stabilizing Rest mRNA and maintaining neural progenitor cell (NPC) proliferation. MEX3B knockdown blocks NPC proliferation and promotes early neuronal differentiation. Loss of Hotair disrupts the complex, while MEX3B RNAi reduces Hotair abundance; Rest mRNA levels are unaffected by Hotair knockdown alone, indicating Hotair acts as a scaffold for bFGF-dependent MEX3B-Rest interaction.","method":"Microarray screen, MEX3B knockdown, co-immunoprecipitation/RNA pulldown (tripartite complex), bFGF stimulation, neurite length/morphology quantification","journal":"Open Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (knockdown, co-IP, RNA interaction assays, morphological readouts), single lab","pmids":["40925537"],"is_preprint":false},{"year":2026,"finding":"MEX3B is a positive pan-inflammasome regulator: genetic depletion of MEX3B inhibits caspase-4, NLRP3, and NLRC4 inflammasome activation, pyroptosis, and cytokine secretion in human cells and murine macrophages. This function requires MEX3B's RNA-binding activity but not its ubiquitin ligase activity.","method":"CRISPR-Cas9 knockout screen (375 E3 ligase lines), genetic depletion in human cells and primary murine macrophages, caspase activation assay, pyroptosis measurement, cytokine secretion assay, domain-function analysis (RNA-binding vs. ligase)","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased CRISPR screen with orthogonal functional assays (caspase, pyroptosis, cytokine) and domain dissection; preprint, not yet peer-reviewed","pmids":["41959334"],"is_preprint":true},{"year":2026,"finding":"MEX3B directly binds TLR4 mRNA via its KH domain (confirmed by RNA immunoprecipitation and domain-deletion assays), increasing TLR4 mRNA and protein levels, promoting TLR4 membrane localization, and activating the NF-κB signaling cascade (p-p65, p-IκBα) and downstream inflammatory mediators in chondrocytes. MEX3B knockout mitigated osteoarthritis progression in vivo, which was reversed by TLR4 agonist.","method":"RNA immunoprecipitation, domain-deletion assays (KH domain), MEX3B knockdown (chondrocytes), NF-κB pathway activation measurement, in vivo ACLT OA mouse model with MEX3B KO and TLR4 agonist rescue","journal":"Journal of Orthopaedic Surgery and Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP with domain deletion, KO mouse in vivo rescue experiment, multiple signaling readouts, single lab","pmids":["41935341"],"is_preprint":false},{"year":2019,"finding":"IL-37b downregulates Mex3B expression in human nasal epithelial cells, and knocking down or overexpressing Mex3B abolishes the inhibitory effect of IL-37b on poly(I:C)-induced TSLP production, placing Mex3B downstream of IL-37 in the IL-37–Mex3B–TLR3 axis in epithelial innate immunity.","method":"siRNA knockdown and lentiviral overexpression of Mex3B in BEAS-2B cells, cytokine stimulation, TSLP production measurement, Western blotting","journal":"Journal of Allergy and Clinical Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function with defined signaling output, epistasis placement, single lab","pmids":["31330219"],"is_preprint":false}],"current_model":"MEX3B is a dual-function RNA-binding E3 ubiquitin ligase that post-transcriptionally regulates target mRNAs (including HLA-A, Bim, TGFBR3, TLR4, DC-STAMP, IL-33, CXCL2, and Rest) by binding their 3' UTRs to modulate stability or miRNA access, while also functioning as a TLR3 coreceptor in endosomes—promoting dsRNA binding, proteolytic processing, and K63-linked ubiquitination of TLR3—and acting as a pan-inflammasome regulator through its RNA-binding (but not ubiquitin ligase) activity, with additional roles as an E3 ligase mediating ubiquitin-dependent degradation of substrates such as Runx3."},"narrative":{"mechanistic_narrative":"MEX3B is a dual-function KH-domain RNA-binding protein and RING E3 ubiquitin ligase that post-transcriptionally controls the abundance of specific target mRNAs and participates in innate immune signaling [PMID:26823206, PMID:19542354]. As a sequence-specific 3' UTR binder it executes opposite fates for different transcripts: it destabilizes HLA-A, TGFBR3, and its own Xenopus mRNA, and degrades DC-STAMP message, while stabilizing or de-repressing others by blocking miRNA access—shielding Bim mRNA from the Argonaute-miR-92a complex to promote apoptosis and antagonizing miR-487b-3p to upregulate IL-33 [PMID:29496759, PMID:19542354, PMID:29849121, PMID:27545879, PMID:36976645, PMID:37192984]. Through HLA-A destabilization it lowers tumor-cell MHC class I surface expression and reduces susceptibility to T-cell killing [PMID:29496759]. Several targets are stabilized in cooperation with the lncRNA HOTAIR/Hotair, which acts as a scaffold: