{"gene":"MTDH","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2004,"finding":"LYRIC/MTDH (also called 3D3/lyric) is a type-1b membrane protein with a single transmembrane domain, localized to the endoplasmic reticulum, nuclear envelope, and nucleolus, as determined by subcellular fractionation and immunostaining.","method":"Subcellular fractionation, immunostaining, Northern blot, antibody characterization","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation + immunostaining + Northern blot) in a single study establishing subcellular localization","pmids":["14980505"],"is_preprint":false},{"year":2004,"finding":"LYRIC/MTDH colocalizes with tight junction proteins ZO-1 and occludin in polarized epithelial cells and dissociates from ZO-1 when junctional complexes are disrupted, indicating it is recruited during tight junction maturation rather than being a structural component.","method":"Immunolocalization of LYRIC with ZO-1 and occludin in polarized epithelial cells; disruption and reformation of tight junctions","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional context, single study","pmids":["15383321"],"is_preprint":false},{"year":2009,"finding":"LYRIC/AEG-1 contains three nuclear localization signals (NLS): NLS-3 (aa 546–582) is the predominant regulator of nuclear localization, NLS-1 (aa 78–130) regulates nucleolar localization, and NLS-2 (aa 415–486) is the site of ubiquitin modification in the cytoplasm.","method":"GFP-NLS fusion proteins, deletion constructs, immunoprecipitation, Western blotting","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — domain mapping with deletion constructs and biochemical validation of ubiquitin modification","pmids":["19383828"],"is_preprint":false},{"year":2009,"finding":"Nuclear LYRIC/AEG-1 interacts with the transcriptional repressor PLZF via the N- and C-termini of LYRIC and the C-terminal region of PLZF (C-terminal to RD2 domain), and co-expression of LYRIC reduces PLZF binding to promoters, relieving PLZF-mediated repression; both proteins co-localize to nuclear bodies containing histone deacetylases.","method":"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, promoter-binding assays, co-localization microscopy","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction confirmed in yeast and mammalian cells with functional promoter-binding assay","pmids":["19648967"],"is_preprint":false},{"year":2008,"finding":"LYRIC/AEG-1 interacts with BCCIPα (a CDKN1A and BRCA2-associated protein) in mammalian cells; co-expression leads to decreased BCCIPα protein levels that is partially reversed by proteasome inhibition, indicating LYRIC promotes proteasomal degradation of BCCIPα.","method":"Yeast two-hybrid screen, co-immunoprecipitation, Western blotting with proteasome inhibitor","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — interaction confirmed in mammalian cells with mechanistic follow-up using proteasome inhibition, single lab","pmids":["18440304"],"is_preprint":false},{"year":2011,"finding":"AEG-1/MTDH represses the glutamate transporter EAAT2 at the transcriptional level by inducing YY1 activity to inhibit CBP function as a coactivator on the EAAT2 promoter, resulting in reduced glutamate uptake and neuronal cell death (excitotoxicity).","method":"Gain- and loss-of-function studies in primary human fetal astrocytes and T98G cells, Pearson correlation analysis in patient samples, transcriptional assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — mechanistic transcriptional pathway (YY1/CBP/EAAT2) established with gain/loss-of-function and patient correlation, multiple approaches","pmids":["21852380"],"is_preprint":false},{"year":2011,"finding":"Cytoplasmic MTDH functions as an RNA-binding protein; it associates with RNA-binding proteins and components of the RNA-induced silencing complex (RISC) in a nucleic acid-dependent manner, regulates protein expression of multiple mRNAs (e.g., PDCD10, KDM6A), and its depletion leads to increased stress granule formation and reduced cell survival.","method":"Subcellular fractionation, co-immunoprecipitation with RNA-binding proteins, mRNA regulation assays, knockdown with stress granule and survival readouts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing RNA-binding function, localization, and functional consequences","pmids":["22199357"],"is_preprint":false},{"year":2014,"finding":"MTDH interacts with and stabilizes SND1 (Staphylococcal nuclease domain-containing 1), supporting tumor-initiating cell survival under oncogenic/stress conditions; silencing MTDH or SND1 individually or disrupting their interaction compromises tumorigenicity in vivo.","method":"Mouse mammary tumor models, Co-IP, in vivo TIC assays, genetic silencing of MTDH and SND1","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — multiple mouse models, reciprocal interaction studies, in vivo functional validation","pmids":["24981741"],"is_preprint":false},{"year":2014,"finding":"The crystal structure of the MTDH-SND1 complex was determined at high resolution, revealing an 11-residue MTDH peptide motif occupying an extended protein groove between SN1/2 domains of SND1, with two MTDH tryptophan residues critical for the interaction; mutagenesis of these residues disrupts cancer-promoting activity and SND1 stability.","method":"X-ray crystallography, mutagenesis, in vitro and in vivo functional assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis with functional validation in breast cancer models","pmids":["25242325"],"is_preprint":false},{"year":2014,"finding":"AEG-1/MTDH interacts with retinoid X receptor (RXR) in the nucleus of non-tumor cells, interfering with recruitment of transcriptional coactivators to RXR. In tumor cells, overexpressed AEG-1 sequesters RXR in the cytoplasm; additionally, ERK activated by AEG-1 phosphorylates RXR, causing its functional inactivation.","method":"Co-immunoprecipitation, immunofluorescence, nuclear/cytoplasmic fractionation, kinase assays, AEG-1 transgenic and knockdown models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, mechanistic dissection of RXR sequestration and ERK-mediated phosphorylation","pmids":["25125681"],"is_preprint":false},{"year":2014,"finding":"AEG-1 is essential for NF-κB activation in hepatocytes and macrophages; AEG-1-deficient mice show defective NF-κB signaling, reduced IL-6 production, and impaired STAT3 activation, conferring resistance to DEN-induced hepatocellular carcinoma.","method":"AEG-1 knockout mouse model, DEN-induced hepatocarcinogenesis, NF-κB and STAT3 pathway analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic knockout with defined molecular pathway phenotype","pmids":["25193383"],"is_preprint":false},{"year":2015,"finding":"MTDH promotes cancer stem-like cell expansion by interacting with the histone acetyltransferase CBP and preventing its ubiquitin-mediated degradation, thereby licensing CBP-mediated histone H3 acetylation on the TWIST1 promoter and activating TWIST1 transcription.","method":"Co-immunoprecipitation of MTDH-CBP, chromatin immunoprecipitation, ubiquitination assays, knockdown/overexpression with CSC phenotype readouts","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, ubiquitination assay) establishing mechanism, single lab","pmids":["26141861"],"is_preprint":false},{"year":2015,"finding":"AEG-1 interacts with RXR and inhibits RXR-dependent activation of liver X receptor and PPARα in enterocytes, resulting in decreased intestinal fat absorption; AEG-1 knockout mice are leaner and resistant to high-fat diet-induced obesity.","method":"AEG-1 knockout mouse model, high-fat diet challenge, nuclear receptor activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with defined mechanistic pathway through nuclear receptor regulation","pmids":["26070567"],"is_preprint":false},{"year":2013,"finding":"CPEB1 binds the MTDH mRNA and represses its translation; phosphorylation of CPEB1 triggers cytoplasmic polyadenylation and translational activation of MTDH mRNA, promoting glioblastoma cell migration and tumor growth.","method":"RNA-binding assay, CPEB1 phosphorylation-deficient mutant, in vitro and in vivo tumor models, reporter mRNA localization","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — direct RNA-binding and functional mutant data, single lab","pmids":["23360795"],"is_preprint":false},{"year":2011,"finding":"The cellular protein Lyric/MTDH interacts with HIV-1 Gag via the Gag matrix (MA) and nucleocapsid (NC) domains; this interaction requires Gag multimerization and Lyric amino acids 101–289; endogenous Lyric is incorporated into HIV-1 virions and cleaved by the viral protease.","method":"Affinity purification, co-immunoprecipitation, domain mapping, virion analysis, viral protease cleavage assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — domain-mapped