{"gene":"YBX3","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2003,"finding":"ZONAB (YBX3) associates with CDK4, and its nuclear localization (regulated by the tight junction protein ZO-1) controls nuclear CDK4 levels and epithelial cell proliferation and cell density.","method":"Co-immunoprecipitation, antisense/RNAi knockdown, ZO-1 overexpression with proliferation and cell density readouts in MDCK cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus KD/KO with defined cellular phenotype, replicated by multiple approaches in same study","pmids":["12566432"],"is_preprint":false},{"year":2006,"finding":"ZONAB (YBX3) directly regulates transcription of PCNA and cyclin D1 by binding to responsive elements in their promoters, thereby promoting G1/S-phase progression and epithelial cell differentiation.","method":"cDNA microarray screening, chromatin immunoprecipitation (ChIP), reporter gene assays, RNAi knockdown and overexpression in MCF-10A and MDCK cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP plus reporter assays plus KD/OE with defined molecular and cellular phenotypes, multiple orthogonal methods","pmids":["16508013"],"is_preprint":false},{"year":1997,"finding":"Human YBX3 (dbpA) binds to the lower strand of the grp78 core promoter stress-inducible change region (SICR) and represses stress-induced grp78 promoter activity; dbpA interacts with YY1 and antagonizes YY1-mediated transcriptional activation.","method":"Expression library screening, gel shift assays, cotransfection reporter assays, Southwestern blot","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple in vitro binding assays plus reporter assays, single lab","pmids":["8972186"],"is_preprint":false},{"year":1991,"finding":"YBX3/dbpA binds to double-stranded, single-stranded, and abasic (depurinated) DNA, with preferential binding to depurinated DNA, and the extent of specificity is influenced by Mg2+.","method":"Phage expression library screening, electrophoretic mobility shift assays (EMSA), DNA binding competition assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct in vitro binding characterization with multiple substrates, single lab","pmids":["1923758"],"is_preprint":false},{"year":1995,"finding":"Human YBX3/dbpA gene encodes a protein localized both in the cytoplasm and nucleus (particularly at the perinuclear region), contains a cold shock domain encoded by exons 2–5, and has an alternative exon 6; the gene is located on chromosome 12p13.1.","method":"Immunofluorescence, Northern blot, in situ hybridization, genomic cloning and sequencing","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct localization by immunofluorescence, genomic characterization","pmids":["7628487"],"is_preprint":false},{"year":1997,"finding":"YBX3/dbpA overexpression stimulates human thymidine kinase (htk) promoter activity through the proximal CCAAT element (TKC1) in a serum-inducible manner.","method":"Recombinant protein binding assays, cell transfection reporter assays","journal":"Cell growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 3 — reporter assay plus recombinant protein binding, single lab","pmids":["9419421"],"is_preprint":false},{"year":1999,"finding":"A C-terminal 172 amino acid domain of YBX3/dbpA binds to CDK5 and strongly inhibits p35-activated CDK5 kinase activity, as well as CDK4/cyclin D1 activity; it does not interact with CDK2.","method":"Yeast two-hybrid screening of HeLa cDNA library, in vitro kinase inhibition assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — yeast two-hybrid plus in vitro biochemical kinase assay, single lab","pmids":["10100871"],"is_preprint":false},{"year":2004,"finding":"RalA (a Ras superfamily GTPase) interacts with ZONAB/YBX3 in a GTP-dependent manner; this interaction increases with epithelial cell density and relieves ZONAB-mediated transcriptional repression; oncogenic Ras alleviates ZONAB repression via RalA.","method":"Reverse Ras recruitment system (yeast), co-immunoprecipitation, reporter gene assays, cell density experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional reporter assays, multiple orthogonal methods","pmids":["15592429"],"is_preprint":false},{"year":2004,"finding":"YBX3/dbpA transcription is positively regulated by E2F1 through a sequence resembling an E2F binding site (-8 to -1) in the promoter region.","method":"E2F1 overexpression, promoter deletion and mutation analysis, luciferase reporter assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — promoter mutagenesis plus reporter assay, single lab","pmids":["15313206"],"is_preprint":false},{"year":2006,"finding":"ZONAB/YBX3 forms a complex with the RNA processing factor symplekin in the nucleus of epithelial cells; this complex can be reconstituted with recombinant proteins; symplekin depletion reduces nuclear ZONAB accumulation and transcriptional activity, cyclin D1 expression, and proliferation.","method":"Co-immunoprecipitation, recombinant protein reconstitution, RNAi knockdown, reporter gene assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP plus in vitro reconstitution plus functional assays, multiple orthogonal methods","pmids":["17158914"],"is_preprint":false},{"year":2006,"finding":"The heat-shock protein Apg-2 binds to the SH3 domain of ZO-1 and competes with ZONAB/YBX3 for ZO-1 binding, thereby modulating ZONAB transcriptional activity and G1/S phase progression in epithelial cells.","method":"Expression library screening, co-immunoprecipitation, in vitro competition binding assays, reporter gene assays, regulated knockdown","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus in vitro competition plus functional reporter assay, multiple orthogonal methods","pmids":["16407410"],"is_preprint":false},{"year":2009,"finding":"ZONAB/YBX3 associates with GEF-H1/Lfc at tight junctions; GEF-H1 overexpression drives ZONAB nuclear accumulation and transcriptional activation; RhoA signaling via GEF-H1 is required for ZONAB-dependent cyclin D1 promoter activity and expression.","method":"Co-immunoprecipitation, nuclear fractionation, reporter gene assays, RNAi knockdown","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus reporter assays plus knockdown, multiple orthogonal methods","pmids":["19730435"],"is_preprint":false},{"year":2009,"finding":"The symplekin/ZONAB (YBX3) complex represses AML1/Runx1 transcription; ZONAB binds to the AML1 gene promoter and represses KLF4 expression, thereby inhibiting intestinal goblet cell differentiation.","method":"RNAi knockdown, reporter gene assays, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP)","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus EMSA plus RNAi KD with defined cellular phenotype, multiple orthogonal methods","pmids":["19328795"],"is_preprint":false},{"year":2010,"finding":"ZONAB/YBX3 overexpression promotes proliferation and represses differentiation (megalin/cubilin expression, brush border, primary cilium) of proximal tubule cells; ZONAB binds to megalin and cubilin promoters as shown by ChIP and reporter assays.","method":"Overexpression, RNAi knockdown, ChIP, reporter gene assays, immunofluorescence in OK cells and mouse kidney","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus reporter assays plus KO/OE with defined cellular phenotypes, multiple orthogonal methods","pmids":["20133480"],"is_preprint":false},{"year":2007,"finding":"Accumulation of phosphatidylethanol (produced by phospholipase D from ethanol) disrupts claudin-1/ZO-1 association and induces nuclear translocation of ZONAB/YBX3, which mediates increased intestinal cell density.","method":"Phosphatidylethanol treatment, claudin-1 endocytosis assays, co-immunoprecipitation, nuclear fractionation, ZONAB knockdown, in vivo mouse colon analysis","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanistic pathway with Co-IP plus KD rescue experiment, single lab","pmids":["18025260"],"is_preprint":false},{"year":2014,"finding":"CFTR interacts with ZO-1 via its PDZ-binding domain, and CFTR inhibition/knockdown induces nuclear translocation of ZONAB/YBX3, leading to upregulation of CCND1 and downregulation of ErbB2 transcription and impaired tubulogenesis.","method":"Co-immunoprecipitation, knockdown, 3D epithelial culture model, in vivo cftr-/- and cftrΔF508 mouse analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including Co-IP, KD, in vivo mouse model","pmids":["25107366"],"is_preprint":false},{"year":2014,"finding":"ZO proteins (ZO-1, ZO-2, ZO-3) redundantly control the junctional retention and stability of ZONAB/YBX3; depletion of ZO-1 and ZO-2 together (but not individually) causes ZONAB cytoplasmic mislocalization and reduced expression rescued by proteasome inhibitor MG132; full-length ZO-1 does not directly interact with ZONAB in vitro.","method":"Depletion of individual and multiple ZO proteins by RNAi, ZO-1 KO Eph4 cells, in vitro binding assays, MG132 rescue, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple KO/KD conditions plus in vitro binding plus pharmacological rescue, multiple orthogonal approaches","pmids":["24986862"],"is_preprint":false},{"year":2010,"finding":"Overexpression of ZONAB/YBX3 or knockdown of ZO-1 in retinal pigment epithelium (RPE) increases proliferation and induces an EMT-like phenotype in vivo, demonstrating that ZO-1 and ZONAB regulate RPE homeostasis.","method":"Lentiviral-mediated overexpression and knockdown in vivo, electron microscopy, fluorescein angiography, EMT marker expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo lentiviral KD/OE with morphological and functional readouts, single study","pmids":["21209887"],"is_preprint":false},{"year":2015,"finding":"Bradykinin increases BTB permeability via NOS/NO signaling, which promotes ZONAB/YBX3 nuclear translocation; nuclear ZONAB then directly binds promoters of claudin-5 and occludin (verified by ChIP), downregulating their expression.","method":"NOS inhibitor treatment, ZONAB overexpression, ChIP assay, BTB permeability assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP plus pharmacological pathway analysis, single lab","pmids":["26106824"],"is_preprint":false},{"year":2018,"finding":"Hypoxia-inducible HIF1α induces miR-191, which suppresses ZONAB/YBX3 expression; miR-191 overexpression promotes G0/G1 arrest and apoptosis, effects abrogated by ZONAB overexpression, placing ZONAB downstream of HIF1α/miR-191 in hepatic IRI.","method":"miR-191 KO mice (CRISPR/Cas9), miR-191 overexpression/inhibition, ZONAB overexpression rescue, ChIP of HIF1α on miR-191 promoter, hepatic IRI mouse model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — genetic KO