MEX3B and HOTAIR drive ubiquitin-dependent degradation of the tumor suppressor Runx3, and a bFGF-dependent tripartite MEX3B–Hotair–Rest mRNA complex stabilizes Rest to sustain neural progenitor proliferation [PMID:29417297, PMID:40925537]. In innate immunity MEX3B associates with TLR3 in endosomes, binds dsRNA to enhance TLR3 ligand binding and proteolytic processing, and promotes K63-linked TLR3 ubiquitination and IRF3-driven IFN-β induction, a coreceptor function abolished by RNA-binding-deficient mutants and operating downstream of IL-37 [PMID:26823206, PMID:37625735, PMID:31330219]. It also binds TLR4 mRNA via its KH domain to increase TLR4 levels and activate NF-κB signaling, and acts as an RNA-binding-dependent (ligase-independent) positive pan-inflammasome regulator required for caspase-4, NLRP3, and NLRC4 activation and pyroptosis [PMID:41935341, PMID:41959334]. MEX3B-driven post-transcriptional programs shape inflammatory phenotypes in vivo, including allergic and neutrophilic airway inflammation (via IL-33 and CXCL2) and osteoarthritis (via TLR4) [PMID:27545879, PMID:31493864, PMID:41935341].","teleology":[{"year":2009,"claim":"Established MEX3B's founding biochemical activity—sequence-specific 3' UTR binding that destabilizes target mRNAs—and embedded it in a developmental signaling circuit.","evidence":"In vivo mRNA stability, RNA binding, and 3'UTR reporter assays in Xenopus embryos (RKHD3 ortholog)","pmids":["19542354"],"confidence":"Medium","gaps":["Performed in Xenopus ortholog; human target spectrum not addressed","Did not resolve which domain confers target specificity"]},{"year":2014,"claim":"Showed MEX3B controls a cytoskeletal/adhesion signaling output by regulating Rap1GAP transport and cortical Rap1-GTP, broadening its role beyond simple mRNA turnover.","evidence":"Mex3b knockout mice, Sertoli cell phagocytosis/adhesion assays, Rap1-GTP pull-down, chemical rescue","pmids":["24803656"],"confidence":"Medium","gaps":["Direct mRNA target linking MEX3B to Rap1GAP not identified","Mechanism connecting RNA binding to spatial Rap1 control unresolved"]},{"year":2016,"claim":"Defined MEX3B as a TLR3 endosomal coreceptor, linking its RNA-binding activity directly to antiviral IFN-β signaling, and as a miRNA-competition regulator that upregulates IL-33 in allergic inflammation.","evidence":"Expression cloning, TLR3 co-IP, dsRNA binding, domain mutagenesis, Mex3b knockout mice (poly(I:C) and allergic airway models)","pmids":["26823206","27545879"],"confidence":"High","gaps":["Phenotype seen with poly(I:C) but not RNA virus, leaving physiological viral relevance open","How dsRNA binding mechanistically promotes TLR3 processing not fully resolved"]},{"year":2018,"claim":"Demonstrated that MEX3B functions as an E3 ligase mediating Runx3 degradation and as a tumor-relevant regulator of HLA-A and Bim, revealing both destabilizing and miRNA-shielding modes of mRNA control.","evidence":"Ubiquitination assays, RIP, RNA pull-down, luciferase/3'UTR reporters, miRNA competition and apoptosis assays in cancer cells","pmids":["29417297","29496759","29849121"],"confidence":"Medium","gaps":["Whether ligase and RNA-binding activities act on the same or distinct targets unresolved","Direct ubiquitination of Runx3 vs. indirect effect not fully separated","Single-lab findings per target"]},{"year":2019,"claim":"Positioned MEX3B within cytokine-regulated inflammatory circuits—downstream of IL-37 in the TLR3 axis and as a post-transcriptional driver of CXCL2-mediated neutrophil recruitment.","evidence":"siRNA/overexpression in BEAS-2B cells, Mex3b knockout mice (neutrophilic airway model), anti-CXCL2 and antisense treatments","pmids":["31330219","31493864"],"confidence":"Medium","gaps":["Direct binding of MEX3B to CXCL2 mRNA not shown","Mechanism of IL-37-driven MEX3B downregulation unknown"]},{"year":2023,"claim":"Extended MEX3B's destabilizing function to TGFBR3, linking it to TGF-β/SMAD2 signaling and collagen output, and defined the domain requirements for its ligase activity toward TLR3.","evidence":"RIP and gain/loss-of-function with SMAD2 and collagen readouts (human nasal epithelium); truncation mutants and K63-ubiquitination assays (grass carp ortholog)","pmids":["36976645","37625735"],"confidence":"Medium","gaps":["Full-length requirement for TLR3 ubiquitination shown in fish ortholog only","Coupling between KH and RING regions mechanistically undefined"]},{"year":2025,"claim":"Revealed a scaffold-dependent stabilizing mode in which a bFGF-induced MEX3B–Hotair–Rest tripartite complex maintains neural progenitor proliferation.","evidence":"Microarray screen, knockdown, co-IP/RNA pulldown, bFGF stimulation, neurite morphology in