interaction, virion incorporation, and protease cleavage confirmed biochemically","pmids":["21957284"],"is_preprint":false},{"year":2016,"finding":"AEG-1 activates Wnt/PCP-Rho signaling to promote EMT and invasion in tongue squamous cell carcinoma; recombinant AEG-1 activates Wnt5a/Rac1/ROCK pathway, and its stimulatory effects are reversed by anti-Wnt5a neutralizing antibody or inhibition of Rac1/ROCK.","method":"Recombinant AEG-1 treatment, neutralizing antibody, kinase inhibitors, xenograft model, EMT marker analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with recombinant protein and pathway inhibitors, single lab","pmids":["26689985"],"is_preprint":false},{"year":2016,"finding":"AEG-1 upregulates transcription of the membrane protein Tetraspanin 8 (TSPAN8), which mediates AEG-1-induced invasion, migration, and angiogenesis in hepatocellular carcinoma; TSPAN8 knockdown abolishes AEG-1-dependent metastasis in an orthotopic xenograft model.","method":"Gene expression analysis, TSPAN8 knockdown, invasion/migration assays, HUVEC tube formation, orthotopic xenograft in nude mice","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined downstream target in vivo, single lab","pmids":["27339400"],"is_preprint":false},{"year":2017,"finding":"AEG-1 promotes gastric cancer metastasis by positively regulating eIF4E expression, which in turn upregulates MMP-9 and Twist; manipulation of eIF4E partially rescues AEG-1-induced EMT, migration, and invasion.","method":"Gain/loss-of-function of AEG-1 and eIF4E, Western blotting, cell migration and invasion assays, orthotopic mouse model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — rescue experiment placing eIF4E downstream of AEG-1, in vivo confirmation, single lab","pmids":["28661037"],"is_preprint":false},{"year":2018,"finding":"LINC01638 interacts with c-Myc protein to prevent SPOP-mediated ubiquitination and degradation of c-Myc; stabilized c-Myc transcriptionally activates MTDH expression, which subsequently activates TWIST1, driving EMT in triple-negative breast cancer.","method":"RNA-protein interaction assay, ubiquitination assay, chromatin immunoprecipitation, knockdown/overexpression in TNBC cells and xenografts","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway established with protein-RNA interaction, ubiquitination, and ChIP evidence","pmids":["30002443"],"is_preprint":false},{"year":2019,"finding":"MTDH as an RNA-binding protein regulates the mRNA stability of FANCD2 and FANCI (Fanconi anemia complementation group proteins); RNA-binding protein immunoprecipitation confirmed direct MTDH-mRNA interaction, and MTDH knockdown reduced FANCD2/FANCI levels, restoring platinum sensitivity.","method":"RNA-binding protein immunoprecipitation (RIP), knockdown, chemosensitivity assays, patient-derived xenograft model","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 2 — direct RIP confirmation of MTDH-mRNA interaction with functional chemosensitivity readout, single lab","pmids":["31477281"],"is_preprint":false},{"year":2020,"finding":"CPEB3 binds the 3'-UTR of MTDH mRNA and suppresses its translation; CPEB3 knockout mice show increased susceptibility to carcinogen-induced hepatocarcinogenesis; CPEB3 overexpression inhibits EMT and metastasis of HCC cells by post-transcriptional suppression of MTDH.","method":"RNA immunoprecipitation (transcriptome-wide), luciferase assay with MTDH 3'-UTR, CPEB3 knockout mice, in vivo metastasis models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — RIP, luciferase 3'-UTR assay, and in vivo knockout model, multiple orthogonal methods","pmids":["32968053"],"is_preprint":false},{"year":2021,"finding":"The MTDH-SND1 complex binds to and destabilizes Tap1/2 mRNAs (encoding antigen-presentation machinery components), reducing tumor antigen presentation and inhibiting T cell infiltration; pharmacological disruption of MTDH-SND1 by compound C26-A6 restores immune surveillance and synergizes with anti-PD-1 therapy.","method":"Genetic and pharmacological disruption of MTDH-SND1 complex, mRNA stability assays for Tap1/2, in vivo preclinical breast cancer models, immune phenotyping","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1–2 — small molecule plus genetic disruption with mechanistic RNA-binding readout and in vivo immune phenotype","pmids":["35121988"],"is_preprint":false},{"year":2021,"finding":"Genetic ablation of Mtdh in mice disrupts the MTDH-SND1 interaction and inhibits breast cancer development; small-molecule inhibitors C26-A2 and C26-A6 that disrupt the MTDH-SND1 protein-protein interaction suppress tumor growth and metastasis and enhance chemotherapy sensitivity in TNBC preclinical models.","method":"Genetically modified mouse models (Mtdh ablation), compound screening, in vivo TNBC models, chemosensitivity assays","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1–2 — genetic and pharmacological evidence converging on MTDH-SND1 PPI as essential, validated in vivo","pmids":["35121987"],"is_preprint":false},{"year":2022,"finding":"AEG-1 undergoes palmitoylation on Cys-75, catalyzed by zDHHC6 and reversed by PPT1/2; palmitoylation adversely regulates AEG-1 protein stability and weakens AEG-1-SND1 interaction, thereby altering RISC activity and expression of tumor suppressors; blocking palmitoylation via Zdhhc6 knockout enhances DEN-induced HCC progression in vivo.","method":"Acyl-RAC assay, Cys-75 point mutation (AEG-1-C75A knock-in mice), Zdhhc6 knockout mice, DEN-induced HCC model, biochemical interaction assays","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 — site-specific mutagenesis, knock-in and knockout mouse models, and biochemical validation of palmitoylation writers/erasers","pmids":["36276642"],"is_preprint":false},{"year":2023,"finding":"AEG-1 promotes radioresistance in ESCC by recruiting the deubiquitinase USP10 to remove K48-linked polyubiquitin chains at Lys425 of PARP1, preventing its proteasomal degradation and thereby facilitating homologous recombination-mediated DNA double-strand break repair.","method":"Co-immunoprecipitation, ubiquitination assays with K48 linkage specificity, PARP1 mutagenesis (Lys425), DNA damage (γH2AX) assays, in vivo xenograft irradiation models","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1–2 — site-specific ubiquitination mapping, deubiquitinase identification, and in vivo functional validation","pmids":["37838281"],"is_preprint":false},{"year":2022,"finding":"DOT1L, a H3K79 methyltransferase, promotes MTDH transcription by increasing H3K79me3 levels on the MTDH promoter as shown by ChIP; MTDH in turn activates NF-κB occupancy on the HIF1α promoter, leading to elevated proangiogenic mediators in TNBC cells.","method":"ChIP assay for H3K79me3 on MTDH promoter, DOT1L inhibitor/siRNA, NF-κB ChIP on HIF1α promoter, angiogenesis assays in vitro and in vivo","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP evidence for epigenetic regulation plus downstream NF-κB-HIF1α pathway, single lab","pmids":["36017623"],"is_preprint":false},{"year":2018,"finding":"FBXW7, an E3 ubiquitin ligase component, targets MTDH for ubiquitin-mediated proteasomal degradation; FBXW7 overexpression decreases MTDH protein levels and induces proliferation arrest and apoptosis in breast cancer cells.","method":"FBXW7 overexpression and knockdown, Western blotting, proliferation and apoptosis assays","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 3 — single study, indirect evidence for ubiquitination via FBXW7; direct ubiquitination not biochemically confirmed","pmids":["29534580"],"is_preprint":false},{"year":2014,"finding":"MTDH mediates trastuzumab resistance in HER2-positive breast cancer by activating IκBα inhibition and nuclear translocation of NF-κB p65, which subsequently decreases PTEN expression; forced PTEN expression restores trastuzumab sensitivity.","method":"MTDH knockdown and overexpression, NF-κB pathway analysis, PTEN rescue experiments, in vivo xenograft models","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 — pathway dissection with rescue experiments, in vivo validation, single lab","pmids":["25417825"],"is_preprint":false},{"year":2021,"finding":"MTDH acts as an RNA-binding protein that directly binds circ-NOL10 (with characterized RBP motifs), and ectopic expression or depletion of MTDH leads to circ-NOL10 expression changes, indicating MTDH modulates circRNA biogenesis or stability.","method":"RNA immunoprecipitation, RBP motif characterization, overexpression/knockdown of MTDH with circ-NOL10 readout","journal":"Molecular therapy. Nucleic acids","confidence":"Low","confidence_rationale":"Tier 3 — single RIP study with indirect functional evidence, single lab","pmids":["34729247"],"is_preprint":false},{"year":2021,"finding":"AEG-1 activates Wnt/β-catenin signaling by