{"gene":"YBX1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2001,"finding":"YB-1 (p50) is a potent cap-dependent mRNA stabilizer; its cold shock domain mediates mRNA stabilizing activity, and YB-1 destabilizes the interaction of eIF4E with the mRNA cap structure while itself associating with mRNA at or near the cap when eIF4E is sequestered.","method":"In vitro mRNA stability assays, in vivo overexpression/depletion, cap-binding competition assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with domain mutagenesis plus in vivo validation, multiple orthogonal methods","pmids":["11574481"],"is_preprint":false},{"year":2001,"finding":"YB-1 (dbpB) is activated by proteolytic cleavage upon thrombin stimulation, which releases it from mRNA in the cytoplasm, allowing nuclear translocation and transcriptional activation of target genes including PDGF-B; cytosolic retention is mediated by region 247–267 which is cleaved during activation.","method":"Biochemical fractionation, oligo(dT) affinity chromatography, immunoprecipitation, RNase treatment, reporter gene assays, nuclear localization imaging","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical methods in one study establishing mechanism of mRNA-release-dependent nuclear translocation","pmids":["11390977"],"is_preprint":false},{"year":2002,"finding":"YB-1 binds specifically to RNA containing 8-oxoguanine (oxidized RNA) but not normal RNA; domain deletion mapping identified the regions required for this binding; expression of YB-1 in E. coli confers resistance to oxidative stress in a binding-activity-dependent manner.","method":"In vitro RNA-binding assays with purified protein, deletion mutant analysis, bacterial oxidative-stress resistance assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — purified protein in vitro binding with mutagenesis, functional validation in bacterial model","pmids":["12379116"],"is_preprint":false},{"year":1994,"finding":"YB-1 represses IFN-γ-induced transcription of class II MHC genes (HLA-DR) and the Invariant chain gene by binding the Y element (inverted CCAAT box) in their promoters.","method":"Co-transfection of YB-1 expression vector with promoter-reporter constructs, transient transfection with >70% efficiency, mRNA and antigen expression analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional promoter assays with exogenous YB-1 plus endogenous gene expression readout, two complementary approaches","pmids":["8163940"],"is_preprint":false},{"year":2009,"finding":"YB-1 localizes to human mitochondria, contributes to mitochondrial mismatch-binding and mismatch-repair activity, and its depletion increases mitochondrial DNA mutagenesis; mitochondrial MMR is distinct from nuclear MMR and does not require canonical nuclear MMR factors such as MSH2.","method":"Subcellular fractionation, mitochondrial extract MMR assays, siRNA depletion, mitochondrial DNA mutagenesis quantification","journal":"DNA repair","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization by fractionation combined with functional biochemical repair assay and genetic depletion with defined readout","pmids":["19272840"],"is_preprint":false},{"year":2009,"finding":"Extracellular secreted YB-1 acts as a ligand for Notch-3 receptor (but not Notch-1), interacting with its extracellular domain; this interaction activates Notch-3 signaling, leading to nuclear translocation of the Notch-3 intracellular domain and upregulation of Notch target genes.","method":"Co-immunoprecipitation, co-localization at cell membranes (GFP fusion), reporter assays for Notch target genes, binding specificity assays comparing Notch-1 vs Notch-3","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and localization data with functional Notch reporter readout, single lab","pmids":["19640841"],"is_preprint":false},{"year":2009,"finding":"HSP60 binds to YB-1 at the YB-NLS region in the cytoplasm, and this interaction regulates YB-1 polysome association and subcellular distribution; HSP60 overexpression decreases YB-1 in heavy-sedimenting polysome fractions and suppresses YB-NLS-mediated nuclear import.","method":"Co-immunoprecipitation, sucrose gradient sedimentation, overexpression/knockdown of HSP60, nuclear localization assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding mapped to YB-NLS with functional consequence on polysome association and nuclear import, single