mouse plus rescue experiment plus ChIP, multiple orthogonal methods","pmids":["29769640"],"is_preprint":false},{"year":2005,"finding":"YBX3/dbpA binds to DNase I hypersensitive site sequences at -250 bp in the MUC1 promoter and upregulates MUC1 promoter activity via this element in COS-7 cells.","method":"Expression library screening, EMSA, Southwestern blot, UV cross-linking, transient reporter gene assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 — library screening plus reporter assay plus EMSA, single lab","pmids":["15893750"],"is_preprint":false},{"year":2019,"finding":"YBX3 directly binds the mRNAs of SLC7A5 and SLC3A2 amino acid transporter genes and stabilizes these mRNAs, maintaining intracellular amino acid levels; YBX3 depletion specifically reduces SLC7A5/SLC3A2 substrates.","method":"YBX3 depletion with integrated proteomics and transcriptomics, iCLIP RNA binding site mapping, mRNA stability assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — iCLIP plus multi-omics integration plus functional amino acid depletion assay, multiple orthogonal methods","pmids":["31189097"],"is_preprint":false},{"year":2023,"finding":"The lncRNA BLACAT3 recruits YBX3 to shuttle into the nucleus where it synergistically enhances NCF2 transcription, activating downstream NF-κB signaling to promote bladder cancer angiogenesis and hematogenous metastasis.","method":"RNA sequencing, mass spectrometry, functional assays, animal models, m6A microarray","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — MS identification plus functional assays in vitro and in vivo, single lab","pmids":["37612524"],"is_preprint":false},{"year":2023,"finding":"CircSERPINE2 interacts with YBX3 via the CCAUC motif, increasing the affinity of YBX3 for ZO-1 and sequestering YBX3 in the cytoplasm; this inhibits YBX3 binding to the PCNA promoter, ultimately affecting p21 ubiquitin-mediated degradation and promoting mesenchymal stem cell senescence.","method":"RNA pulldown followed by mass spectrometry, siRNA knockdown, overexpression, ChIP, co-immunoprecipitation, in vivo intra-articular injection","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 — RNA pulldown MS plus ChIP plus Co-IP plus in vivo rescue, multiple orthogonal methods","pmids":["37831180"],"is_preprint":false},{"year":2010,"finding":"YBX3/CSDA overexpression in squamous cell carcinoma cells directly represses production of VEGF-A and VEGF-C by binding to hypoxia response elements (HRE) and serum response elements (SRE) in their promoters, inhibiting tumor angiogenesis and lymph node metastasis.","method":"YBX3/CSDA overexpression via plasmid transfection, VEGF-A/C measurement, in vivo tumor and metastasis assays","journal":"Clinical & experimental metastasis","confidence":"Medium","confidence_rationale":"Tier 2–3 — overexpression with defined molecular and in vivo readouts, single lab","pmids":["20623179"],"is_preprint":false},{"year":2012,"finding":"YBX3/CSDA physically interacts with Egr1 mRNA via a CSD element in its 3' UTR, and siRNA-mediated reduction of CSDA attenuates GnRH-regulated LHB reporter activity, establishing a posttranscriptional regulatory role for YBX3 in gonadotroph cells.","method":"RNA immunoprecipitation, siRNA knockdown, reporter gene assays with 3'UTR CSD element, transient expression studies","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2–3 — RNA IP plus reporter assays plus siRNA KD, single lab","pmids":["22053098"],"is_preprint":false},{"year":2020,"finding":"YBX3 interacts with the influenza A virus ribonucleoprotein (vRNP) complex; YBX3 overexpression inhibits vRNA synthesis and viral protein expression, while YBX3 knockdown increases virus growth, augments nuclear NP accumulation and primary transcription.","method":"Strep-tag affinity purification and mass spectrometry, overexpression, RNAi knockdown, vRNA synthesis measurement","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2–3 — affinity purification MS plus KD/OE with functional viral readouts, single lab","pmids":["32553055"],"is_preprint":false},{"year":2023,"finding":"YBX3 directly binds and stabilizes SLC1A5 mRNA via its 3' UTR in mouse skeletal muscle cells; YBX3 depletion specifically reduces SLC1A5 amino acid transporter substrates, reduces proliferation, and impairs differentiation of skeletal muscle cells.","method":"RIP (RNA immunoprecipitation), 3' UTR reporter assays, YBX3 depletion, amino acid measurement, proliferation and differentiation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — RIP plus 3'UTR reporter plus KD with defined metabolic and cellular phenotype, multiple orthogonal methods","pmids":["38159852"],"is_preprint":false},{"year":2024,"finding":"YBX3 stabilizes Slc3a2 and Pparg mRNAs in brown adipocytes, facilitating branched-chain amino acid (BCAA) influx and catabolism; BAT-specific Ybx3 loss dampens thermogenesis and worsens diet-induced obesity in mice, while overexpression is protective.","method":"AAV-mediated BAT-specific KD/OE, transcriptome analysis, mitochondrial stress test, in vitro KD/OE, mRNA stability analysis","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 — in vivo tissue-specific KO/OE plus transcriptomics plus functional metabolic readouts, multiple orthogonal methods","pmids":["39481849"],"is_preprint":false},{"year":2023,"finding":"YBX3 (DbpA) expression is induced in activated renal fibroblasts during obstructive nephropathy; Ybx3-deficient mice have reduced immune cell infiltration and extracellular matrix deposition in obstructed kidneys, establishing a role for YBX3 in renal fibrosis.","method":"UUO mouse model, Ybx3 KO mice, RNAseq, histological analysis of fibrosis and immune infiltration","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse model with defined tissue phenotype and transcriptomic characterization, single lab","pmids":["37408260"],"is_preprint":false},{"year":2025,"finding":"CHK2 (CHEK2), YBX1, and YBX3 form a regulatory hub in glioma cells; these proteins reciprocally regulate each other's expression and collectively repress pro-inflammatory gene transcription; ChIP-seq confirmed common inflammatory gene targets; targeting this hub with YBX1 inhibitor SU056 degrades the complex and enhances antigen presentation.","method":"Immunoprecipitation/mass spectrometry, phosphoproteomics, single-gene KO/OE, RNA-seq, ChIP-seq, pharmacological inhibition","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — IP-MS plus ChIP-seq plus genetic KO/OE, preprint not yet peer-reviewed","pmids":["40161682"],"is_preprint":true}],"current_model":"YBX3 (ZONAB/DbpA) is a cold shock domain-containing DNA/RNA-binding protein that shuttles between tight junctions (where it is sequestered by ZO proteins and regulated by CDK4, RalA, GEF-H1, Apg-2, and symplekin interactions) and the nucleus, where it functions as a transcription factor activating proliferative genes (cyclin D1, PCNA, CDK5/CDK4 targets) and repressing differentiation genes (claudin-5, occludin, megalin, cubilin, AML1), and also acts as an RNA-binding protein that stabilizes specific mRNAs (SLC7A5, SLC3A2, SLC1A5, Slc3a2, Pparg) to control amino acid transporter expression and cellular metabolism."},"narrative":{"teleology":[{"year":1991,"claim":"Establishing the fundamental DNA-binding specificity of YBX3 resolved whether this cold shock domain protein preferentially recognized damaged versus intact DNA, revealing broad nucleic acid binding capacity with enhanced affinity for depurinated substrates.","evidence":"EMSA and competition assays with double-stranded, single-stranded, and abasic DNA substrates","pmids":["1923758"],"confidence":"Medium","gaps":["No in vivo relevance to DNA repair demonstrated","Structural basis for depurinated DNA preference unknown"]},{"year":1997,"claim":"Discovery that YBX3 represses stress-induced grp78 transcription and activates the thymidine kinase promoter established its dual role as a context-dependent transcriptional activator and repressor.","evidence":"Reporter assays, EMSA, and Southwestern blots on grp78 and htk promoters; functional antagonism with YY1","pmids":["8972186","9419421"],"confidence":"Medium","gaps":["No ChIP confirmation of endogenous promoter occupancy","Mechanisms determining activator versus repressor function unresolved"]},{"year":2003,"claim":"The finding that ZO-1 sequesters YBX3/ZONAB at tight junctions and that nuclear YBX3 controls CDK4 levels and cell proliferation established the paradigm of junctional retention as a mechanism coupling cell density to proliferative signaling.","evidence":"Co-immunoprecipitation, antisense/RNAi knockdown, ZO-1 overexpression with proliferation and cell density readouts in MDCK cells","pmids":["12566432"],"confidence":"High","gaps":["Direct structural basis of ZO-1–ZONAB interaction debated; later work showed full-length ZO-1 does not directly bind ZONAB in vitro","Contribution of ZO-2/ZO-3 redundancy not yet appreciated"]},{"year":2006,"claim":"Identification of cyclin D1 and PCNA as direct transcriptional targets via ChIP, and discovery of symplekin as a nuclear co-factor and Apg-2 as a ZO-1 competitor, built a multi-component regulatory circuit explaining how YBX3 integrates junctional signals into G1/S progression.","evidence":"ChIP, reporter assays, RNAi, recombinant protein reconstitution in MCF-10A, MDCK, and Eph4 cells","pmids":["16508013","17158914","16407410"],"confidence":"High","gaps":["No genome-wide target map at this stage","How symplekin modulates YBX3 DNA-binding specificity unknown"]},{"year":2009,"claim":"Demonstration that GEF-H1/RhoA signaling drives ZONAB nuclear translocation and that the symplekin/ZONAB complex represses AML1 and KLF4 to inhibit goblet cell differentiation extended the model from proliferation control to lineage decisions in intestinal epithelium.","evidence":"Co-IP, reporter assays, ChIP, EMSA, RNAi in epithelial and intestinal cell systems","pmids":["19730435","19328795"],"confidence":"High","gaps":["In vivo intestinal phenotype of Ybx3 loss not examined","Whether GEF-H1 and symplekin pathways converge on the same ZONAB pool unclear"]},{"year":2010,"claim":"Extension to kidney proximal tubule cells and retinal pigment epithelium demonstrated that YBX3 represses differentiation markers (megalin, cubilin) and promotes EMT-like changes in vivo, generalizing its role beyond simple cell lines.","evidence":"ChIP, reporter assays, overexpression/knockdown in OK cells, lentiviral manipulation in mouse RPE","pmids":["20133480","21209887"],"confidence":"High","gaps":["Genetic loss-of-function in kidney epithelium not performed at this stage","Downstream