NPCs","pmids":["40925537"],"confidence":"Medium","gaps":["Structural basis of the tripartite complex unknown","How bFGF signaling gates complex assembly unresolved"]},{"year":2026,"claim":"Identified MEX3B as a TLR4-mRNA-binding NF-κB activator and an RNA-binding-dependent positive pan-inflammasome regulator, cleanly separating its RNA-binding from its ligase function in inflammation.","evidence":"RIP with KH-domain deletion, NF-κB readouts, OA mouse KO with TLR4-agonist rescue; CRISPR E3-ligase screen with caspase/pyroptosis/cytokine assays and domain dissection (preprint)","pmids":["41935341","41959334"],"confidence":"Medium","gaps":["Inflammasome findings from a preprint, not yet peer-reviewed","Direct inflammasome-component mRNA targets of MEX3B not identified","How RNA-binding activity mechanistically enables inflammasome assembly unresolved"]},{"year":null,"claim":"It remains unresolved how MEX3B's RNA-binding and E3 ligase activities are coordinated at single targets, and what determines whether a bound 3' UTR is destabilized versus protected from miRNAs.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying rule for stabilizing vs. destabilizing outcomes","Target-recognition code of the KH domains undefined","Physiological substrate set of the ligase activity incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4,6,8,13]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,12,13]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4,6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,8,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,12]}],"complexes":["MEX3B-Hotair-Rest tripartite complex"],"partners":["TLR3","HOTAIR","TLR4","RUNX3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ZN04","full_name":"RNA-binding protein MEX3B","aliases":["RING finger and KH domain-containing protein 3","RING finger protein 195"],"length_aa":569,"mass_kda":58.8,"function":"RNA-binding protein. May be involved in post-transcriptional regulatory mechanisms","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, P-body; Cytoplasmic granule","url":"https://www.uniprot.org/uniprotkb/Q6ZN04/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MEX3B","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MEX3B","total_profiled":1310},"omim":[{"mim_id":"611008","title":"MEX3 RNA-BINDING FAMILY MEMBER B; MEX3B","url":"https://www.omim.org/entry/611008"},{"mim_id":"611007","title":"MEX3 RNA-BINDING FAMILY MEMBER A; MEX3A","url":"https://www.omim.org/entry/611007"},{"mim_id":"611005","title":"MEX3 RNA-BINDING FAMILY MEMBER C; MEX3C","url":"https://www.omim.org/entry/611005"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":12.4},{"tissue":"testis","ntpm":45.1}],"url":"https://www.proteinatlas.org/search/MEX3B"},"hgnc":{"alias_symbol":["DKFZp434J0617","RNF195"],"prev_symbol":["RKHD3"]},"alphafold":{"accession":"Q6ZN04","domains":[{"cath_id":"3.30.1370.10","chopping":"67-141","consensus_level":"high","plddt":95.4363,"start":67,"end":141},{"cath_id":"3.30.1370.10","chopping":"162-230","consensus_level":"high","plddt":92.6272,"start":162,"end":230},{"cath_id":"-","chopping":"529-567","consensus_level":"high","plddt":93.7951,"start":529,"end":567}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZN04","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZN04-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZN04-F1-predicted_aligned_error_v6.png","plddt_mean":61.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MEX3B","jax_strain_url":"https://www.jax.org/strain/search?query=MEX3B"},"sequence":{"accession":"Q6ZN04","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZN04.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZN04/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZN04"}},"corpus_meta":[{"pmid":"29496759","id":"PMC_29496759","title":"The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression.","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/29496759","citation_count":83,"is_preprint":false},{"pmid":"29417297","id":"PMC_29417297","title":"HOTAIR induces the ubiquitination of Runx3 by interacting with Mex3b and enhances the invasion of gastric cancer cells.","date":"2018","source":"Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association","url":"https://pubmed.ncbi.nlm.nih.gov/29417297","citation_count":69,"is_preprint":false},{"pmid":"26823206","id":"PMC_26823206","title":"The RNA-binding protein Mex3B is a coreceptor of Toll-like receptor 3 in innate antiviral response.","date":"2016","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/26823206","citation_count":50,"is_preprint":false},{"pmid":"31330219","id":"PMC_31330219","title":"The IL-37-Mex3B-Toll-like receptor 3 axis in epithelial cells in patients with eosinophilic chronic rhinosinusitis with nasal polyps.","date":"2019","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31330219","citation_count":35,"is_preprint":false},{"pmid":"27545879","id":"PMC_27545879","title":"The RNA Binding Protein Mex-3B Is Required for IL-33 Induction in the Development of Allergic Airway Inflammation.