directly interacting with GSK-3β in the cytoplasm of glioma cells, as shown by co-immunoprecipitation and immunofluorescence co-localization.","method":"Co-immunoprecipitation, immunofluorescence co-localization, Western blot for β-catenin pathway components","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct interaction with GSK-3β established by Co-IP and co-localization, functional consequence on Wnt pathway shown, single lab","pmids":["34462446"],"is_preprint":false}],"current_model":"MTDH/AEG-1 is a multifunctional transmembrane/ER protein that acts as a scaffold: it interacts with SND1 (structurally defined by crystal structure, functionally required for tumor-initiating cell survival and immune evasion via Tap1/2 mRNA destabilization), with the transcriptional coactivator CBP (protecting it from ubiquitination to drive TWIST1 expression), with RXR (sequestering it to inhibit retinoid signaling and control lipid metabolism), with PLZF (relieving transcriptional repression), with GSK-3β (activating Wnt/β-catenin), and with USP10 (stabilizing PARP1 via K48-deubiquitination to promote DNA repair and radioresistance); in the cytoplasm it functions as an RNA-binding protein regulating mRNA stability and translation (including MDR1, FANCD2/FANCI, and others through RISC association); its activity is modulated by palmitoylation at Cys-75 (by zDHHC6/PPT1/2), ubiquitination at NLS-2, and transcriptional induction through H3K79 methylation by DOT1L, collectively enabling its roles in oncogenesis, chemoresistance, metastasis, and immune evasion."},"narrative":{"teleology":[{"year":2004,"claim":"The basic identity and topology of MTDH were established: it is a type-1b transmembrane protein residing at the ER, nuclear envelope, and nucleolus, resolving its subcellular distribution and membrane orientation.","evidence":"Subcellular fractionation, immunostaining, and Northern blot in multiple cell types","pmids":["14980505"],"confidence":"High","gaps":["Determinants of dynamic redistribution between ER, nuclear envelope, and nucleolus were not defined","Membrane topology model based on single study"]},{"year":2004,"claim":"MTDH was found to colocalize with tight junction proteins ZO-1 and occludin in polarized epithelial cells, suggesting a role in junction maturation rather than structural integrity.","evidence":"Immunolocalization during tight junction disruption and reformation in polarized epithelial cells","pmids":["15383321"],"confidence":"Medium","gaps":["No direct biochemical interaction with ZO-1 demonstrated","Functional consequence of junction association not tested by loss-of-function"]},{"year":2008,"claim":"Identification of BCCIP as an MTDH-binding partner revealed a mechanism by which MTDH promotes proteasomal degradation of a tumor suppressor-associated protein.","evidence":"Yeast two-hybrid and co-immunoprecipitation with proteasome inhibitor rescue","pmids":["18440304"],"confidence":"Medium","gaps":["Direct ubiquitination of BCCIP by MTDH-associated E3 ligase not identified","In vivo significance not tested"]},{"year":2009,"claim":"Mapping of three NLS motifs and identification of ubiquitin modification at NLS-2 established that MTDH localization is actively regulated and that its cytoplasmic retention involves ubiquitination, explaining how a single protein operates in multiple compartments.","evidence":"GFP-NLS fusion deletion constructs, immunoprecipitation, Western blotting","pmids":["19383828"],"confidence":"High","gaps":["E3 ligase responsible for NLS-2 ubiquitination not identified at this stage","Ubiquitin chain type not determined"]},{"year":2009,"claim":"Discovery that nuclear MTDH binds the transcriptional repressor PLZF and displaces it from promoters established MTDH as a modulator of transcription factor access to chromatin.","evidence":"Yeast two-hybrid, reciprocal co-IP in mammalian cells, promoter-binding assays, co-localization with HDAC-containing nuclear bodies","pmids":["19648967"],"confidence":"High","gaps":["Genome-wide targets of PLZF derepression by MTDH not characterized","Physiological relevance in non-cancer contexts unknown"]},{"year":2011,"claim":"Defining MTDH as a cytoplasmic RNA-binding protein that associates with RISC components and regulates mRNA translation and stress granule dynamics fundamentally expanded its functional repertoire beyond transcriptional regulation.","evidence":"Subcellular fractionation, co-IP with RNA-binding proteins, mRNA regulation and stress granule assays upon knockdown","pmids":["22199357"],"confidence":"High","gaps":["Direct RNA-binding domain not mapped","Specificity of mRNA target selection unclear","Whether RISC association is direct or bridged by SND1 not resolved"]},{"year":2011,"claim":"MTDH was shown to repress EAAT2 transcription through a YY1–CBP axis, linking it to excitotoxic neuronal death and revealing its first non-cancer pathological function.","evidence":"Gain/loss-of-function in astrocytes and glioma cells, patient correlation, transcriptional reporter assays","pmids":["21852380"],"confidence":"High","gaps":["Whether YY1 recruitment is via direct MTDH–YY1 interaction not resolved","Relevance to neurodegenerative disease in vivo not tested"]},{"year":2011,"claim":"MTDH was identified as a host factor incorporated into HIV-1 virions via interaction with Gag MA/NC domains, establishing a viral biology dimension.","evidence":"Affinity purification, co-IP, domain mapping, virion incorporation, viral protease cleavage","pmids":["21957284"],"confidence":"High","gaps":["Functional consequence of MTDH incorporation for viral infectivity not determined","Whether MTDH affects HIV-1 assembly or entry not tested"]},{"year":2014,"claim":"The MTDH–SND1 interaction was structurally resolved at atomic resolution, identifying a two-tryptophan peptide motif in MTDH that inserts into an SND1 groove; disruption of this interface abolished tumorigenicity, validating it as a druggable cancer target.","evidence":"X-ray crystallography of MTDH–SND1 complex, tryptophan mutagenesis, in vivo tumor-initiating cell assays and mouse models","pmids":["24981741","25242325"],"confidence":"High","gaps":["Structural basis for how SND1 binding connects to RISC activity not resolved","Whether other MTDH regions contribute to SND1 regulation beyond the 11-residue motif unknown"]},{"year":2014,"claim":"MTDH was shown to inhibit retinoid signaling by sequestering RXR in the cytoplasm and by activating ERK-mediated RXR phosphorylation, providing a mechanistic basis for its role in both oncogenesis and lipid metabolism.","evidence":"Co-IP, immunofluorescence, fractionation, kinase assays in transgenic and knockdown models; confirmed in enterocyte-specific knockout for lipid absorption","pmids":["25125681","26070567"],"confidence":"High","gaps":["Direct binding site on RXR not mapped","Whether MTDH–RXR interaction is druggable not explored"]},{"year":2014,"claim":"Genetic knockout of MTDH in mice revealed its essential role in NF-κB activation in hepatocytes and macrophages, establishing it as a non-redundant signaling node for inflammation-driven hepatocarcinogenesis.","evidence":"Mtdh knockout mice, DEN-induced HCC model, NF-κB and STAT3 pathway analysis","pmids":["25193383"],"confidence":"High","gaps":["Molecular mechanism by which MTDH activates IKK/NF-κB not fully defined","Whether NF-κB role is direct or mediated through SND1 unclear"]},{"year":2015,"claim":"MTDH was found to stabilize CBP by preventing its ubiquitin-mediated degradation, thereby licensing H3 acetylation at the TWIST1 promoter and cancer stem cell expansion — establishing a second epigenetic mechanism distinct from RXR sequestration.","evidence":"Co-IP of MTDH–CBP, ChIP for H3 acetylation, ubiquitination assays, CSC functional readouts","pmids":["26141861"],"confidence":"High","gaps":["E3 ligase targeting CBP in this context not identified","Whether MTDH–CBP interaction is direct or scaffold-mediated unknown"]},{"year":2019,"claim":"MTDH's RNA-binding activity was shown to directly regulate FANCD2/FANCI mRNA stability, mechanistically linking MTDH to the Fanconi anemia DNA repair pathway and platinum chemoresistance.","evidence":"RNA immunoprecipitation confirming direct MTDH–mRNA binding, knockdown with chemosensitivity readout, patient-derived xenograft model","pmids":["31477281"],"confidence":"Medium","gaps":["RNA-binding domain/motif in MTDH not defined","Whether regulation occurs through RISC or independent mechanism not distinguished"]},{"year":2021,"claim":"The MTDH–SND1 complex was shown to destabilize Tap1/2 mRNAs encoding antigen-presentation machinery, directly linking this interaction to tumor immune evasion; pharmacological disruption with C26-A6 restored T cell infiltration and synergized with anti-PD-1 therapy.","evidence":"Genetic and pharmacological