effectors of EMT phenotype not fully mapped"]},{"year":2014,"claim":"Findings that ZO-1, ZO-2, and ZO-3 redundantly stabilize ZONAB at junctions (with proteasomal degradation upon combined depletion) and that CFTR signals through ZO-1 to regulate ZONAB localization refined the junctional retention model and linked it to cystic fibrosis pathophysiology.","evidence":"Combined ZO-protein depletion, MG132 rescue, in vitro binding, CFTR KO mice and 3D culture","pmids":["24986862","25107366"],"confidence":"High","gaps":["Identity of E3 ligase targeting ZONAB for proteasomal degradation unknown","Whether CFTR–ZO-1–ZONAB axis operates in human CF lung tissue not tested"]},{"year":2019,"claim":"iCLIP mapping and multi-omics integration revealed that YBX3 functions as an mRNA stability factor for amino acid transporter mRNAs (SLC7A5, SLC3A2), fundamentally expanding its role from transcription factor to post-transcriptional regulator of cellular metabolism.","evidence":"iCLIP, integrated proteomics and transcriptomics, mRNA stability assays upon YBX3 depletion","pmids":["31189097"],"confidence":"High","gaps":["Structural basis for mRNA target selectivity unresolved","Relative contribution of transcriptional versus post-transcriptional roles in the same cell type not quantified"]},{"year":2023,"claim":"Multiple studies established that non-coding RNAs (circSERPINE2, lncRNA BLACAT3) regulate YBX3 localization and activity, that YBX3 stabilizes SLC1A5 mRNA in muscle, and that Ybx3-deficient mice are protected from renal fibrosis — collectively demonstrating tissue-specific in vivo functions and RNA-mediated regulation.","evidence":"RNA pulldown/MS, RIP, 3ʹ UTR reporters, ChIP, Ybx3 KO mice with UUO model, skeletal muscle differentiation assays","pmids":["37831180","37612524","38159852","37408260"],"confidence":"High","gaps":["Global landscape of regulatory RNAs controlling YBX3 unknown","Whether fibrosis role is transcriptional or post-transcriptional not distinguished"]},{"year":2024,"claim":"BAT-specific Ybx3 manipulation demonstrated that YBX3-mediated stabilization of Slc3a2 and Pparg mRNAs drives BCAA catabolism and thermogenesis, directly linking YBX3 mRNA stabilization to systemic metabolic control.","evidence":"AAV-mediated BAT-specific KD/OE in mice, transcriptomics, mRNA stability assays, metabolic phenotyping","pmids":["39481849"],"confidence":"High","gaps":["Whether YBX3 also controls thermogenesis through transcriptional targets not excluded","Mechanism by which YBX3 is regulated in response to cold or dietary cues unknown"]},{"year":null,"claim":"Key open questions include: the structural basis for YBX3's dual DNA/RNA-binding target selectivity; the identity of the E3 ligase mediating its proteasomal turnover upon loss of junctional anchoring; how its transcriptional and mRNA-stabilizing functions are coordinated in the same cell; and the full scope of its in vivo metabolic roles across tissues.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of YBX3 bound to mRNA or DNA target","E3 ligase for ZONAB degradation unidentified","No systematic in vivo comparison of transcriptional versus post-transcriptional contributions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,3,5,12,13,18,20]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[21,25,27,28]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,9,12,13,15,18,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,4,9,11,14,15,18,22,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,16,23]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,10,11,16]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,6,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,9,12,13,18,24]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[21,25,27,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,11,15]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,10,16]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[21,27,28]}],"complexes":["symplekin/ZONAB complex","CHK2/YBX1/YBX3 hub"],"partners":["TJP1","SYMPK","CDK4","RALA","ARHGEF2","HSPA4","TJP2","YBX1"],"other_free_text":[]},"mechanistic_narrative":"YBX3 (also known as ZONAB/DbpA/CSDA) is a cold shock domain-containing protein that functions as both a transcription factor and an mRNA stability factor, coupling cell density sensing at tight junctions to the control of proliferation, differentiation, and amino acid metabolism. At tight junctions, YBX3 is sequestered by ZO-1/ZO-2 and regulated by competing interactions with CDK4, RalA, GEF-H1/RhoA, Apg-2, and symplekin; release from this junctional pool permits nuclear translocation, where YBX3 activates proliferative gene promoters (cyclin D1, PCNA) and represses differentiation-associated targets (megalin, cubilin, AML1, claudin-5, occludin) [PMID:12566432, PMID:16508013, PMID:19328795, PMID:20133480, PMID:26106824]. As an RNA-binding protein, YBX3 directly binds and stabilizes mRNAs encoding amino acid transporters (SLC7A5, SLC3A2, SLC1A5) and metabolic regulators (Pparg), thereby maintaining intracellular amino acid pools and supporting processes including brown adipose thermogenesis and skeletal muscle differentiation [PMID:31189097, PMID:38159852, PMID:39481849]. In vivo, tissue-specific loss of Ybx3 impairs brown fat thermogenesis and exacerbates diet-induced obesity, while in kidney it reduces fibrotic remodeling, underscoring context-dependent roles in metabolic homeostasis and tissue injury [PMID:39481849, PMID:37408260]."},"prefetch_data":{"uniprot":{"accession":"P16989","full_name":"Y-box-binding protein 3","aliases":["Cold shock domain-containing protein A","DNA-binding protein A","Single-strand DNA-binding protein NF-GMB"],"length_aa":372,"mass_kda":40.1,"function":"Binds to the GM-CSF promoter. Seems to act as a repressor. Also binds to full-length mRNA and to short RNA sequences containing the consensus site 5'-UCCAUCA-3'. May have a role in translation repression (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P16989/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/YBX3","classification":"Not Classified","n_dependent_lines":23,"n_total_lines":1208,"dependency_fraction":0.01903973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX21","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YBX3","total_profiled":1310},"omim":[{"mim_id":"616207","title":"NEGATIVE REGULATOR OF ANTIVIRAL RESPONSE, NONCODING; NRAV","url":"https://www.omim.org/entry/616207"},{"mim_id":"603437","title":"Y-BOX BINDING PROTEIN 3; YBX3","url":"https://www.omim.org/entry/603437"},{"mim_id":"602101","title":"CLAUDIN 5; CLDN5","url":"https://www.omim.org/entry/602101"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":4495.4},{"tissue":"tongue","ntpm":1528.5}],"url":"https://www.proteinatlas.org/search/YBX3"},"hgnc":{"alias_symbol":["dbpA","ZONAB","CSDA1"],"prev_symbol":["CSDA"]},"alphafold":{"accession":"P16989","domains":[{"cath_id":"2.40.50.140","chopping":"85-172","consensus_level":"high","plddt":93.4918,"start":85,"end":172}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P16989","model_url":"https://alphafold.ebi.ac.uk/files/AF-P16989-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P16989-F1-predicted_aligned_error_v6.png","plddt_mean":59.28},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YBX3","jax_strain_url":"https://www.jax.org/strain/search?query=YBX3"},"sequence":{"accession":"P16989","fasta_url":"https://rest.uniprot.org/uniprotkb/P16989.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P16989/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P16989"}},"corpus_meta":[{"pmid":"12566432","id":"PMC_12566432","title":"The ZO-1-associated Y-box factor ZONAB regulates epithelial cell proliferation and cell density.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12566432","citation_count":311,"is_preprint":false},{"pmid":"11675503","id":"PMC_11675503","title":"Expression of Borrelia burgdorferi OspC and DbpA is controlled by a RpoN-RpoS regulatory pathway.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11675503","citation_count":293,"is_preprint":false},{"pmid":"15148362","id":"PMC_15148362","title":"CsdA, a cold-shock RNA helicase from Escherichia coli, is involved in the biogenesis of 50S ribosomal subunit.","date":"2004","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/15148362","citation_count":202,"is_preprint":false},{"pmid":"16508013","id":"PMC_16508013","title":"Regulation of PCNA and cyclin D1 expression and epithelial morphogenesis by the ZO-1-regulated transcription factor ZONAB/DbpA.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16508013","citation_count":181,"is_preprint":false},{"pmid":"15554978","id":"PMC_15554978","title":"Physical and functional interactions among RNase E, polynucleotide phosphorylase and the cold-shock protein, CsdA: evidence for a 'cold shock degradosome'.","date":"2004","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15554978","citation_count":156,"is_preprint":false},{"pmid":"8253085","id":"PMC_8253085","title":"DbpA: a DEAD box protein specifically activated by 23s rRNA.","date":"1993","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8253085","citation_count":139,"is_preprint":false},{"pmid":"11574482","id":"PMC_11574482","title":"Escherichia coli DbpA is an RNA helicase that requires hairpin 92 of 23S rRNA.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11574482","citation_count":125,"is_preprint":false},{"pmid":"9573101","id":"PMC_9573101","title":"Active and passive immunity against Borrelia burgdorferi decorin binding protein A (DbpA) protects against infection.","date":"1998","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/9573101","citation_count":116,"is_preprint":false},{"pmid":"1923758","id":"PMC_1923758","title":"DNA binding properties of YB-1 and dbpA: binding to double-stranded, single-stranded, and abasic site containing DNAs.","date":"1991","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1923758","citation_count":113,"is_preprint":false},{"pmid":"25107366","id":"PMC_25107366","title":"CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation through the ZONAB pathway.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25107366","citation_count":106,"is_preprint":false},{"pmid":"18237742","id":"PMC_18237742","title":"The ATPase cycle mechanism of the DEAD-box rRNA helicase, DbpA.","date":"2007","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18237742","citation_count":102,"is_preprint":false},{"pmid":"21209887","id":"PMC_21209887","title":"The tight junction associated signalling proteins ZO-1 and ZONAB regulate retinal pigment epithelium homeostasis in mice.