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27545879","citation_count":33,"is_preprint":false},{"pmid":"19542354","id":"PMC_19542354","title":"The RNA-binding protein Mex3b has a fine-tuning system for mRNA regulation in early Xenopus development.","date":"2009","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19542354","citation_count":19,"is_preprint":false},{"pmid":"24803656","id":"PMC_24803656","title":"The RNA-binding protein Mex3b regulates the spatial organization of the Rap1 pathway.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24803656","citation_count":18,"is_preprint":false},{"pmid":"32963265","id":"PMC_32963265","title":"Body temperature-dependent microRNA expression analysis in rats: rno-miR-374-5p regulates apoptosis in skeletal muscle cells via Mex3B under hypothermia.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32963265","citation_count":12,"is_preprint":false},{"pmid":"29849121","id":"PMC_29849121","title":"Mex-3B induces apoptosis by inhibiting miR-92a access to the Bim-3'UTR.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29849121","citation_count":12,"is_preprint":false},{"pmid":"26940660","id":"PMC_26940660","title":"Mex3B: a coreceptor to present dsRNA to TLR3.","date":"2016","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/26940660","citation_count":9,"is_preprint":false},{"pmid":"36976645","id":"PMC_36976645","title":"MEX3B inhibits collagen production in eosinophilic nasal polyps by downregulating epithelial cell TGFBR3 mRNA stability.","date":"2023","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/36976645","citation_count":8,"is_preprint":false},{"pmid":"37625735","id":"PMC_37625735","title":"Grass carp (Ctenopharyngodon idella) Mex3B positively regulates innate immunity by promoting the K63-linked ubiquitination of TLR3.","date":"2023","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37625735","citation_count":7,"is_preprint":false},{"pmid":"31493864","id":"PMC_31493864","title":"The RNA-binding protein Mex-3B plays critical roles in the development of steroid-resistant neutrophilic airway inflammation.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31493864","citation_count":6,"is_preprint":false},{"pmid":"37192984","id":"PMC_37192984","title":"Mex3B inhibits DC-STAMP mRNA level and osteoclastogenesis.","date":"2022","source":"Cell insight","url":"https://pubmed.ncbi.nlm.nih.gov/37192984","citation_count":3,"is_preprint":false},{"pmid":"36198254","id":"PMC_36198254","title":"rno-miR-203a-3p and Mex3B contribute to cell survival of iliopsoas muscle via the Socs3-Casp3 axis under severe hypothermia in rats.","date":"2022","source":"Legal medicine (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/36198254","citation_count":3,"is_preprint":false},{"pmid":"40925537","id":"PMC_40925537","title":"The E3 ligase MEX3B forms a tripartite complex with Rest and Hotair to determine the proliferative capacity of neural progenitor cells.","date":"2025","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/40925537","citation_count":1,"is_preprint":false},{"pmid":"41959334","id":"PMC_41959334","title":"MEX3B is a positive pan-inflammasome regulator.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41959334","citation_count":0,"is_preprint":false},{"pmid":"41935341","id":"PMC_41935341","title":"MEX3B aggravates osteoarthritis progression by post-transcriptionally activating TLR4-NF-κB signaling axis.","date":"2026","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/41935341","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.06.28.601280","title":"The RNA binding ubiquitination ligase MEX3B regulates bFGF-dependent neuronal proliferation","date":"2024-07-02","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.28.601280","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11632,"output_tokens":4005,"usd":0.047485,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11798,"output_tokens":3671,"usd":0.075383,"stage2_stop_reason":"end_turn"},"total_usd":0.122868,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"MEX3B binds to the 3' UTR of HLA-A mRNA and destabilizes it, leading to reduced HLA-A surface expression on tumor cells and decreased susceptibility to T-cell killing. This was demonstrated by RNA-binding protein immunoprecipitation and luciferase reporter assays.