MTDH–SND1 disruption, mRNA stability assays for Tap1/2, in vivo immune phenotyping in breast cancer models","pmids":["35121988","35121987"],"confidence":"High","gaps":["Full spectrum of mRNAs destabilized by MTDH–SND1 not cataloged","Whether C26-A6 has off-target effects in immune cells not fully assessed","Clinical translation of MTDH–SND1 inhibitors not yet tested"]},{"year":2022,"claim":"Palmitoylation at Cys-75 by zDHHC6 (reversed by PPT1/2) was identified as a post-translational switch that destabilizes MTDH protein and weakens MTDH–SND1 binding, with Zdhhc6 knockout enhancing hepatocarcinogenesis — revealing lipid modification as a regulatory layer.","evidence":"Acyl-RAC assay, Cys-75 knock-in mice, Zdhhc6 knockout mice, DEN-induced HCC model","pmids":["36276642"],"confidence":"High","gaps":["Structural basis for how Cys-75 palmitoylation disrupts SND1 binding not determined","Whether palmitoylation affects other MTDH interactions (CBP, RXR) not tested"]},{"year":2023,"claim":"MTDH was found to recruit USP10 to deubiquitinate K48-linked polyubiquitin at PARP1-Lys425, preventing PARP1 degradation and enabling homologous recombination repair — establishing a direct mechanism for MTDH-driven radioresistance.","evidence":"Co-IP, K48 linkage-specific ubiquitination assays, PARP1-K425R mutagenesis, γH2AX assays, xenograft irradiation models","pmids":["37838281"],"confidence":"High","gaps":["Whether MTDH–USP10 interaction is direct or bridged not fully resolved","Generalizability beyond ESCC not tested","Whether other DNA repair substrates are regulated by MTDH–USP10 unknown"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for MTDH's RNA-binding specificity, the complete catalog of mRNA targets regulated through RISC, whether the NF-κB activation mechanism involves a direct molecular interaction with IKK complex components, and whether clinical-grade MTDH–SND1 inhibitors can achieve therapeutic efficacy in patients.","evidence":"","pmids":[],"confidence":"Low","gaps":["RNA-binding domain/motif in MTDH not structurally defined","Transcriptome-wide identification of MTDH-bound mRNAs incomplete","Direct versus indirect mechanism of NF-κB activation unresolved","No clinical trial data for MTDH-SND1 inhibitors"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6,19,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,9,11,24]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8,24]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,23,29]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,10,15,27,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21,22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,5,11,25]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[24]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,19,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8,22]}],"complexes":["MTDH-SND1 complex","RISC"],"partners":["SND1","CBP","RXR","PLZF","USP10","GSK3B","BCCIP","PARP1"],"other_free_text":[]},"mechanistic_narrative":"MTDH/AEG-1 is a multifunctional scaffold protein that integrates transcriptional regulation, RNA metabolism, and signal transduction to promote oncogenesis, metastasis, chemoresistance, and immune evasion. As a type-1b membrane protein localized to the ER, nuclear envelope, and nucleolus [PMID:14980505], MTDH operates through structurally defined protein–protein interactions: it binds SND1 via an 11-residue peptide motif to stabilize SND1 and destabilize Tap1/2 mRNAs encoding antigen-presentation machinery, thereby suppressing anti-tumor immunity [PMID:25242325, PMID:35121988]; it protects CBP from ubiquitin-mediated degradation to drive TWIST1 transcription and cancer stemness [PMID:26141861]; it sequesters RXR to inhibit retinoid and lipid-metabolic nuclear receptor signaling [PMID:25125681, PMID:26070567]; and it recruits USP10 to deubiquitinate PARP1 at K48-linked Lys425, promoting DNA repair and radioresistance [PMID:37838281]. In the cytoplasm, MTDH functions as an RNA-binding protein that associates with RISC components and regulates mRNA stability and translation of targets including FANCD2/FANCI [PMID:22199357, PMID:31477281], with its activity modulated by palmitoylation at Cys-75 catalyzed by zDHHC6 [PMID:36276642] and by NF-κB pathway activation essential for hepatocarcinogenesis [PMID:25193383]."},"prefetch_data":{"uniprot":{"accession":"Q86UE4","full_name":"Protein LYRIC","aliases":["3D3/LYRIC","Astrocyte elevated gene-1 protein","AEG-1","Lysine-rich CEACAM1 co-isolated protein","Metadherin","Metastasis adhesion protein"],"length_aa":582,"mass_kda":63.8,"function":"Down-regulates SLC1A2/EAAT2 promoter activity when expressed ectopically. Activates the nuclear factor kappa-B (NF-kappa-B) transcription factor. Promotes anchorage-independent growth of immortalized melanocytes and astrocytes which is a key component in tumor cell expansion. Promotes lung metastasis and also has an effect on bone and brain metastasis, possibly by enhancing the seeding of tumor cells to the target organ endothelium. 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Gag.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21957284","citation_count":23,"is_preprint":false},{"pmid":"28661037","id":"PMC_28661037","title":"AEG-1 induces gastric cancer metastasis by upregulation of eIF4E expression.","date":"2017","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28661037","citation_count":23,"is_preprint":false},{"pmid":"34203598","id":"PMC_34203598","title":"Emerging Role and Clinicopathological Significance of AEG-1 in Different Cancer Types: A Concise Review.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34203598","citation_count":22,"is_preprint":false},{"pmid":"27090750","id":"PMC_27090750","title":"Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND.","date":"2016","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27090750","citation_count":22,"is_preprint":false},{"pmid":"29207012","id":"PMC_29207012","title":"MicroRNA‑30a‑5p suppresses tumor cell proliferation of human renal cancer via the MTDH/PTEN/AKT pathway.","date":"2017","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29207012","citation_count":22,"is_preprint":false},{"pmid":"22844377","id":"PMC_22844377","title":"Serum anti-AEG-1 auto-antibody is a potential novel biomarker for malignant tumors.","date":"2012","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/22844377","citation_count":22,"is_preprint":false},{"pmid":"28275050","id":"PMC_28275050","title":"Novel Thiosemicarbazones Inhibit Lysine-Rich Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) Coisolated (LYRIC) and the LYRIC-Induced Epithelial-Mesenchymal Transition via Upregulation of N-Myc Downstream-Regulated Gene 1 (NDRG1).","date":"2017","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28275050","citation_count":22,"is_preprint":false},{"pmid":"34552061","id":"PMC_34552061","title":"MiR-9-3p regulates the biological functions and drug resistance of gemcitabine-treated breast cancer cells and affects tumor growth through targeting MTDH.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34552061","citation_count":21,"is_preprint":false},{"pmid":"28174206","id":"PMC_28174206","title":"Down-regulated miR-26a promotes proliferation, migration, and invasion via negative regulation of MTDH in esophageal squamous cell carcinoma.","date":"2017","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/28174206","citation_count":21,"is_preprint":false},{"pmid":"35152973","id":"PMC_35152973","title":"Metadherin (AEG-1/MTDH/LYRIC) expression: Significance in malignancy and crucial role in colorectal cancer.","date":"2021","source":"Advances in clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35152973","citation_count":20,"is_preprint":false},{"pmid":"34462446","id":"PMC_34462446","title":"AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34462446","citation_count":20,"is_preprint":false},{"pmid":"25993398","id":"PMC_25993398","title":"Molecular Modification of Metadherin/MTDH Impacts the Sensitivity of Breast Cancer to Doxorubicin.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25993398","citation_count":20,"is_preprint":false},{"pmid":"31114332","id":"PMC_31114332","title":"microRNA-877 inhibits malignant progression of colorectal cancer by directly targeting MTDH and regulating the PTEN/Akt pathway.","date":"2019","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/31114332","citation_count":20,"is_preprint":false},{"pmid":"31477281","id":"PMC_31477281","title":"MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy.","date":"2019","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31477281","citation_count":20,"is_preprint":false},{"pmid":"30912021","id":"PMC_30912021","title":"3D-3 Tumor Models in Drug Discovery for Analysis of Immune Cell Infiltration.","date":"2019","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/30912021","citation_count":20,"is_preprint":false},{"pmid":"33671513","id":"PMC_33671513","title":"The Scope of Astrocyte Elevated Gene-1/Metadherin (AEG-1/MTDH) in Cancer Clinicopathology: A Review.