Affinage

MEX3B

RNA-binding protein MEX3B · UniProt Q6ZN04

Length
569 aa
Mass
58.8 kDa
Annotated
2026-06-10
18 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2009 Medium

    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)

    PMID:19542354

    Open questions at the time
    • Performed in Xenopus ortholog; human target spectrum not addressed
    • Did not resolve which domain confers target specificity
  2. 2014 Medium

    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

    PMID:24803656

    Open questions at the time
    • Direct mRNA target linking MEX3B to Rap1GAP not identified
    • Mechanism connecting RNA binding to spatial Rap1 control unresolved
  3. 2016 High

    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)

    PMID:26823206 PMID:27545879

    Open questions at the time
    • 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
  4. 2018 Medium

    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

    PMID:29417297 PMID:29496759 PMID:29849121

    Open questions at the time
    • 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
  5. 2019 Medium

    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

    PMID:31330219 PMID:31493864

    Open questions at the time
    • Direct binding of MEX3B to CXCL2 mRNA not shown
    • Mechanism of IL-37-driven MEX3B downregulation unknown
  6. 2023 Medium

    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)

    PMID:36976645 PMID:37625735

    Open questions at the time
    • Full-length requirement for TLR3 ubiquitination shown in fish ortholog only
    • Coupling between KH and RING regions mechanistically undefined
  7. 2025 Medium

    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

    PMID:40925537

    Open questions at the time
    • Structural basis of the tripartite complex unknown
    • How bFGF signaling gates complex assembly unresolved
  8. 2026 Medium

    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)

    PMID:41935341 PMID:41959334

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0016874 ligase activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0060089 molecular transducer activity 1
Localization
GO:0005768 endosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2
Partners
HOTAIRRUNX3TLR3TLR4
Complex memberships
MEX3B-Hotair-Rest tripartite complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 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. RNA-binding protein immunoprecipitation, luciferase reporter assay, ORF overexpression screen, exogenous HLA-A2 rescue experiment Clinical Cancer Research Medium 29496759
2018 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. Immunoprecipitation (ubiquitination assay), RNA immunoprecipitation, RNA pull-down, siRNA knockdown of Mex3b/HOTAIR Gastric Cancer Medium 29417297
2016 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. Expression cloning screen, co-immunoprecipitation (TLR3-Mex3B), dsRNA binding assay, domain mutagenesis, Mex3b knockout mice, endosomal colocalization Cell Research High 26823206
2016 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. Mex3b knockout mice (allergic airway inflammation model), molecular interaction/reporter assays, antisense oligonucleotide treatment Cell Reports Medium 27545879
2009 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. In vivo mRNA stability assays in Xenopus embryos, RNA binding experiments, 3'UTR reporter assays, gain/loss-of-function embryology Development Medium 19542354
2014 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. Mex3b knockout mice, Sertoli cell functional assays (phagocytosis, adhesion), Rap1-GTP pull-down/measurement, chemical rescue, immunofluorescence localization Development Medium 24803656
2018 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. RNA immunoprecipitation, 3'UTR reporter assays, miRNA competition assay, knockdown/overexpression, apoptosis assays Oncogene Medium 29849121
2019 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. Mex3b knockout mice (neutrophilic airway inflammation model), anti-CXCL2 antibody and antisense oligonucleotide treatments, measurement of CXCL2 post-transcriptional regulation Biochemical and Biophysical Research Communications Medium 31493864
2023 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. RNA immunoprecipitation (MEX3B binding to TGFBR3 3'UTR), MEX3B knockdown/overexpression, SMAD2 phosphorylation assay, collagen production assay JCI Insight Medium 36976645
2022 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. Mex3b gain/loss-of-function experiments in osteoclast differentiation assay, DC-STAMP mRNA level measurement Cell Insight Low 37192984
2023 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. Truncation mutant analysis, co-immunoprecipitation, ubiquitination assay (K63-linkage), fluorescence colocalization, IRF3 phosphorylation assay Fish & Shellfish Immunology Medium 37625735
2025 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. Microarray screen, MEX3B knockdown, co-immunoprecipitation/RNA pulldown (tripartite complex), bFGF stimulation, neurite length/morphology quantification Open Biology Medium 40925537
2026 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. 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) bioRxiv (preprint)preprint Medium 41959334
2026 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. 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 of Orthopaedic Surgery and Research Medium 41935341
2019 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. siRNA knockdown and lentiviral overexpression of Mex3B in BEAS-2B cells, cytokine stimulation, TSLP production measurement, Western blotting Journal of Allergy and Clinical Immunology Medium 31330219

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression. Clinical cancer research : an official journal of the American Association for Cancer Research 83 29496759
2018 HOTAIR induces the ubiquitination of Runx3 by interacting with Mex3b and enhances the invasion of gastric cancer cells. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 69 29417297
2016 The RNA-binding protein Mex3B is a coreceptor of Toll-like receptor 3 in innate antiviral response. Cell research 50 26823206
2019 The IL-37-Mex3B-Toll-like receptor 3 axis in epithelial cells in patients with eosinophilic chronic rhinosinusitis with nasal polyps. The Journal of allergy and clinical immunology 35 31330219
2016 The RNA Binding Protein Mex-3B Is Required for IL-33 Induction in the Development of Allergic Airway Inflammation. Cell reports 33 27545879
2009 The RNA-binding protein Mex3b has a fine-tuning system for mRNA regulation in early Xenopus development. Development (Cambridge, England) 19 19542354
2014 The RNA-binding protein Mex3b regulates the spatial organization of the Rap1 pathway. Development (Cambridge, England) 18 24803656
2020 Body temperature-dependent microRNA expression analysis in rats: rno-miR-374-5p regulates apoptosis in skeletal muscle cells via Mex3B under hypothermia. Scientific reports 12 32963265
2018 Mex-3B induces apoptosis by inhibiting miR-92a access to the Bim-3'UTR. Oncogene 12 29849121
2016 Mex3B: a coreceptor to present dsRNA to TLR3. Cell research 9 26940660
2023 MEX3B inhibits collagen production in eosinophilic nasal polyps by downregulating epithelial cell TGFBR3 mRNA stability. JCI insight 8 36976645
2023 Grass carp (Ctenopharyngodon idella) Mex3B positively regulates innate immunity by promoting the K63-linked ubiquitination of TLR3. Fish & shellfish immunology 7 37625735
2019 The RNA-binding protein Mex-3B plays critical roles in the development of steroid-resistant neutrophilic airway inflammation. Biochemical and biophysical research communications 6 31493864
2022 rno-miR-203a-3p and Mex3B contribute to cell survival of iliopsoas muscle via the Socs3-Casp3 axis under severe hypothermia in rats. Legal medicine (Tokyo, Japan) 3 36198254
2022 Mex3B inhibits DC-STAMP mRNA level and osteoclastogenesis. Cell insight 3 37192984
2025 The E3 ligase MEX3B forms a tripartite complex with Rest and Hotair to determine the proliferative capacity of neural progenitor cells. Open biology 1 40925537
2026 MEX3B aggravates osteoarthritis progression by post-transcriptionally activating TLR4-NF-κB signaling axis. Journal of orthopaedic surgery and research 0 41935341
2026 MEX3B is a positive pan-inflammasome regulator. bioRxiv : the preprint server for biology 0 41959334

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