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21209887","citation_count":98,"is_preprint":false},{"pmid":"15901727","id":"PMC_15901727","title":"Analysis of the heteromeric CsdA-CsdE cysteine desulfurase, assisting Fe-S cluster biogenesis in Escherichia coli.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15901727","citation_count":95,"is_preprint":false},{"pmid":"20133480","id":"PMC_20133480","title":"ZONAB promotes proliferation and represses differentiation of proximal tubule epithelial cells.","date":"2010","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/20133480","citation_count":94,"is_preprint":false},{"pmid":"16045494","id":"PMC_16045494","title":"Expression of zonula occludens-1 (ZO-1) and the transcription factor ZO-1-associated nucleic acid-binding protein (ZONAB)-MsY3 in glial cells and colocalization at oligodendrocyte and astrocyte gap junctions in mouse brain.","date":"2005","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16045494","citation_count":89,"is_preprint":false},{"pmid":"10899883","id":"PMC_10899883","title":"Decorin-binding protein A (DbpA) of Borrelia burgdorferi is not protective when immunized mice are challenged via tick infestation and correlates with the lack of DbpA expression by B. burgdorferi in ticks.","date":"2000","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10899883","citation_count":87,"is_preprint":false},{"pmid":"11350034","id":"PMC_11350034","title":"The Escherichia coli DEAD protein DbpA recognizes a small RNA hairpin in 23S rRNA.","date":"2001","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11350034","citation_count":86,"is_preprint":false},{"pmid":"12068815","id":"PMC_12068815","title":"Effects of ribosomal proteins S1, S2 and the DeaD/CsdA DEAD-box helicase on translation of leaderless and canonical mRNAs in Escherichia coli.","date":"2002","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12068815","citation_count":86,"is_preprint":false},{"pmid":"15592429","id":"PMC_15592429","title":"RalA interacts with ZONAB in a cell density-dependent manner and regulates its transcriptional activity.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15592429","citation_count":85,"is_preprint":false},{"pmid":"20160110","id":"PMC_20160110","title":"Pathway of ATP utilization and duplex rRNA unwinding by the DEAD-box helicase, DbpA.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20160110","citation_count":77,"is_preprint":false},{"pmid":"8524828","id":"PMC_8524828","title":"The \"DEAD box\" protein DbpA interacts specifically with the peptidyltransferase center in 23S rRNA.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8524828","citation_count":72,"is_preprint":false},{"pmid":"9836593","id":"PMC_9836593","title":"Kinetic analysis of the RNA-dependent adenosinetriphosphatase activity of DbpA, an Escherichia coli DEAD protein specific for 23S ribosomal RNA.","date":"1998","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9836593","citation_count":71,"is_preprint":false},{"pmid":"8972186","id":"PMC_8972186","title":"Suppression of grp78 core promoter element-mediated stress induction by the dbpA and dbpB (YB-1) cold shock domain proteins.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8972186","citation_count":63,"is_preprint":false},{"pmid":"11888286","id":"PMC_11888286","title":"Cooperative binding of ATP and RNA substrates to the DEAD/H protein DbpA.","date":"2002","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11888286","citation_count":62,"is_preprint":false},{"pmid":"31189097","id":"PMC_31189097","title":"The RNA-Binding Protein YBX3 Controls Amino Acid Levels by Regulating SLC mRNA Abundance.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31189097","citation_count":60,"is_preprint":false},{"pmid":"17557820","id":"PMC_17557820","title":"Complementation analysis of the cold-sensitive phenotype of the Escherichia coli csdA deletion strain.","date":"2007","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/17557820","citation_count":60,"is_preprint":false},{"pmid":"19734347","id":"PMC_19734347","title":"A dominant negative mutant of the E. coli RNA helicase DbpA blocks assembly of the 50S ribosomal subunit.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19734347","citation_count":60,"is_preprint":false},{"pmid":"17158914","id":"PMC_17158914","title":"Functional interaction between the ZO-1-interacting transcription factor ZONAB/DbpA and the RNA processing factor symplekin.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17158914","citation_count":57,"is_preprint":false},{"pmid":"12624072","id":"PMC_12624072","title":"Significant improvement of the recombinant Borrelia-specific immunoglobulin G immunoblot test by addition of VlsE and a DbpA homologue derived from Borrelia garinii for diagnosis of early neuroborreliosis.","date":"2003","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12624072","citation_count":54,"is_preprint":false},{"pmid":"21708995","id":"PMC_21708995","title":"Allelic variation of the Lyme disease spirochete adhesin DbpA influences spirochetal binding to decorin, dermatan sulfate, and mammalian cells.","date":"2011","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21708995","citation_count":54,"is_preprint":false},{"pmid":"18565105","id":"PMC_18565105","title":"Ribosome assembly in Escherichia coli strains lacking the RNA helicase DeaD/CsdA or DbpA.","date":"2008","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/18565105","citation_count":54,"is_preprint":false},{"pmid":"20054882","id":"PMC_20054882","title":"The CsdA cysteine desulphurase promotes Fe/S biogenesis by recruiting Suf components and participates to a new sulphur transfer pathway by recruiting CsdL (ex-YgdL), a ubiquitin-modifying-like protein.","date":"2009","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20054882","citation_count":52,"is_preprint":false},{"pmid":"7628487","id":"PMC_7628487","title":"Characterization of the gene for dbpA, a family member of the nucleic-acid-binding proteins containing a cold-shock domain.","date":"1995","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7628487","citation_count":51,"is_preprint":false},{"pmid":"16407410","id":"PMC_16407410","title":"The heat-shock protein Apg-2 binds to the tight junction protein ZO-1 and regulates transcriptional activity of ZONAB.","date":"2006","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16407410","citation_count":51,"is_preprint":false},{"pmid":"29769640","id":"PMC_29769640","title":"Hypoxia-induced microRNA-191 contributes to hepatic ischemia/reperfusion injury through the ZONAB/Cyclin D1 axis.","date":"2018","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/29769640","citation_count":47,"is_preprint":false},{"pmid":"11296244","id":"PMC_11296244","title":"Visualization of unwinding activity of duplex RNA by DbpA, a DEAD box helicase, at single-molecule resolution by atomic force microscopy.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11296244","citation_count":47,"is_preprint":false},{"pmid":"19730435","id":"PMC_19730435","title":"The Y-box factor ZONAB/DbpA associates with GEF-H1/Lfc and mediates Rho-stimulated transcription.","date":"2009","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/19730435","citation_count":46,"is_preprint":false},{"pmid":"18973575","id":"PMC_18973575","title":"Ablation of Cx47 in transgenic mice leads to the loss of MUPP1, ZONAB and multiple connexins at oligodendrocyte-astrocyte gap junctions.","date":"2008","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18973575","citation_count":46,"is_preprint":false},{"pmid":"10525403","id":"PMC_10525403","title":"Interaction of the Escherichia coli DEAD box protein DbpA with 23 S ribosomal RNA.","date":"1999","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10525403","citation_count":44,"is_preprint":false},{"pmid":"17986459","id":"PMC_17986459","title":"Mutation of the arginine finger in the active site of Escherichia coli DbpA abolishes ATPase and helicase activity and confers a dominant slow growth phenotype.","date":"2007","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/17986459","citation_count":41,"is_preprint":false},{"pmid":"15654752","id":"PMC_15654752","title":"Equilibrium and kinetic analysis of nucleotide binding to the DEAD-box RNA helicase DbpA.","date":"2005","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15654752","citation_count":40,"is_preprint":false},{"pmid":"9419421","id":"PMC_9419421","title":"Positive and negative regulation of the human thymidine kinase promoter mediated by CCAAT binding transcription factors NF-Y/CBF, dbpA, and CDP/cut.","date":"1997","source":"Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/9419421","citation_count":40,"is_preprint":false},{"pmid":"23913692","id":"PMC_23913692","title":"Structural changes during cysteine desulfurase CsdA and sulfur acceptor CsdE interactions provide insight into the trans-persulfuration.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23913692","citation_count":38,"is_preprint":false},{"pmid":"37612524","id":"PMC_37612524","title":"M6A-mediated-upregulation of lncRNA BLACAT3 promotes bladder cancer angiogenesis and hematogenous metastasis through YBX3 nuclear shuttling and enhancing NCF2 transcription.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/37612524","citation_count":37,"is_preprint":false},{"pmid":"15313206","id":"PMC_15313206","title":"Transcription of dbpA, a Y box binding protein, is positively regulated by E2F1: implications in hepatocarcinogenesis.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15313206","citation_count":37,"is_preprint":false},{"pmid":"14648148","id":"PMC_14648148","title":"Diagnosis of Lyme neuroborreliosis with antibodies to recombinant proteins DbpA, BBK32, and OspC, and VlsE IR6 peptide.","date":"2003","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/14648148","citation_count":37,"is_preprint":false},{"pmid":"17259309","id":"PMC_17259309","title":"Mutational analysis of the Escherichia coli DEAD box protein CsdA.","date":"2007","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/17259309","citation_count":36,"is_preprint":false},{"pmid":"16530482","id":"PMC_16530482","title":"Molecular analysis of decorin-binding protein A (DbpA) reveals five major groups among European Borrelia burgdorferi sensu lato strains with impact for the development of serological assays and indicates lateral gene transfer of the dbpA gene.","date":"2006","source":"International journal of medical microbiology : IJMM","url":"https://pubmed.ncbi.nlm.nih.gov/16530482","citation_count":36,"is_preprint":false},{"pmid":"19328795","id":"PMC_19328795","title":"The symplekin/ZONAB complex inhibits intestinal cell differentiation by the repression of AML1/Runx1.","date":"2009","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/19328795","citation_count":34,"is_preprint":false},{"pmid":"24986862","id":"PMC_24986862","title":"ZO proteins redundantly regulate the transcription factor DbpA/ZONAB.