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33671513","citation_count":19,"is_preprint":false},{"pmid":"34142340","id":"PMC_34142340","title":"Circular RNA circHIPK3 modulates prostate cancer progression via targeting miR-448/MTDH signaling.","date":"2021","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/34142340","citation_count":19,"is_preprint":false},{"pmid":"34729247","id":"PMC_34729247","title":"circ-NOL10 regulated by MTDH/CASC3 inhibits breast cancer progression and metastasis via multiple miRNAs and PDCD4.","date":"2021","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/34729247","citation_count":19,"is_preprint":false},{"pmid":"26798451","id":"PMC_26798451","title":"The role of AEG-1 in the development of liver cancer.","date":"2015","source":"Hepatic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26798451","citation_count":18,"is_preprint":false},{"pmid":"36017623","id":"PMC_36017623","title":"DOT1L regulates MTDH-mediated angiogenesis in triple-negative breast cancer: intermediacy of NF-κB-HIF1α axis.","date":"2022","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/36017623","citation_count":18,"is_preprint":false},{"pmid":"31698701","id":"PMC_31698701","title":"AEG-1/miR-221 Axis Cooperatively Regulates the Progression of Hepatocellular Carcinoma by Targeting PTEN/PI3K/AKT Signaling Pathway.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31698701","citation_count":18,"is_preprint":false},{"pmid":"29770329","id":"PMC_29770329","title":"AEG-1 Contributes to Metastasis in Hypoxia-Related Ovarian Cancer by Modulating the HIF-1alpha/NF-kappaB/VEGF Pathway.","date":"2018","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/29770329","citation_count":18,"is_preprint":false},{"pmid":"30132507","id":"PMC_30132507","title":"Serum miR-30d as a novel biomarker for multiple myeloma and its antitumor role in U266 cells through the targeting of the MTDH/PI3K/Akt signaling pathway.","date":"2018","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30132507","citation_count":18,"is_preprint":false},{"pmid":"33225366","id":"PMC_33225366","title":"Downregulation of Long Noncoding RNA TUG1 Attenuates MTDH-Mediated Inflammatory Damage via Targeting miR-29b-1-5p After Spinal Cord Ischemia Reperfusion.","date":"2021","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33225366","citation_count":18,"is_preprint":false},{"pmid":"29257267","id":"PMC_29257267","title":"miR‑96 inhibits EMT by targeting AEG‑1 in glioblastoma cancer cells.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29257267","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51410,"output_tokens":6938,"usd":0.12915},"stage2":{"model":"claude-opus-4-6","input_tokens":10732,"output_tokens":4099,"usd":0.234203},"total_usd":0.363353,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"LYRIC/MTDH (also called 3D3/lyric) is a type-1b membrane protein with a single transmembrane domain, localized to the endoplasmic reticulum, nuclear envelope, and nucleolus, as determined by subcellular fractionation and immunostaining.\",\n      \"method\": \"Subcellular fractionation, immunostaining, Northern blot, antibody characterization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation + immunostaining + Northern blot) in a single study establishing subcellular localization\",\n      \"pmids\": [\"14980505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LYRIC/MTDH colocalizes with tight junction proteins ZO-1 and occludin in polarized epithelial cells and dissociates from ZO-1 when junctional complexes are disrupted, indicating it is recruited during tight junction maturation rather than being a structural component.\",\n      \"method\": \"Immunolocalization of LYRIC with ZO-1 and occludin in polarized epithelial cells; disruption and reformation of tight junctions\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional context, single study\",\n      \"pmids\": [\"15383321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LYRIC/AEG-1 contains three nuclear localization signals (NLS): NLS-3 (aa 546–582) is the predominant regulator of nuclear localization, NLS-1 (aa 78–130) regulates nucleolar localization, and NLS-2 (aa 415–486) is the site of ubiquitin modification in the cytoplasm.\",\n      \"method\": \"GFP-NLS fusion proteins, deletion constructs, immunoprecipitation, Western blotting\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain mapping with deletion constructs and biochemical validation of ubiquitin modification\",\n      \"pmids\": [\"19383828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nuclear LYRIC/AEG-1 interacts with the transcriptional repressor PLZF via the N- and C-termini of LYRIC and the C-terminal region of PLZF (C-terminal to RD2 domain), and co-expression of LYRIC reduces PLZF binding to promoters, relieving PLZF-mediated repression; both proteins co-localize to nuclear bodies containing histone deacetylases.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, promoter-binding assays, co-localization microscopy\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmed in yeast and mammalian cells with functional promoter-binding assay\",\n      \"pmids\": [\"19648967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LYRIC/AEG-1 interacts with BCCIPα (a CDKN1A and BRCA2-associated protein) in mammalian cells; co-expression leads to decreased BCCIPα protein levels that is partially reversed by proteasome inhibition, indicating LYRIC promotes proteasomal degradation of BCCIPα.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, Western blotting with proteasome inhibitor\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — interaction confirmed in mammalian cells with mechanistic follow-up using proteasome inhibition, single lab\",\n      \"pmids\": [\"18440304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AEG-1/MTDH represses the glutamate transporter EAAT2 at the transcriptional level by inducing YY1 activity to inhibit CBP function as a coactivator on the EAAT2 promoter, resulting in reduced glutamate uptake and neuronal cell death (excitotoxicity).\",\n      \"method\": \"Gain- and loss-of-function studies in primary human fetal astrocytes and T98G cells, Pearson correlation analysis in patient samples, transcriptional assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic transcriptional pathway (YY1/CBP/EAAT2) established with gain/loss-of-function and patient correlation, multiple approaches\",\n      \"pmids\": [\"21852380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cytoplasmic MTDH functions as an RNA-binding protein; it associates with RNA-binding proteins and components of the RNA-induced silencing complex (RISC) in a nucleic acid-dependent manner, regulates protein expression of multiple mRNAs (e.g., PDCD10, KDM6A), and its depletion leads to increased stress granule formation and reduced cell survival.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation with RNA-binding proteins, mRNA regulation assays, knockdown with stress granule and survival readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing RNA-binding function, localization, and functional consequences\",\n      \"pmids\": [\"22199357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MTDH interacts with and stabilizes SND1 (Staphylococcal nuclease domain-containing 1), supporting tumor-initiating cell survival under oncogenic/stress conditions; silencing MTDH or SND1 individually or disrupting their interaction compromises tumorigenicity in vivo.\",\n      \"method\": \"Mouse mammary tumor models, Co-IP, in vivo TIC assays, genetic silencing of MTDH and SND1\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple mouse models, reciprocal interaction studies, in vivo functional validation\",\n      \"pmids\": [\"24981741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The crystal structure of the MTDH-SND1 complex was determined at high resolution, revealing an 11-residue MTDH peptide motif occupying an extended protein groove between SN1/2 domains of SND1, with two MTDH tryptophan residues critical for the interaction; mutagenesis of these residues disrupts cancer-promoting activity and SND1 stability.