\",\n      \"method\": \"RNA-binding protein immunoprecipitation, luciferase reporter assay, ORF overexpression screen, exogenous HLA-A2 rescue experiment\",\n      \"journal\": \"Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal RIP and luciferase reporter assay in a single lab, two orthogonal methods with functional rescue\",\n      \"pmids\": [\"29496759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MEX3B (Mex3b) acts as an E3 ubiquitin ligase that, in conjunction with the lncRNA HOTAIR, mediates ubiquitination and proteasomal degradation of the tumor suppressor Runx3, promoting gastric cancer cell invasion.\",\n      \"method\": \"Immunoprecipitation (ubiquitination assay), RNA immunoprecipitation, RNA pull-down, siRNA knockdown of Mex3b/HOTAIR\",\n      \"journal\": \"Gastric Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, RIP, RNA pulldown, functional rescue) in a single lab\",\n      \"pmids\": [\"29417297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mex3B physically associates with TLR3 in endosomes, binds dsRNA to enhance TLR3 dsRNA-binding activity, and promotes proteolytic processing of TLR3, functioning as a coreceptor required for TLR3-mediated IFN-β induction. RNA-binding-deficient Mex3B mutants lost this activity. Mex3b-/- mice showed reduced IFN-β in response to poly(I:C) but not RNA virus infection.\",\n      \"method\": \"Expression cloning screen, co-immunoprecipitation (TLR3-Mex3B), dsRNA binding assay, domain mutagenesis, Mex3b knockout mice, endosomal colocalization\",\n      \"journal\": \"Cell Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, binding assay, mutagenesis, KO mouse phenotype), consistent findings across experiments\",\n      \"pmids\": [\"26823206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mex-3B post-transcriptionally upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33 mRNA. Mex3b-/- mice develop significantly less allergic airway inflammation due to reduced IL-33 induction.\",\n      \"method\": \"Mex3b knockout mice (allergic airway inflammation model), molecular interaction/reporter assays, antisense oligonucleotide treatment\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cellular phenotype, miR-competition mechanism established in single lab\",\n      \"pmids\": [\"27545879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Xenopus Mex3b (RKHD3) binds the 3' long conserved UTR (3'LCU) of its own mRNA to promote destabilization, forming a negative autoregulatory loop. It also destabilizes mRNAs for FGF signaling components Syndecan 2 and Ets1b through their 3' UTRs, thereby attenuating FGF signaling and contributing to anteroposterior neural patterning.\",\n      \"method\": \"In vivo mRNA stability assays in Xenopus embryos, RNA binding experiments, 3'UTR reporter assays, gain/loss-of-function embryology\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in Xenopus model system, single lab, ortholog\",\n      \"pmids\": [\"19542354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mex3b regulates the spatial organization of the Rap1 pathway in Sertoli cells by controlling activation and transport of Rap1GAP, thereby maintaining cortical Rap1-GTP at physiological levels. Loss of Mex3b leads to excess membrane-cortical Rap1-GTP, disrupting phagocytosis and cell-cell adhesion (N-cadherin/connexin 43 mislocalization). Chemical restoration of Rap1-GTP levels rescues phagocytic and adhesion defects in Mex3b-deficient Sertoli cells.\",\n      \"method\": \"Mex3b knockout mice, Sertoli cell functional assays (phagocytosis, adhesion), Rap1-GTP pull-down/measurement, chemical rescue, immunofluorescence localization\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cellular phenotype, chemical rescue, multiple readouts, single lab\",\n      \"pmids\": [\"24803656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mex-3B binds the 3' UTR of Bim mRNA and blocks access of the Argonaute-miR-92a complex to a miR-92a target site within Bim mRNA, thereby post-transcriptionally upregulating Bim and promoting DNA stress-induced apoptosis.\",\n      \"method\": \"RNA immunoprecipitation, 3'UTR reporter assays, miRNA competition assay, knockdown/overexpression, apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, reporter assay, functional apoptosis readout) in single lab\",\n      \"pmids\": [\"29849121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mex-3B post-transcriptionally upregulates CXCL2 (a neutrophil chemokine) expression, and Mex3b-deficient mice show significantly reduced neutrophil infiltration in a steroid-resistant neutrophilic airway inflammation model.