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24986862","citation_count":33,"is_preprint":false},{"pmid":"21045550","id":"PMC_21045550","title":"Requirement of the CsdA DEAD-box helicase for low temperature riboregulation of rpoS mRNA.","date":"2010","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/21045550","citation_count":32,"is_preprint":false},{"pmid":"18025260","id":"PMC_18025260","title":"Phosphatidylethanol accumulation promotes intestinal hyperplasia by inducing ZONAB-mediated cell density increase in response to chronic ethanol exposure.","date":"2007","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/18025260","citation_count":31,"is_preprint":false},{"pmid":"15173385","id":"PMC_15173385","title":"Interaction of Escherichia coli DbpA with 23S rRNA in different functional states of the enzyme.","date":"2004","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/15173385","citation_count":30,"is_preprint":false},{"pmid":"15910005","id":"PMC_15910005","title":"Escherichia coli DbpA is a 3' --> 5' RNA helicase.","date":"2005","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15910005","citation_count":28,"is_preprint":false},{"pmid":"9016593","id":"PMC_9016593","title":"Characterization of DbpA, an Escherichia coli DEAD box protein with ATP independent RNA unwinding activity.","date":"1997","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9016593","citation_count":27,"is_preprint":false},{"pmid":"24842928","id":"PMC_24842928","title":"Identification of lysine residues in the Borrelia burgdorferi DbpA adhesin required for murine infection.","date":"2014","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/24842928","citation_count":26,"is_preprint":false},{"pmid":"26106824","id":"PMC_26106824","title":"Bradykinin increased the permeability of BTB via NOS/NO/ZONAB-mediating down-regulation of claudin-5 and occludin.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26106824","citation_count":24,"is_preprint":false},{"pmid":"33480613","id":"PMC_33480613","title":"Notoginsenoside R1 attenuates breast cancer progression by targeting CCND2 and YBX3.","date":"2021","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/33480613","citation_count":23,"is_preprint":false},{"pmid":"33816248","id":"PMC_33816248","title":"YBX3 Mediates the Metastasis of Nasopharyngeal Carcinoma via PI3K/AKT Signaling.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33816248","citation_count":23,"is_preprint":false},{"pmid":"22957931","id":"PMC_22957931","title":"Escherichia coli cold-shock gene profiles in response to over-expression/deletion of CsdA, RNase R and PNPase and relevance to low-temperature RNA metabolism.","date":"2012","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/22957931","citation_count":23,"is_preprint":false},{"pmid":"12239625","id":"PMC_12239625","title":"Somatic mutation and SNP in the promoter of dbpA and human hepatocarcinogenesis.","date":"2002","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12239625","citation_count":22,"is_preprint":false},{"pmid":"29107486","id":"PMC_29107486","title":"Insights into the Structure of Dimeric RNA Helicase CsdA and Indispensable Role of Its C-Terminal Regions.","date":"2017","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/29107486","citation_count":21,"is_preprint":false},{"pmid":"12324462","id":"PMC_12324462","title":"The RNA helicase DbpA exhibits a markedly different conformation in the ADP-bound state when compared with the ATP- or RNA-bound states.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12324462","citation_count":21,"is_preprint":false},{"pmid":"19749785","id":"PMC_19749785","title":"Upregulation of human DNA binding protein A (dbpA) in gastric cancer cells.","date":"2009","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/19749785","citation_count":20,"is_preprint":false},{"pmid":"34453003","id":"PMC_34453003","title":"Structural basis for the activation of the DEAD-box RNA helicase DbpA by the nascent ribosome.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34453003","citation_count":19,"is_preprint":false},{"pmid":"10100871","id":"PMC_10100871","title":"DNA binding protein dbpA binds Cdk5 and inhibits its activity.","date":"1999","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10100871","citation_count":19,"is_preprint":false},{"pmid":"16325852","id":"PMC_16325852","title":"Hydrodynamic characterization of the DEAD-box RNA helicase DbpA.","date":"2005","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16325852","citation_count":18,"is_preprint":false},{"pmid":"36059530","id":"PMC_36059530","title":"Identification and verification of YBX3 and its regulatory gene HEIH as an oncogenic system: A multidimensional analysis in colon cancer.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36059530","citation_count":17,"is_preprint":false},{"pmid":"22156424","id":"PMC_22156424","title":"Requirement for RNA helicase CsdA for growth of Yersinia pseudotuberculosis IP32953 at low temperatures.","date":"2011","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22156424","citation_count":17,"is_preprint":false},{"pmid":"27194011","id":"PMC_27194011","title":"Time course of large ribosomal subunit assembly in E. coli cells overexpressing a helicase inactive DbpA protein.","date":"2016","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27194011","citation_count":16,"is_preprint":false},{"pmid":"37831180","id":"PMC_37831180","title":"Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/37831180","citation_count":15,"is_preprint":false},{"pmid":"21819147","id":"PMC_21819147","title":"Probing conformational variations at the ATPase site of the RNA helicase DbpA by high-field electron-nuclear double resonance spectroscopy.","date":"2011","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/21819147","citation_count":15,"is_preprint":false},{"pmid":"20623179","id":"PMC_20623179","title":"Cold shock domain protein A (CSDA) overexpression inhibits tumor growth and lymph node metastasis in a mouse model of squamous cell carcinoma.","date":"2010","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/20623179","citation_count":15,"is_preprint":false},{"pmid":"27813083","id":"PMC_27813083","title":"DbpA is a region-specific RNA helicase.","date":"2017","source":"Biopolymers","url":"https://pubmed.ncbi.nlm.nih.gov/27813083","citation_count":13,"is_preprint":false},{"pmid":"23291905","id":"PMC_23291905","title":"Characterization of the kinetics of RNA annealing and strand displacement activities of the E. coli DEAD-box helicase CsdA.","date":"2013","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/23291905","citation_count":12,"is_preprint":false},{"pmid":"37963872","id":"PMC_37963872","title":"Fungal secondary metabolism is governed by an RNA-binding protein CsdA/RsdA complex.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37963872","citation_count":9,"is_preprint":false},{"pmid":"31335954","id":"PMC_31335954","title":"Modulation of Contact Inhibition by ZO-1/ZONAB Gene Transfer-A New Strategy to Increase the Endothelial Cell Density of Corneal Grafts.","date":"2019","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/31335954","citation_count":9,"is_preprint":false},{"pmid":"37221012","id":"PMC_37221012","title":"Structural basis for RNA-duplex unwinding by the DEAD-box helicase DbpA.","date":"2023","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/37221012","citation_count":9,"is_preprint":false},{"pmid":"21359956","id":"PMC_21359956","title":"Escherichia coli cold shock protein CsdA effects an increase in septation and the resultant formation of coccobacilli at low temperature.","date":"2011","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/21359956","citation_count":9,"is_preprint":false},{"pmid":"26755693","id":"PMC_26755693","title":"The DbpA catalytic core unwinds double-helix substrates by directly loading on them.","date":"2016","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26755693","citation_count":9,"is_preprint":false},{"pmid":"15893750","id":"PMC_15893750","title":"MZF-1 and DbpA interact with DNase I hypersensitive sites that correlate with expression of the human MUC1 mucin gene.","date":"2005","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/15893750","citation_count":9,"is_preprint":false},{"pmid":"32553055","id":"PMC_32553055","title":"Y-Box-Binding Protein 3 (YBX3) Restricts Influenza A Virus by Interacting with Viral Ribonucleoprotein Complex and Imparing its Function.","date":"2020","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/32553055","citation_count":8,"is_preprint":false},{"pmid":"38159852","id":"PMC_38159852","title":"The YBX3 RNA-binding protein posttranscriptionally controls SLC1A5 mRNA in proliferating and differentiating skeletal muscle cells.