\",\n      \"method\": \"X-ray crystallography, mutagenesis, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis with functional validation in breast cancer models\",\n      \"pmids\": [\"25242325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AEG-1/MTDH interacts with retinoid X receptor (RXR) in the nucleus of non-tumor cells, interfering with recruitment of transcriptional coactivators to RXR. In tumor cells, overexpressed AEG-1 sequesters RXR in the cytoplasm; additionally, ERK activated by AEG-1 phosphorylates RXR, causing its functional inactivation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, nuclear/cytoplasmic fractionation, kinase assays, AEG-1 transgenic and knockdown models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, mechanistic dissection of RXR sequestration and ERK-mediated phosphorylation\",\n      \"pmids\": [\"25125681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AEG-1 is essential for NF-κB activation in hepatocytes and macrophages; AEG-1-deficient mice show defective NF-κB signaling, reduced IL-6 production, and impaired STAT3 activation, conferring resistance to DEN-induced hepatocellular carcinoma.\",\n      \"method\": \"AEG-1 knockout mouse model, DEN-induced hepatocarcinogenesis, NF-κB and STAT3 pathway analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic knockout with defined molecular pathway phenotype\",\n      \"pmids\": [\"25193383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MTDH promotes cancer stem-like cell expansion by interacting with the histone acetyltransferase CBP and preventing its ubiquitin-mediated degradation, thereby licensing CBP-mediated histone H3 acetylation on the TWIST1 promoter and activating TWIST1 transcription.\",\n      \"method\": \"Co-immunoprecipitation of MTDH-CBP, chromatin immunoprecipitation, ubiquitination assays, knockdown/overexpression with CSC phenotype readouts\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, ubiquitination assay) establishing mechanism, single lab\",\n      \"pmids\": [\"26141861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AEG-1 interacts with RXR and inhibits RXR-dependent activation of liver X receptor and PPARα in enterocytes, resulting in decreased intestinal fat absorption; AEG-1 knockout mice are leaner and resistant to high-fat diet-induced obesity.\",\n      \"method\": \"AEG-1 knockout mouse model, high-fat diet challenge, nuclear receptor activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with defined mechanistic pathway through nuclear receptor regulation\",\n      \"pmids\": [\"26070567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CPEB1 binds the MTDH mRNA and represses its translation; phosphorylation of CPEB1 triggers cytoplasmic polyadenylation and translational activation of MTDH mRNA, promoting glioblastoma cell migration and tumor growth.\",\n      \"method\": \"RNA-binding assay, CPEB1 phosphorylation-deficient mutant, in vitro and in vivo tumor models, reporter mRNA localization\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA-binding and functional mutant data, single lab\",\n      \"pmids\": [\"23360795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The cellular protein Lyric/MTDH interacts with HIV-1 Gag via the Gag matrix (MA) and nucleocapsid (NC) domains; this interaction requires Gag multimerization and Lyric amino acids 101–289; endogenous Lyric is incorporated into HIV-1 virions and cleaved by the viral protease.\",\n      \"method\": \"Affinity purification, co-immunoprecipitation, domain mapping, virion analysis, viral protease cleavage assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-mapped interaction, virion incorporation, and protease cleavage confirmed biochemically\",\n      \"pmids\": [\"21957284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AEG-1 activates Wnt/PCP-Rho signaling to promote EMT and invasion in tongue squamous cell carcinoma; recombinant AEG-1 activates Wnt5a/Rac1/ROCK pathway, and its stimulatory effects are reversed by anti-Wnt5a neutralizing antibody or inhibition of Rac1/ROCK.\",\n      \"method\": \"Recombinant AEG-1 treatment, neutralizing antibody, kinase inhibitors, xenograft model, EMT marker analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with recombinant protein and pathway inhibitors, single lab\",\n      \"pmids\": [\"26689985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AEG-1 upregulates transcription of the membrane protein Tetraspanin 8 (TSPAN8), which mediates AEG-1-induced invasion, migration, and angiogenesis in hepatocellular carcinoma; TSPAN8 knockdown abolishes AEG-1-dependent metastasis in an orthotopic xenograft model.\",\n      \"method\": \"Gene expression analysis, TSPAN8 knockdown, invasion/migration assays, HUVEC tube formation, orthotopic xenograft in nude mice\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined downstream target in vivo, single lab\",\n      \"pmids\": [\"27339400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AEG-1 promotes gastric cancer metastasis by positively regulating eIF4E expression, which in turn upregulates MMP-9 and Twist; manipulation of eIF4E partially rescues AEG-1-induced EMT, migration, and invasion.\",\n      \"method\": \"Gain/loss-of-function of AEG-1 and eIF4E, Western blotting, cell migration and invasion assays, orthotopic mouse model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — rescue experiment placing eIF4E downstream of AEG-1, in vivo confirmation, single lab\",\n      \"pmids\": [\"28661037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LINC01638 interacts with c-Myc protein to prevent SPOP-mediated ubiquitination and degradation of c-Myc; stabilized c-Myc transcriptionally activates MTDH expression, which subsequently activates TWIST1, driving EMT in triple-negative breast cancer.\",\n      \"method\": \"RNA-protein interaction assay, ubiquitination assay, chromatin immunoprecipitation, knockdown/overexpression in TNBC cells and xenografts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway established with protein-RNA interaction, ubiquitination, and ChIP evidence\",\n      \"pmids\": [\"30002443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MTDH as an RNA-binding protein regulates the mRNA stability of FANCD2 and FANCI (Fanconi anemia complementation group proteins); RNA-binding protein immunoprecipitation confirmed direct MTDH-mRNA interaction, and MTDH knockdown reduced FANCD2/FANCI levels, restoring platinum sensitivity.\",\n      \"method\": \"RNA-binding protein immunoprecipitation (RIP), knockdown, chemosensitivity assays, patient-derived xenograft model\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RIP confirmation of MTDH-mRNA interaction with functional chemosensitivity readout, single lab\",\n      \"pmids\": [\"31477281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CPEB3 binds the 3'-UTR of MTDH mRNA and suppresses its translation; CPEB3 knockout mice show increased susceptibility to carcinogen-induced hepatocarcinogenesis; CPEB3 overexpression inhibits EMT and metastasis of HCC cells by post-transcriptional suppression of MTDH.\",\n      \"method\": \"RNA immunoprecipitation (transcriptome-wide), luciferase assay with MTDH 3'-UTR, CPEB3 knockout mice, in vivo metastasis models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RIP, luciferase 3'-UTR assay, and in vivo knockout model, multiple orthogonal methods\",\n      \"pmids\": [\"32968053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The MTDH-SND1 complex binds to and destabilizes Tap1/2 mRNAs (encoding antigen-presentation machinery components), reducing tumor antigen presentation and inhibiting T cell infiltration; pharmacological disruption of MTDH-SND1 by compound C26-A6 restores immune surveillance and synergizes with anti-PD-1 therapy.\",\n      \"method\": \"Genetic and pharmacological disruption of MTDH-SND1 complex, mRNA stability assays for Tap1/2, in vivo preclinical breast cancer models, immune phenotyping\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — small molecule plus genetic disruption with mechanistic RNA-binding readout and in vivo immune phenotype\",\n      \"pmids\": [\"35121988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genetic ablation of Mtdh in mice disrupts the MTDH-SND1 interaction and inhibits breast cancer development; small-molecule inhibitors C26-A2 and C26-A6 that disrupt the MTDH-SND1 protein-protein interaction suppress tumor growth and metastasis and enhance chemotherapy sensitivity in TNBC preclinical models.\",\n      \"method\": \"Genetically modified mouse models (Mtdh ablation), compound screening, in vivo TNBC models, chemosensitivity assays\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic and pharmacological evidence converging on MTDH-SND1 PPI as essential, validated in vivo\",\n      \"pmids\": [\"35121987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AEG-1 undergoes palmitoylation on Cys-75, catalyzed by zDHHC6 and reversed by PPT1/2; palmitoylation adversely regulates AEG-1 protein stability and weakens AEG-1-SND1 interaction, thereby altering RISC activity and expression of tumor suppressors; blocking palmitoylation via Zdhhc6 knockout enhances DEN-induced HCC progression in vivo.