\",\n      \"method\": \"Mex3b knockout mice (neutrophilic airway inflammation model), anti-CXCL2 antibody and antisense oligonucleotide treatments, measurement of CXCL2 post-transcriptional regulation\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotype with defined molecular target (CXCL2), single lab\",\n      \"pmids\": [\"31493864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MEX3B binds to the 3' UTR of TGFBR3 mRNA in human nasal epithelial cells and reduces its stability, leading to decreased TGF-βR3 expression, impaired TGF-β2-induced SMAD2 phosphorylation, and reduced collagen production.\",\n      \"method\": \"RNA immunoprecipitation (MEX3B binding to TGFBR3 3'UTR), MEX3B knockdown/overexpression, SMAD2 phosphorylation assay, collagen production assay\",\n      \"journal\": \"JCI Insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus gain/loss-of-function with defined downstream signaling readouts, single lab\",\n      \"pmids\": [\"36976645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MEX3B (Mex3b) down-regulates DC-STAMP mRNA levels, inhibiting osteoclast cell fusion and osteoclastogenesis. During osteoclast differentiation, RANKL and TNFα cytokines reduce Mex3b expression, relieving suppression of DC-STAMP.\",\n      \"method\": \"Mex3b gain/loss-of-function experiments in osteoclast differentiation assay, DC-STAMP mRNA level measurement\",\n      \"journal\": \"Cell Insight\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, no explicit 3'UTR or binding assay described\",\n      \"pmids\": [\"37192984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Grass carp (ortholog) CiMex3B promotes K63-linked ubiquitination of TLR3, co-localizes with TLR3 in late endosomes after poly(I:C) stimulation, and potentiates IRF3 phosphorylation-mediated antiviral innate immune responses. Both KH domains (N-terminal, aa 1-220) and RING domain region (aa 221-525) are individually insufficient to support K63-linked ubiquitination of TLR3, requiring the full-length protein.\",\n      \"method\": \"Truncation mutant analysis, co-immunoprecipitation, ubiquitination assay (K63-linkage), fluorescence colocalization, IRF3 phosphorylation assay\",\n      \"journal\": \"Fish & Shellfish Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (truncation mutants, ubiquitination assay, Co-IP, colocalization), fish ortholog\",\n      \"pmids\": [\"37625735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MEX3B interacts with Rest mRNA and the lncRNA Hotair to form a tripartite complex in the presence of bFGF, stabilizing Rest mRNA and maintaining neural progenitor cell (NPC) proliferation. MEX3B knockdown blocks NPC proliferation and promotes early neuronal differentiation. Loss of Hotair disrupts the complex, while MEX3B RNAi reduces Hotair abundance; Rest mRNA levels are unaffected by Hotair knockdown alone, indicating Hotair acts as a scaffold for bFGF-dependent MEX3B-Rest interaction.\",\n      \"method\": \"Microarray screen, MEX3B knockdown, co-immunoprecipitation/RNA pulldown (tripartite complex), bFGF stimulation, neurite length/morphology quantification\",\n      \"journal\": \"Open Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (knockdown, co-IP, RNA interaction assays, morphological readouts), single lab\",\n      \"pmids\": [\"40925537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MEX3B is a positive pan-inflammasome regulator: genetic depletion of MEX3B inhibits caspase-4, NLRP3, and NLRC4 inflammasome activation, pyroptosis, and cytokine secretion in human cells and murine macrophages. This function requires MEX3B's RNA-binding activity but not its ubiquitin ligase activity.\",\n      \"method\": \"CRISPR-Cas9 knockout screen (375 E3 ligase lines), genetic depletion in human cells and primary murine macrophages, caspase activation assay, pyroptosis measurement, cytokine secretion assay, domain-function analysis (RNA-binding vs. ligase)\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased CRISPR screen with orthogonal functional assays (caspase, pyroptosis, cytokine) and domain dissection; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41959334\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MEX3B directly binds TLR4 mRNA via its KH domain (confirmed by RNA immunoprecipitation and domain-deletion assays), increasing TLR4 mRNA and protein levels, promoting TLR4 membrane localization, and activating the NF-κB signaling cascade (p-p65, p-IκBα) and downstream inflammatory mediators in chondrocytes. MEX3B knockout mitigated osteoarthritis progression in vivo, which was reversed by TLR4 agonist.