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38159852","citation_count":8,"is_preprint":false},{"pmid":"29214235","id":"PMC_29214235","title":"Kinetics and Thermodynamics of DbpA Protein's C-Terminal Domain Interaction with RNA.","date":"2017","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/29214235","citation_count":8,"is_preprint":false},{"pmid":"29393348","id":"PMC_29393348","title":"Decreased ZONAB expression promotes excessive transdifferentiation of alveolar epithelial cells in hyperoxia-induced bronchopulmonary dysplasia.","date":"2018","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29393348","citation_count":7,"is_preprint":false},{"pmid":"35481783","id":"PMC_35481783","title":"RNA Post-Transcriptional Modifications in Two Large Subunit Intermediates Populated in E. coli Cells Expressing Helicase Inactive R331A DbpA.","date":"2022","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35481783","citation_count":7,"is_preprint":false},{"pmid":"39481849","id":"PMC_39481849","title":"RNA-binding protein YBX3 promotes PPARγ-SLC3A2 mediated BCAA metabolism fueling brown adipogenesis and thermogenesis.","date":"2024","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39481849","citation_count":5,"is_preprint":false},{"pmid":"26057109","id":"PMC_26057109","title":"Functional csdA is needed for effective adaptation and initiation of growth of Clostridium botulinum ATCC 3502 at suboptimal temperature.","date":"2015","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26057109","citation_count":5,"is_preprint":false},{"pmid":"32089391","id":"PMC_32089391","title":"DNA sequence-specific ligands. XVIII. Synthesis, physico-chemical properties; genetic, virological, and biochemical studies of fluorescent dimeric bisbenzimidazoles DBPA(n).","date":"2020","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32089391","citation_count":5,"is_preprint":false},{"pmid":"22053098","id":"PMC_22053098","title":"Cold-shock-domain protein A (CSDA) contributes posttranscriptionally to gonadotropin-releasing hormone-regulated expression of Egr1 and indirectly to Lhb.","date":"2012","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/22053098","citation_count":5,"is_preprint":false},{"pmid":"29568941","id":"PMC_29568941","title":"Bradykinin potentially stimulates cell proliferation in rabbit corneal endothelial cells through the ZO‑1/ZONAB pathway.","date":"2018","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29568941","citation_count":4,"is_preprint":false},{"pmid":"23334249","id":"PMC_23334249","title":"Stopping power and CSDA range calculations for incident electrons and positrons in breast and brain tissues.","date":"2013","source":"Radiation and environmental biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/23334249","citation_count":4,"is_preprint":false},{"pmid":"41025501","id":"PMC_41025501","title":"YBX1&YBX3 as novel targets to potentiate immune checkpoint blockade response in gliomas.","date":"2026","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41025501","citation_count":3,"is_preprint":false},{"pmid":"35382648","id":"PMC_35382648","title":"A novel 27-bp indel in the intron region of the YBX3 gene is associated with growth traits in chickens.","date":"2022","source":"British poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/35382648","citation_count":3,"is_preprint":false},{"pmid":"26201636","id":"PMC_26201636","title":"Up-regulation of dbpA mRNA in hepatocellular carcinoma associated with metabolic syndrome.","date":"2012","source":"Hepatology international","url":"https://pubmed.ncbi.nlm.nih.gov/26201636","citation_count":3,"is_preprint":false},{"pmid":"37408260","id":"PMC_37408260","title":"Cold Shock Domain Protein DbpA Orchestrates Tubular Cell Damage and Interstitial Fibrosis in Inflammatory Kidney Disease.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/37408260","citation_count":3,"is_preprint":false},{"pmid":"37418046","id":"PMC_37418046","title":"Identification of RNA-binding protein YBX3 as an oncogene in clear cell renal cell carcinoma.","date":"2023","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37418046","citation_count":3,"is_preprint":false},{"pmid":"40161682","id":"PMC_40161682","title":"Targeting CHEK2-YBX1&YBX3 regulatory hub to potentiate immune checkpoint blockade response in gliomas.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40161682","citation_count":2,"is_preprint":false},{"pmid":"33277687","id":"PMC_33277687","title":"Assignment of the Ile, Leu, Val, Met and Ala methyl group resonances of the DEAD-box RNA helicase DbpA from E. coli.","date":"2020","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/33277687","citation_count":2,"is_preprint":false},{"pmid":"35876530","id":"PMC_35876530","title":"Serological Analysis Identifies Consequential B Cell Epitopes on the Flexible Linker and C-Terminus of Decorin Binding Protein A (DbpA) from Borrelia burgdorferi.","date":"2022","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/35876530","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46196,"output_tokens":6644,"usd":0.119124},"stage2":{"model":"claude-opus-4-6","input_tokens":10376,"output_tokens":3225,"usd":0.198758},"total_usd":0.317882,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"ZONAB (YBX3) associates with CDK4, and its nuclear localization (regulated by the tight junction protein ZO-1) controls nuclear CDK4 levels and epithelial cell proliferation and cell density.\",\n      \"method\": \"Co-immunoprecipitation, antisense/RNAi knockdown, ZO-1 overexpression with proliferation and cell density readouts in MDCK cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus KD/KO with defined cellular phenotype, replicated by multiple approaches in same study\",\n      \"pmids\": [\"12566432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ZONAB (YBX3) directly regulates transcription of PCNA and cyclin D1 by binding to responsive elements in their promoters, thereby promoting G1/S-phase progression and epithelial cell differentiation.\",\n      \"method\": \"cDNA microarray screening, chromatin immunoprecipitation (ChIP), reporter gene assays, RNAi knockdown and overexpression in MCF-10A and MDCK cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP plus reporter assays plus KD/OE with defined molecular and cellular phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"16508013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human YBX3 (dbpA) binds to the lower strand of the grp78 core promoter stress-inducible change region (SICR) and represses stress-induced grp78 promoter activity; dbpA interacts with YY1 and antagonizes YY1-mediated transcriptional activation.\",\n      \"method\": \"Expression library screening, gel shift assays, cotransfection reporter assays, Southwestern blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple in vitro binding assays plus reporter assays, single lab\",\n      \"pmids\": [\"8972186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"YBX3/dbpA binds to double-stranded, single-stranded, and abasic (depurinated) DNA, with preferential binding to depurinated DNA, and the extent of specificity is influenced by Mg2+.\",\n      \"method\": \"Phage expression library screening, electrophoretic mobility shift assays (EMSA), DNA binding competition assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct in vitro binding characterization with multiple substrates, single lab\",\n      \"pmids\": [\"1923758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human YBX3/dbpA gene encodes a protein localized both in the cytoplasm and nucleus (particularly at the perinuclear region), contains a cold shock domain encoded by exons 2–5, and has an alternative exon 6; the gene is located on chromosome 12p13.1.\",\n      \"method\": \"Immunofluorescence, Northern blot, in situ hybridization, genomic cloning and sequencing\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct localization by immunofluorescence, genomic characterization\",\n      \"pmids\": [\"7628487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"YBX3/dbpA overexpression stimulates human thymidine kinase (htk) promoter activity through the proximal CCAAT element (TKC1) in a serum-inducible manner.\",\n      \"method\": \"Recombinant protein binding assays, cell transfection reporter assays\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reporter assay plus recombinant protein binding, single lab\",\n      \"pmids\": [\"9419421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A C-terminal 172 amino acid domain of YBX3/dbpA binds to CDK5 and strongly inhibits p35-activated CDK5 kinase activity, as well as CDK4/cyclin D1 activity; it does not interact with CDK2.\",\n      \"method\": \"Yeast two-hybrid screening of HeLa cDNA library, in vitro kinase inhibition assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid plus in vitro biochemical kinase assay, single lab\",\n      \"pmids\": [\"10100871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RalA (a Ras superfamily GTPase) interacts with ZONAB/YBX3 in a GTP-dependent manner; this interaction increases with epithelial cell density and relieves ZONAB-mediated transcriptional repression; oncogenic Ras alleviates ZONAB repression via RalA.\",\n      \"method\": \"Reverse Ras recruitment system (yeast), co-immunoprecipitation, reporter gene assays, cell density experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional reporter assays, multiple orthogonal methods\",\n      \"pmids\": [\"15592429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"YBX3/dbpA transcription is positively regulated by E2F1 through a sequence resembling an E2F binding site (-8 to -1) in the promoter region.\",\n      \"method\": \"E2F1 overexpression, promoter deletion and mutation analysis, luciferase reporter assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — promoter mutagenesis plus reporter assay, single lab\",\n      \"pmids\": [\"15313206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ZONAB/YBX3 forms a complex with the RNA processing factor symplekin in the nucleus of epithelial cells; this complex can be reconstituted with recombinant proteins; symplekin depletion reduces nuclear ZONAB accumulation and transcriptional activity, cyclin D1 expression, and proliferation.\",\n      \"method\": \"Co-immunoprecipitation, recombinant protein reconstitution, RNAi knockdown, reporter gene assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP plus in vitro reconstitution plus functional assays, multiple orthogonal methods\",\n      \"pmids\": [\"17158914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The heat-shock protein Apg-2 binds to the SH3 domain of ZO-1 and competes with ZONAB/YBX3 for ZO-1 binding, thereby modulating ZONAB transcriptional activity and G1/S phase progression in epithelial cells.\",\n      \"method\": \"Expression library screening, co-immunoprecipitation, in vitro competition binding assays, reporter gene assays, regulated knockdown\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vitro competition plus functional reporter assay, multiple orthogonal methods\",\n      \"pmids\": [\"16407410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ZONAB/YBX3 associates with GEF-H1/Lfc at tight junctions; GEF-H1 overexpression drives ZONAB nuclear accumulation and transcriptional activation; RhoA signaling via GEF-H1 is required for ZONAB-dependent cyclin D1 promoter activity and expression.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, reporter gene assays, RNAi knockdown\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus reporter assays plus knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"19730435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The symplekin/ZONAB (YBX3) complex represses AML1/Runx1 transcription; ZONAB binds to the AML1 gene promoter and represses KLF4 expression, thereby inhibiting intestinal goblet cell differentiation.