\",\n      \"method\": \"Acyl-RAC assay, Cys-75 point mutation (AEG-1-C75A knock-in mice), Zdhhc6 knockout mice, DEN-induced HCC model, biochemical interaction assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — site-specific mutagenesis, knock-in and knockout mouse models, and biochemical validation of palmitoylation writers/erasers\",\n      \"pmids\": [\"36276642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AEG-1 promotes radioresistance in ESCC by recruiting the deubiquitinase USP10 to remove K48-linked polyubiquitin chains at Lys425 of PARP1, preventing its proteasomal degradation and thereby facilitating homologous recombination-mediated DNA double-strand break repair.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays with K48 linkage specificity, PARP1 mutagenesis (Lys425), DNA damage (γH2AX) assays, in vivo xenograft irradiation models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — site-specific ubiquitination mapping, deubiquitinase identification, and in vivo functional validation\",\n      \"pmids\": [\"37838281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DOT1L, a H3K79 methyltransferase, promotes MTDH transcription by increasing H3K79me3 levels on the MTDH promoter as shown by ChIP; MTDH in turn activates NF-κB occupancy on the HIF1α promoter, leading to elevated proangiogenic mediators in TNBC cells.\",\n      \"method\": \"ChIP assay for H3K79me3 on MTDH promoter, DOT1L inhibitor/siRNA, NF-κB ChIP on HIF1α promoter, angiogenesis assays in vitro and in vivo\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP evidence for epigenetic regulation plus downstream NF-κB-HIF1α pathway, single lab\",\n      \"pmids\": [\"36017623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXW7, an E3 ubiquitin ligase component, targets MTDH for ubiquitin-mediated proteasomal degradation; FBXW7 overexpression decreases MTDH protein levels and induces proliferation arrest and apoptosis in breast cancer cells.\",\n      \"method\": \"FBXW7 overexpression and knockdown, Western blotting, proliferation and apoptosis assays\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single study, indirect evidence for ubiquitination via FBXW7; direct ubiquitination not biochemically confirmed\",\n      \"pmids\": [\"29534580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MTDH mediates trastuzumab resistance in HER2-positive breast cancer by activating IκBα inhibition and nuclear translocation of NF-κB p65, which subsequently decreases PTEN expression; forced PTEN expression restores trastuzumab sensitivity.\",\n      \"method\": \"MTDH knockdown and overexpression, NF-κB pathway analysis, PTEN rescue experiments, in vivo xenograft models\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway dissection with rescue experiments, in vivo validation, single lab\",\n      \"pmids\": [\"25417825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MTDH acts as an RNA-binding protein that directly binds circ-NOL10 (with characterized RBP motifs), and ectopic expression or depletion of MTDH leads to circ-NOL10 expression changes, indicating MTDH modulates circRNA biogenesis or stability.\",\n      \"method\": \"RNA immunoprecipitation, RBP motif characterization, overexpression/knockdown of MTDH with circ-NOL10 readout\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single RIP study with indirect functional evidence, single lab\",\n      \"pmids\": [\"34729247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AEG-1 activates Wnt/β-catenin signaling by directly interacting with GSK-3β in the cytoplasm of glioma cells, as shown by co-immunoprecipitation and immunofluorescence co-localization.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, Western blot for β-catenin pathway components\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct interaction with GSK-3β established by Co-IP and co-localization, functional consequence on Wnt pathway shown, single lab\",\n      \"pmids\": [\"34462446\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTDH/AEG-1 is a multifunctional transmembrane/ER protein that acts as a scaffold: it interacts with SND1 (structurally defined by crystal structure, functionally required for tumor-initiating cell survival and immune evasion via Tap1/2 mRNA destabilization), with the transcriptional coactivator CBP (protecting it from ubiquitination to drive TWIST1 expression), with RXR (sequestering it to inhibit retinoid signaling and control lipid metabolism), with PLZF (relieving transcriptional repression), with GSK-3β (activating Wnt/β-catenin), and with USP10 (stabilizing PARP1 via K48-deubiquitination to promote DNA repair and radioresistance); in the cytoplasm it functions as an RNA-binding protein regulating mRNA stability and translation (including MDR1, FANCD2/FANCI, and others through RISC association); its activity is modulated by palmitoylation at Cys-75 (by zDHHC6/PPT1/2), ubiquitination at NLS-2, and transcriptional induction through H3K79 methylation by DOT1L, collectively enabling its roles in oncogenesis, chemoresistance, metastasis, and immune evasion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MTDH/AEG-1 is a multifunctional scaffold protein that integrates transcriptional regulation, RNA metabolism, and signal transduction to promote oncogenesis, metastasis, chemoresistance, and immune evasion. As a type-1b membrane protein localized to the ER, nuclear envelope, and nucleolus [PMID:14980505], MTDH operates through structurally defined protein–protein interactions: it binds SND1 via an 11-residue peptide motif to stabilize SND1 and destabilize Tap1/2 mRNAs encoding antigen-presentation machinery, thereby suppressing anti-tumor immunity [PMID:25242325, PMID:35121988]; it protects CBP from ubiquitin-mediated degradation to drive TWIST1 transcription and cancer stemness [PMID:26141861]; it sequesters RXR to inhibit retinoid and lipid-metabolic nuclear receptor signaling [PMID:25125681, PMID:26070567]; and it recruits USP10 to deubiquitinate PARP1 at K48-linked Lys425, promoting DNA repair and radioresistance [PMID:37838281]. In the cytoplasm, MTDH functions as an RNA-binding protein that associates with RISC components and regulates mRNA stability and translation of targets including FANCD2/FANCI [PMID:22199357, PMID:31477281], with its activity modulated by palmitoylation at Cys-75 catalyzed by zDHHC6 [PMID:36276642] and by NF-κB pathway activation essential for hepatocarcinogenesis [PMID:25193383].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"The basic identity and topology of MTDH were established: it is a type-1b transmembrane protein residing at the ER, nuclear envelope, and nucleolus, resolving its subcellular distribution and membrane orientation.\",\n      \"evidence\": \"Subcellular fractionation, immunostaining, and Northern blot in multiple cell types\",\n      \"pmids\": [\"14980505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of dynamic redistribution between ER, nuclear envelope, and nucleolus were not defined\", \"Membrane topology model based on single study\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"MTDH was found to colocalize with tight junction proteins ZO-1 and occludin in polarized epithelial cells, suggesting a role in junction maturation rather than structural integrity.\",\n      \"evidence\": \"Immunolocalization during tight junction disruption and reformation in polarized epithelial cells\",\n      \"pmids\": [\"15383321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical interaction with ZO-1 demonstrated\", \"Functional consequence of junction association not tested by loss-of-function\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of BCCIP as an MTDH-binding partner revealed a mechanism by which MTDH promotes proteasomal degradation of a tumor suppressor-associated protein.\",\n      \"evidence\": \"Yeast two-hybrid and co-immunoprecipitation with proteasome inhibitor rescue\",\n      \"pmids\": [\"18440304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination of BCCIP by MTDH-associated E3 ligase not identified\", \"In vivo significance not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapping of three NLS motifs and identification of ubiquitin modification at NLS-2 established that MTDH localization is actively regulated and that its cytoplasmic retention involves ubiquitination, explaining how a single protein operates in multiple compartments.\",\n      \"evidence\": \"GFP-NLS fusion deletion constructs, immunoprecipitation, Western blotting\",\n      \"pmids\": [\"19383828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible for NLS-2 ubiquitination not identified at this stage\", \"Ubiquitin chain type not determined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery that nuclear MTDH binds the transcriptional repressor PLZF and displaces it from promoters established MTDH as a modulator of transcription factor access to chromatin.