\",\n      \"method\": \"RNA immunoprecipitation, domain-deletion assays (KH domain), MEX3B knockdown (chondrocytes), NF-κB pathway activation measurement, in vivo ACLT OA mouse model with MEX3B KO and TLR4 agonist rescue\",\n      \"journal\": \"Journal of Orthopaedic Surgery and Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP with domain deletion, KO mouse in vivo rescue experiment, multiple signaling readouts, single lab\",\n      \"pmids\": [\"41935341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-37b downregulates Mex3B expression in human nasal epithelial cells, and knocking down or overexpressing Mex3B abolishes the inhibitory effect of IL-37b on poly(I:C)-induced TSLP production, placing Mex3B downstream of IL-37 in the IL-37–Mex3B–TLR3 axis in epithelial innate immunity.\",\n      \"method\": \"siRNA knockdown and lentiviral overexpression of Mex3B in BEAS-2B cells, cytokine stimulation, TSLP production measurement, Western blotting\",\n      \"journal\": \"Journal of Allergy and Clinical Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function with defined signaling output, epistasis placement, single lab\",\n      \"pmids\": [\"31330219\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MEX3B is a dual-function RNA-binding E3 ubiquitin ligase that post-transcriptionally regulates target mRNAs (including HLA-A, Bim, TGFBR3, TLR4, DC-STAMP, IL-33, CXCL2, and Rest) by binding their 3' UTRs to modulate stability or miRNA access, while also functioning as a TLR3 coreceptor in endosomes—promoting dsRNA binding, proteolytic processing, and K63-linked ubiquitination of TLR3—and acting as a pan-inflammasome regulator through its RNA-binding (but not ubiquitin ligase) activity, with additional roles as an E3 ligase mediating ubiquitin-dependent degradation of substrates such as Runx3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MEX3B is a dual-function KH-domain RNA-binding protein and RING E3 ubiquitin ligase that post-transcriptionally controls the abundance of specific target mRNAs and participates in innate immune signaling [#2, #4]. As a sequence-specific 3' UTR binder it executes opposite fates for different transcripts: it destabilizes HLA-A, TGFBR3, and its own Xenopus mRNA, and degrades DC-STAMP message, while stabilizing or de-repressing others by blocking miRNA access—shielding Bim mRNA from the Argonaute-miR-92a complex to promote apoptosis and antagonizing miR-487b-3p to upregulate IL-33 [#0, #4, #6, #3, #8, #9]. Through HLA-A destabilization it lowers tumor-cell MHC class I surface expression and reduces susceptibility to T-cell killing [#0]. Several targets are stabilized in cooperation with the lncRNA HOTAIR/Hotair, which acts as a scaffold: MEX3B and HOTAIR drive ubiquitin-dependent degradation of the tumor suppressor Runx3, and a bFGF-dependent tripartite MEX3B–Hotair–Rest mRNA complex stabilizes Rest to sustain neural progenitor proliferation [#1, #11]. In innate immunity MEX3B associates with TLR3 in endosomes, binds dsRNA to enhance TLR3 ligand binding and proteolytic processing, and promotes K63-linked TLR3 ubiquitination and IRF3-driven IFN-\\u03b2 induction, a coreceptor function abolished by RNA-binding-deficient mutants and operating downstream of IL-37 [#2, #10, #14]. It also binds TLR4 mRNA via its KH domain to increase TLR4 levels and activate NF-\\u03baB signaling, and acts as an RNA-binding-dependent (ligase-independent) positive pan-inflammasome regulator required for caspase-4, NLRP3, and NLRC4 activation and pyroptosis [#13, #12]. MEX3B-driven post-transcriptional programs shape inflammatory phenotypes in vivo, including allergic and neutrophilic airway inflammation (via IL-33 and CXCL2) and osteoarthritis (via TLR4) [#3, #7, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established MEX3B's founding biochemical activity—sequence-specific 3' UTR binding that destabilizes target mRNAs—and embedded it in a developmental signaling circuit.\",\n      \"evidence\": \"In vivo mRNA stability, RNA binding, and 3'UTR reporter assays in Xenopus embryos (RKHD3 ortholog)\",\n      \"pmids\": [\"19542354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed in Xenopus ortholog; human target spectrum not addressed\", \"Did not resolve which domain confers target specificity\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed MEX3B controls a cytoskeletal/adhesion signaling output by regulating Rap1GAP transport and cortical Rap1-GTP, broadening its role beyond simple mRNA turnover.\",\n      \"evidence\": \"Mex3b knockout mice, Sertoli cell phagocytosis/adhesion assays, Rap1-GTP pull-down, chemical rescue\",\n      \"pmids\": [\"24803656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mRNA target linking MEX3B to Rap1GAP not identified\", \"Mechanism connecting RNA binding to spatial Rap1 control unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined MEX3B as a TLR3 endosomal coreceptor, linking its RNA-binding activity directly to antiviral IFN-\\u03b2 signaling, and as a miRNA-competition regulator that upregulates IL-33 in allergic inflammation.