\",\n      \"method\": \"RNAi knockdown, reporter gene assays, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus EMSA plus RNAi KD with defined cellular phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"19328795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ZONAB/YBX3 overexpression promotes proliferation and represses differentiation (megalin/cubilin expression, brush border, primary cilium) of proximal tubule cells; ZONAB binds to megalin and cubilin promoters as shown by ChIP and reporter assays.\",\n      \"method\": \"Overexpression, RNAi knockdown, ChIP, reporter gene assays, immunofluorescence in OK cells and mouse kidney\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus reporter assays plus KO/OE with defined cellular phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"20133480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Accumulation of phosphatidylethanol (produced by phospholipase D from ethanol) disrupts claudin-1/ZO-1 association and induces nuclear translocation of ZONAB/YBX3, which mediates increased intestinal cell density.\",\n      \"method\": \"Phosphatidylethanol treatment, claudin-1 endocytosis assays, co-immunoprecipitation, nuclear fractionation, ZONAB knockdown, in vivo mouse colon analysis\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanistic pathway with Co-IP plus KD rescue experiment, single lab\",\n      \"pmids\": [\"18025260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CFTR interacts with ZO-1 via its PDZ-binding domain, and CFTR inhibition/knockdown induces nuclear translocation of ZONAB/YBX3, leading to upregulation of CCND1 and downregulation of ErbB2 transcription and impaired tubulogenesis.\",\n      \"method\": \"Co-immunoprecipitation, knockdown, 3D epithelial culture model, in vivo cftr-/- and cftrΔF508 mouse analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including Co-IP, KD, in vivo mouse model\",\n      \"pmids\": [\"25107366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZO proteins (ZO-1, ZO-2, ZO-3) redundantly control the junctional retention and stability of ZONAB/YBX3; depletion of ZO-1 and ZO-2 together (but not individually) causes ZONAB cytoplasmic mislocalization and reduced expression rescued by proteasome inhibitor MG132; full-length ZO-1 does not directly interact with ZONAB in vitro.\",\n      \"method\": \"Depletion of individual and multiple ZO proteins by RNAi, ZO-1 KO Eph4 cells, in vitro binding assays, MG132 rescue, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple KO/KD conditions plus in vitro binding plus pharmacological rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"24986862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of ZONAB/YBX3 or knockdown of ZO-1 in retinal pigment epithelium (RPE) increases proliferation and induces an EMT-like phenotype in vivo, demonstrating that ZO-1 and ZONAB regulate RPE homeostasis.\",\n      \"method\": \"Lentiviral-mediated overexpression and knockdown in vivo, electron microscopy, fluorescein angiography, EMT marker expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo lentiviral KD/OE with morphological and functional readouts, single study\",\n      \"pmids\": [\"21209887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Bradykinin increases BTB permeability via NOS/NO signaling, which promotes ZONAB/YBX3 nuclear translocation; nuclear ZONAB then directly binds promoters of claudin-5 and occludin (verified by ChIP), downregulating their expression.\",\n      \"method\": \"NOS inhibitor treatment, ZONAB overexpression, ChIP assay, BTB permeability assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP plus pharmacological pathway analysis, single lab\",\n      \"pmids\": [\"26106824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hypoxia-inducible HIF1α induces miR-191, which suppresses ZONAB/YBX3 expression; miR-191 overexpression promotes G0/G1 arrest and apoptosis, effects abrogated by ZONAB overexpression, placing ZONAB downstream of HIF1α/miR-191 in hepatic IRI.\",\n      \"method\": \"miR-191 KO mice (CRISPR/Cas9), miR-191 overexpression/inhibition, ZONAB overexpression rescue, ChIP of HIF1α on miR-191 promoter, hepatic IRI mouse model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO mouse plus rescue experiment plus ChIP, multiple orthogonal methods\",\n      \"pmids\": [\"29769640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"YBX3/dbpA binds to DNase I hypersensitive site sequences at -250 bp in the MUC1 promoter and upregulates MUC1 promoter activity via this element in COS-7 cells.\",\n      \"method\": \"Expression library screening, EMSA, Southwestern blot, UV cross-linking, transient reporter gene assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — library screening plus reporter assay plus EMSA, single lab\",\n      \"pmids\": [\"15893750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"YBX3 directly binds the mRNAs of SLC7A5 and SLC3A2 amino acid transporter genes and stabilizes these mRNAs, maintaining intracellular amino acid levels; YBX3 depletion specifically reduces SLC7A5/SLC3A2 substrates.\",\n      \"method\": \"YBX3 depletion with integrated proteomics and transcriptomics, iCLIP RNA binding site mapping, mRNA stability assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — iCLIP plus multi-omics integration plus functional amino acid depletion assay, multiple orthogonal methods\",\n      \"pmids\": [\"31189097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The lncRNA BLACAT3 recruits YBX3 to shuttle into the nucleus where it synergistically enhances NCF2 transcription, activating downstream NF-κB signaling to promote bladder cancer angiogenesis and hematogenous metastasis.\",\n      \"method\": \"RNA sequencing, mass spectrometry, functional assays, animal models, m6A microarray\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — MS identification plus functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"37612524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CircSERPINE2 interacts with YBX3 via the CCAUC motif, increasing the affinity of YBX3 for ZO-1 and sequestering YBX3 in the cytoplasm; this inhibits YBX3 binding to the PCNA promoter, ultimately affecting p21 ubiquitin-mediated degradation and promoting mesenchymal stem cell senescence.\",\n      \"method\": \"RNA pulldown followed by mass spectrometry, siRNA knockdown, overexpression, ChIP, co-immunoprecipitation, in vivo intra-articular injection\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNA pulldown MS plus ChIP plus Co-IP plus in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"37831180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"YBX3/CSDA overexpression in squamous cell carcinoma cells directly represses production of VEGF-A and VEGF-C by binding to hypoxia response elements (HRE) and serum response elements (SRE) in their promoters, inhibiting tumor angiogenesis and lymph node metastasis.\",\n      \"method\": \"YBX3/CSDA overexpression via plasmid transfection, VEGF-A/C measurement, in vivo tumor and metastasis assays\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — overexpression with defined molecular and in vivo readouts, single lab\",\n      \"pmids\": [\"20623179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"YBX3/CSDA physically interacts with Egr1 mRNA via a CSD element in its 3' UTR, and siRNA-mediated reduction of CSDA attenuates GnRH-regulated LHB reporter activity, establishing a posttranscriptional regulatory role for YBX3 in gonadotroph cells.\",\n      \"method\": \"RNA immunoprecipitation, siRNA knockdown, reporter gene assays with 3'UTR CSD element, transient expression studies\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RNA IP plus reporter assays plus siRNA KD, single lab\",\n      \"pmids\": [\"22053098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YBX3 interacts with the influenza A virus ribonucleoprotein (vRNP) complex; YBX3 overexpression inhibits vRNA synthesis and viral protein expression, while YBX3 knockdown increases virus growth, augments nuclear NP accumulation and primary transcription.\",\n      \"method\": \"Strep-tag affinity purification and mass spectrometry, overexpression, RNAi knockdown, vRNA synthesis measurement\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — affinity purification MS plus KD/OE with functional viral readouts, single lab\",\n      \"pmids\": [\"32553055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YBX3 directly binds and stabilizes SLC1A5 mRNA via its 3' UTR in mouse skeletal muscle cells; YBX3 depletion specifically reduces SLC1A5 amino acid transporter substrates, reduces proliferation, and impairs differentiation of skeletal muscle cells.\",\n      \"method\": \"RIP (RNA immunoprecipitation), 3' UTR reporter assays, YBX3 depletion, amino acid measurement, proliferation and differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RIP plus 3'UTR reporter plus KD with defined metabolic and cellular phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"38159852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YBX3 stabilizes Slc3a2 and Pparg mRNAs in brown adipocytes, facilitating branched-chain amino acid (BCAA) influx and catabolism; BAT-specific Ybx3 loss dampens thermogenesis and worsens diet-induced obesity in mice, while overexpression is protective.\",\n      \"method\": \"AAV-mediated BAT-specific KD/OE, transcriptome analysis, mitochondrial stress test, in vitro KD/OE, mRNA stability analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo tissue-specific KO/OE plus transcriptomics plus functional metabolic readouts, multiple orthogonal methods\",\n      \"pmids\": [\"39481849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YBX3 (DbpA) expression is induced in activated renal fibroblasts during obstructive nephropathy; Ybx3-deficient mice have reduced immune cell infiltration and extracellular matrix deposition in obstructed kidneys, establishing a role for YBX3 in renal fibrosis.\",\n      \"method\": \"UUO mouse model, Ybx3 KO mice, RNAseq, histological analysis of fibrosis and immune infiltration\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined tissue phenotype and transcriptomic characterization, single lab\",\n      \"pmids\": [\"37408260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHK2 (CHEK2), YBX1, and YBX3 form a regulatory hub in glioma cells; these proteins reciprocally regulate each other's expression and collectively repress pro-inflammatory gene transcription; ChIP-seq confirmed common inflammatory gene targets; targeting this hub with YBX1 inhibitor SU056 degrades the complex and enhances antigen presentation.