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP in mammalian cells, promoter-binding assays, co-localization with HDAC-containing nuclear bodies\",\n      \"pmids\": [\"19648967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide targets of PLZF derepression by MTDH not characterized\", \"Physiological relevance in non-cancer contexts unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining MTDH as a cytoplasmic RNA-binding protein that associates with RISC components and regulates mRNA translation and stress granule dynamics fundamentally expanded its functional repertoire beyond transcriptional regulation.\",\n      \"evidence\": \"Subcellular fractionation, co-IP with RNA-binding proteins, mRNA regulation and stress granule assays upon knockdown\",\n      \"pmids\": [\"22199357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA-binding domain not mapped\", \"Specificity of mRNA target selection unclear\", \"Whether RISC association is direct or bridged by SND1 not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"MTDH was shown to repress EAAT2 transcription through a YY1–CBP axis, linking it to excitotoxic neuronal death and revealing its first non-cancer pathological function.\",\n      \"evidence\": \"Gain/loss-of-function in astrocytes and glioma cells, patient correlation, transcriptional reporter assays\",\n      \"pmids\": [\"21852380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YY1 recruitment is via direct MTDH–YY1 interaction not resolved\", \"Relevance to neurodegenerative disease in vivo not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"MTDH was identified as a host factor incorporated into HIV-1 virions via interaction with Gag MA/NC domains, establishing a viral biology dimension.\",\n      \"evidence\": \"Affinity purification, co-IP, domain mapping, virion incorporation, viral protease cleavage\",\n      \"pmids\": [\"21957284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MTDH incorporation for viral infectivity not determined\", \"Whether MTDH affects HIV-1 assembly or entry not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The MTDH–SND1 interaction was structurally resolved at atomic resolution, identifying a two-tryptophan peptide motif in MTDH that inserts into an SND1 groove; disruption of this interface abolished tumorigenicity, validating it as a druggable cancer target.\",\n      \"evidence\": \"X-ray crystallography of MTDH–SND1 complex, tryptophan mutagenesis, in vivo tumor-initiating cell assays and mouse models\",\n      \"pmids\": [\"24981741\", \"25242325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how SND1 binding connects to RISC activity not resolved\", \"Whether other MTDH regions contribute to SND1 regulation beyond the 11-residue motif unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"MTDH was shown to inhibit retinoid signaling by sequestering RXR in the cytoplasm and by activating ERK-mediated RXR phosphorylation, providing a mechanistic basis for its role in both oncogenesis and lipid metabolism.\",\n      \"evidence\": \"Co-IP, immunofluorescence, fractionation, kinase assays in transgenic and knockdown models; confirmed in enterocyte-specific knockout for lipid absorption\",\n      \"pmids\": [\"25125681\", \"26070567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding site on RXR not mapped\", \"Whether MTDH–RXR interaction is druggable not explored\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic knockout of MTDH in mice revealed its essential role in NF-κB activation in hepatocytes and macrophages, establishing it as a non-redundant signaling node for inflammation-driven hepatocarcinogenesis.\",\n      \"evidence\": \"Mtdh knockout mice, DEN-induced HCC model, NF-κB and STAT3 pathway analysis\",\n      \"pmids\": [\"25193383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which MTDH activates IKK/NF-κB not fully defined\", \"Whether NF-κB role is direct or mediated through SND1 unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"MTDH was found to stabilize CBP by preventing its ubiquitin-mediated degradation, thereby licensing H3 acetylation at the TWIST1 promoter and cancer stem cell expansion — establishing a second epigenetic mechanism distinct from RXR sequestration.\",\n      \"evidence\": \"Co-IP of MTDH–CBP, ChIP for H3 acetylation, ubiquitination assays, CSC functional readouts\",\n      \"pmids\": [\"26141861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase targeting CBP in this context not identified\", \"Whether MTDH–CBP interaction is direct or scaffold-mediated unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"MTDH's RNA-binding activity was shown to directly regulate FANCD2/FANCI mRNA stability, mechanistically linking MTDH to the Fanconi anemia DNA repair pathway and platinum chemoresistance.\",\n      \"evidence\": \"RNA immunoprecipitation confirming direct MTDH–mRNA binding, knockdown with chemosensitivity readout, patient-derived xenograft model\",\n      \"pmids\": [\"31477281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA-binding domain/motif in MTDH not defined\", \"Whether regulation occurs through RISC or independent mechanism not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The MTDH–SND1 complex was shown to destabilize Tap1/2 mRNAs encoding antigen-presentation machinery, directly linking this interaction to tumor immune evasion; pharmacological disruption with C26-A6 restored T cell infiltration and synergized with anti-PD-1 therapy.\",\n      \"evidence\": \"Genetic and pharmacological MTDH–SND1 disruption, mRNA stability assays for Tap1/2, in vivo immune phenotyping in breast cancer models\",\n      \"pmids\": [\"35121988\", \"35121987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full spectrum of mRNAs destabilized by MTDH–SND1 not cataloged\", \"Whether C26-A6 has off-target effects in immune cells not fully assessed\", \"Clinical translation of MTDH–SND1 inhibitors not yet tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Palmitoylation at Cys-75 by zDHHC6 (reversed by PPT1/2) was identified as a post-translational switch that destabilizes MTDH protein and weakens MTDH–SND1 binding, with Zdhhc6 knockout enhancing hepatocarcinogenesis — revealing lipid modification as a regulatory layer.\",\n      \"evidence\": \"Acyl-RAC assay, Cys-75 knock-in mice, Zdhhc6 knockout mice, DEN-induced HCC model\",\n      \"pmids\": [\"36276642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how Cys-75 palmitoylation disrupts SND1 binding not determined\", \"Whether palmitoylation affects other MTDH interactions (CBP, RXR) not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"MTDH was found to recruit USP10 to deubiquitinate K48-linked polyubiquitin at PARP1-Lys425, preventing PARP1 degradation and enabling homologous recombination repair — establishing a direct mechanism for MTDH-driven radioresistance.\",\n      \"evidence\": \"Co-IP, K48 linkage-specific ubiquitination assays, PARP1-K425R mutagenesis, γH2AX assays, xenograft irradiation models\",\n      \"pmids\": [\"37838281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MTDH–USP10 interaction is direct or bridged not fully resolved\", \"Generalizability beyond ESCC not tested\", \"Whether other DNA repair substrates are regulated by MTDH–USP10 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for MTDH's RNA-binding specificity, the complete catalog of mRNA targets regulated through RISC, whether the NF-κB activation mechanism involves a direct molecular interaction with IKK complex components, and whether clinical-grade MTDH–SND1 inhibitors can achieve therapeutic efficacy in patients.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"RNA-binding domain/motif in MTDH not structurally defined\", \"Transcriptome-wide identification of MTDH-bound mRNAs incomplete\", \"Direct versus indirect mechanism of NF-κB activation unresolved\", \"No clinical trial data for MTDH-SND1 inhibitors\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 19, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 9, 11, 24]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 23, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 10, 15, 27, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 5, 11, 25]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 19, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8, 22]}\n    ],\n    \"complexes\": [\n      \"MTDH-SND1 complex\",\n      \"RISC\"\n    ],\n    \"partners\": [\n      \"SND1\",\n      \"CBP\",\n      \"RXR\",\n      \"PLZF\",\n      \"USP10\",\n      \"GSK3B\",\n      \"BCCIP\",\n      \"PARP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}