\",\n      \"evidence\": \"Expression cloning, TLR3 co-IP, dsRNA binding, domain mutagenesis, Mex3b knockout mice (poly(I:C) and allergic airway models)\",\n      \"pmids\": [\"26823206\", \"27545879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phenotype seen with poly(I:C) but not RNA virus, leaving physiological viral relevance open\", \"How dsRNA binding mechanistically promotes TLR3 processing not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that MEX3B functions as an E3 ligase mediating Runx3 degradation and as a tumor-relevant regulator of HLA-A and Bim, revealing both destabilizing and miRNA-shielding modes of mRNA control.\",\n      \"evidence\": \"Ubiquitination assays, RIP, RNA pull-down, luciferase/3'UTR reporters, miRNA competition and apoptosis assays in cancer cells\",\n      \"pmids\": [\"29417297\", \"29496759\", \"29849121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ligase and RNA-binding activities act on the same or distinct targets unresolved\", \"Direct ubiquitination of Runx3 vs. indirect effect not fully separated\", \"Single-lab findings per target\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Positioned MEX3B within cytokine-regulated inflammatory circuits—downstream of IL-37 in the TLR3 axis and as a post-transcriptional driver of CXCL2-mediated neutrophil recruitment.\",\n      \"evidence\": \"siRNA/overexpression in BEAS-2B cells, Mex3b knockout mice (neutrophilic airway model), anti-CXCL2 and antisense treatments\",\n      \"pmids\": [\"31330219\", \"31493864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of MEX3B to CXCL2 mRNA not shown\", \"Mechanism of IL-37-driven MEX3B downregulation unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended MEX3B's destabilizing function to TGFBR3, linking it to TGF-\\u03b2/SMAD2 signaling and collagen output, and defined the domain requirements for its ligase activity toward TLR3.\",\n      \"evidence\": \"RIP and gain/loss-of-function with SMAD2 and collagen readouts (human nasal epithelium); truncation mutants and K63-ubiquitination assays (grass carp ortholog)\",\n      \"pmids\": [\"36976645\", \"37625735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full-length requirement for TLR3 ubiquitination shown in fish ortholog only\", \"Coupling between KH and RING regions mechanistically undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a scaffold-dependent stabilizing mode in which a bFGF-induced MEX3B–Hotair–Rest tripartite complex maintains neural progenitor proliferation.\",\n      \"evidence\": \"Microarray screen, knockdown, co-IP/RNA pulldown, bFGF stimulation, neurite morphology in NPCs\",\n      \"pmids\": [\"40925537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the tripartite complex unknown\", \"How bFGF signaling gates complex assembly unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified MEX3B as a TLR4-mRNA-binding NF-\\u03baB activator and an RNA-binding-dependent positive pan-inflammasome regulator, cleanly separating its RNA-binding from its ligase function in inflammation.\",\n      \"evidence\": \"RIP with KH-domain deletion, NF-\\u03baB readouts, OA mouse KO with TLR4-agonist rescue; CRISPR E3-ligase screen with caspase/pyroptosis/cytokine assays and domain dissection (preprint)\",\n      \"pmids\": [\"41935341\", \"41959334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inflammasome findings from a preprint, not yet peer-reviewed\", \"Direct inflammasome-component mRNA targets of MEX3B not identified\", \"How RNA-binding activity mechanistically enables inflammasome assembly unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how MEX3B's RNA-binding and E3 ligase activities are coordinated at single targets, and what determines whether a bound 3' UTR is destabilized versus protected from miRNAs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying rule for stabilizing vs. destabilizing outcomes\", \"Target-recognition code of the KH domains undefined\", \"Physiological substrate set of the ligase activity incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 6, 8, 13]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 12, 13]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 8, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"complexes\": [\n      \"MEX3B-Hotair-Rest tripartite complex\"\n    ],\n    \"partners\": [\n      \"TLR3\",\n      \"HOTAIR\",\n      \"TLR4\",\n      \"Runx3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}