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry, phosphoproteomics, single-gene KO/OE, RNA-seq, ChIP-seq, pharmacological inhibition\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IP-MS plus ChIP-seq plus genetic KO/OE, preprint not yet peer-reviewed\",\n      \"pmids\": [\"40161682\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"YBX3 (ZONAB/DbpA) is a cold shock domain-containing DNA/RNA-binding protein that shuttles between tight junctions (where it is sequestered by ZO proteins and regulated by CDK4, RalA, GEF-H1, Apg-2, and symplekin interactions) and the nucleus, where it functions as a transcription factor activating proliferative genes (cyclin D1, PCNA, CDK5/CDK4 targets) and repressing differentiation genes (claudin-5, occludin, megalin, cubilin, AML1), and also acts as an RNA-binding protein that stabilizes specific mRNAs (SLC7A5, SLC3A2, SLC1A5, Slc3a2, Pparg) to control amino acid transporter expression and cellular metabolism.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"YBX3 (also known as ZONAB/DbpA/CSDA) is a cold shock domain-containing protein that functions as both a transcription factor and an mRNA stability factor, coupling cell density sensing at tight junctions to the control of proliferation, differentiation, and amino acid metabolism. At tight junctions, YBX3 is sequestered by ZO-1/ZO-2 and regulated by competing interactions with CDK4, RalA, GEF-H1/RhoA, Apg-2, and symplekin; release from this junctional pool permits nuclear translocation, where YBX3 activates proliferative gene promoters (cyclin D1, PCNA) and represses differentiation-associated targets (megalin, cubilin, AML1, claudin-5, occludin) [PMID:12566432, PMID:16508013, PMID:19328795, PMID:20133480, PMID:26106824]. As an RNA-binding protein, YBX3 directly binds and stabilizes mRNAs encoding amino acid transporters (SLC7A5, SLC3A2, SLC1A5) and metabolic regulators (Pparg), thereby maintaining intracellular amino acid pools and supporting processes including brown adipose thermogenesis and skeletal muscle differentiation [PMID:31189097, PMID:38159852, PMID:39481849]. In vivo, tissue-specific loss of Ybx3 impairs brown fat thermogenesis and exacerbates diet-induced obesity, while in kidney it reduces fibrotic remodeling, underscoring context-dependent roles in metabolic homeostasis and tissue injury [PMID:39481849, PMID:37408260].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing the fundamental DNA-binding specificity of YBX3 resolved whether this cold shock domain protein preferentially recognized damaged versus intact DNA, revealing broad nucleic acid binding capacity with enhanced affinity for depurinated substrates.\",\n      \"evidence\": \"EMSA and competition assays with double-stranded, single-stranded, and abasic DNA substrates\",\n      \"pmids\": [\"1923758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo relevance to DNA repair demonstrated\", \"Structural basis for depurinated DNA preference unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Discovery that YBX3 represses stress-induced grp78 transcription and activates the thymidine kinase promoter established its dual role as a context-dependent transcriptional activator and repressor.\",\n      \"evidence\": \"Reporter assays, EMSA, and Southwestern blots on grp78 and htk promoters; functional antagonism with YY1\",\n      \"pmids\": [\"8972186\", \"9419421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ChIP confirmation of endogenous promoter occupancy\", \"Mechanisms determining activator versus repressor function unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The finding that ZO-1 sequesters YBX3/ZONAB at tight junctions and that nuclear YBX3 controls CDK4 levels and cell proliferation established the paradigm of junctional retention as a mechanism coupling cell density to proliferative signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, antisense/RNAi knockdown, ZO-1 overexpression with proliferation and cell density readouts in MDCK cells\",\n      \"pmids\": [\"12566432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis of ZO-1–ZONAB interaction debated; later work showed full-length ZO-1 does not directly bind ZONAB in vitro\", \"Contribution of ZO-2/ZO-3 redundancy not yet appreciated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of cyclin D1 and PCNA as direct transcriptional targets via ChIP, and discovery of symplekin as a nuclear co-factor and Apg-2 as a ZO-1 competitor, built a multi-component regulatory circuit explaining how YBX3 integrates junctional signals into G1/S progression.\",\n      \"evidence\": \"ChIP, reporter assays, RNAi, recombinant protein reconstitution in MCF-10A, MDCK, and Eph4 cells\",\n      \"pmids\": [\"16508013\", \"17158914\", \"16407410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No genome-wide target map at this stage\", \"How symplekin modulates YBX3 DNA-binding specificity unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstration that GEF-H1/RhoA signaling drives ZONAB nuclear translocation and that the symplekin/ZONAB complex represses AML1 and KLF4 to inhibit goblet cell differentiation extended the model from proliferation control to lineage decisions in intestinal epithelium.\",\n      \"evidence\": \"Co-IP, reporter assays, ChIP, EMSA, RNAi in epithelial and intestinal cell systems\",\n      \"pmids\": [\"19730435\", \"19328795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo intestinal phenotype of Ybx3 loss not examined\", \"Whether GEF-H1 and symplekin pathways converge on the same ZONAB pool unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extension to kidney proximal tubule cells and retinal pigment epithelium demonstrated that YBX3 represses differentiation markers (megalin, cubilin) and promotes EMT-like changes in vivo, generalizing its role beyond simple cell lines.\",\n      \"evidence\": \"ChIP, reporter assays, overexpression/knockdown in OK cells, lentiviral manipulation in mouse RPE\",\n      \"pmids\": [\"20133480\", \"21209887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genetic loss-of-function in kidney epithelium not performed at this stage\", \"Downstream effectors of EMT phenotype not fully mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Findings that ZO-1, ZO-2, and ZO-3 redundantly stabilize ZONAB at junctions (with proteasomal degradation upon combined depletion) and that CFTR signals through ZO-1 to regulate ZONAB localization refined the junctional retention model and linked it to cystic fibrosis pathophysiology.\",\n      \"evidence\": \"Combined ZO-protein depletion, MG132 rescue, in vitro binding, CFTR KO mice and 3D culture\",\n      \"pmids\": [\"24986862\", \"25107366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of E3 ligase targeting ZONAB for proteasomal degradation unknown\", \"Whether CFTR–ZO-1–ZONAB axis operates in human CF lung tissue not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"iCLIP mapping and multi-omics integration revealed that YBX3 functions as an mRNA stability factor for amino acid transporter mRNAs (SLC7A5, SLC3A2), fundamentally expanding its role from transcription factor to post-transcriptional regulator of cellular metabolism.\",\n      \"evidence\": \"iCLIP, integrated proteomics and transcriptomics, mRNA stability assays upon YBX3 depletion\",\n      \"pmids\": [\"31189097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for mRNA target selectivity unresolved\", \"Relative contribution of transcriptional versus post-transcriptional roles in the same cell type not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple studies established that non-coding RNAs (circSERPINE2, lncRNA BLACAT3) regulate YBX3 localization and activity, that YBX3 stabilizes SLC1A5 mRNA in muscle, and that Ybx3-deficient mice are protected from renal fibrosis — collectively demonstrating tissue-specific in vivo functions and RNA-mediated regulation.\",\n      \"evidence\": \"RNA pulldown/MS, RIP, 3ʹ UTR reporters, ChIP, Ybx3 KO mice with UUO model, skeletal muscle differentiation assays\",\n      \"pmids\": [\"37831180\", \"37612524\", \"38159852\", \"37408260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Global landscape of regulatory RNAs controlling YBX3 unknown\", \"Whether fibrosis role is transcriptional or post-transcriptional not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"BAT-specific Ybx3 manipulation demonstrated that YBX3-mediated stabilization of Slc3a2 and Pparg mRNAs drives BCAA catabolism and thermogenesis, directly linking YBX3 mRNA stabilization to systemic metabolic control.\",\n      \"evidence\": \"AAV-mediated BAT-specific KD/OE in mice, transcriptomics, mRNA stability assays, metabolic phenotyping\",\n      \"pmids\": [\"39481849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether YBX3 also controls thermogenesis through transcriptional targets not excluded\", \"Mechanism by which YBX3 is regulated in response to cold or dietary cues unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the structural basis for YBX3's dual DNA/RNA-binding target selectivity; the identity of the E3 ligase mediating its proteasomal turnover upon loss of junctional anchoring; how its transcriptional and mRNA-stabilizing functions are coordinated in the same cell; and the full scope of its in vivo metabolic roles across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of YBX3 bound to mRNA or DNA target\", \"E3 ligase for ZONAB degradation unidentified\", \"No systematic in vivo comparison of transcriptional versus post-transcriptional contributions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 3, 5, 12, 13, 18, 20]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [21, 25, 27, 28]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 9, 12, 13, 15, 18, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 4, 9, 11, 14, 15, 18, 22, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 16, 23]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 10, 11, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 6, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 9, 12, 13, 18, 24]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [21, 25, 27, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 11, 15]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 10, 16]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [21, 27, 28]}\n    ],\n    \"complexes\": [\n      \"symplekin/ZONAB complex\",\n      \"CHK2/YBX1/YBX3 hub\"\n    ],\n    \"partners\": [\n      \"TJP1\",\n      \"SYMPK\",\n      \"CDK4\",\n      \"RALA\",\n      \"ARHGEF2\",\n      \"HSPA4\",\n      \"TJP2\",\n      \"YBX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}