lab","pmids":["19470374"],"is_preprint":false},{"year":2008,"finding":"YB-1 interacts with tubulin and microtubules and stimulates microtubule assembly in vitro; high-resolution microscopy shows YB-1 coats the outer microtubule wall; tubulin binding interferes with RNA:YB-1 complexes.","method":"In vitro microtubule assembly assays, electron microscopy, atomic force microscopy, co-sedimentation assays, RNA competition assays","journal":"BMC biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with structural imaging, single lab","pmids":["18793384"],"is_preprint":false},{"year":2015,"finding":"tRNA-derived fragments (tRFs) from tRNA(Glu), tRNA(Asp), tRNA(Gly), and tRNA(Tyr) suppress the stability of oncogenic transcripts by displacing their 3'UTRs from YBX1; these tRFs share a common motif matching the YBX1 recognition sequence, demonstrating sequence-specific displacement of mRNAs from YBX1.","method":"RNA-binding protein immunoprecipitation, LNA loss-of-function, synthetic RNA mimetics gain-of-function, in vitro displacement assays, invasion/metastasis assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (RIP, LNA, synthetic mimetics), mechanistic model validated in vitro and in vivo","pmids":["25957686"],"is_preprint":false},{"year":2015,"finding":"YB-1 directly binds to and translationally activates the 5'UTR of G3BP1 mRNA, controlling G3BP1 protein availability for stress granule (SG) nucleation; YB-1 inactivation dramatically reduces G3BP1 protein and SG formation.","method":"Direct RNA binding assays (5'UTR), translational reporter assays, YB-1 siRNA knockdown, in vivo xenograft SG formation analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct 5'UTR binding demonstrated, translational activation validated with multiple methods including in vivo","pmids":["25800057"],"is_preprint":false},{"year":2015,"finding":"HACE1 E3 ubiquitin ligase polyubiquitinates YB-1 via non-canonical K27-linked ubiquitin chains; this ubiquitination promotes YB-1 interaction with TSG101 (a component of the MVB pathway) and is required for YB-1 extracellular secretion.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, secretion assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific E3 ligase identified with K27-linkage characterization and TSG101 interaction, single lab","pmids":["26343856"],"is_preprint":false},{"year":2016,"finding":"Transportin-1 mediates YB-1 nuclear import; YB-1 and transportin-1 form a complex in HeLa cell extracts; nuclear import is abolished by a transportin-1 competitor substrate, the transportin-1 inhibitor M9M, and inactivating mutations in the transportin-1-dependent NLS (P201A/Y202A).","method":"In vitro nuclear import assay, co-immunoprecipitation from cell extracts, site-directed mutagenesis of NLS, pharmacological inhibition","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro transport assay with mutagenesis of NLS and pharmacological inhibition, multiple orthogonal approaches","pmids":["27794479"],"is_preprint":false},{"year":2016,"finding":"YB-1 phosphorylation at serine 102 promotes its nuclear translocation and CCL5 promoter binding; calcineurin (CN) dephosphorylates YB-1 at S102, reducing its CCL5 transcriptional activation; YB-1/CN interact directly by co-immunoprecipitation.","method":"Co-immunoprecipitation, ChIP, reporter assays, calcineurin inhibitor (cyclosporine A) treatment in vivo and in vitro, phospho-specific antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, ChIP, functional promoter assays, in vivo pharmacological validation across multiple systems","pmids":["24947514"],"is_preprint":false},{"year":2019,"finding":"Class I HDAC inhibitor MS-275 promotes YB-1 acetylation at lysine-81, blocking its binding to 5'UTRs of NFE2L2 (NRF2), HIF1A, and G3BP1 mRNAs and thereby reducing their translation; an MS-275-resistant YB-1(K81A) mutant restores translational activation of these targets and metastatic capacity.","method":"Global acetylomics, in vivo metastasis assays, MS-275-resistant point mutant (K81A), mRNA binding assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — acetylomics identifies modification site, mutagenesis (K81A) functionally validates it, in vivo rescue experiment","pmids":["31668005"],"is_preprint":false},{"year":2020,"finding":"YB-1 CSD with C-terminal extension (CSDex) adopts a rigid structure (not disordered); phosphorylation of S102 destabilizes the protein and causes partial unfolding; CSDex provides a unique DNA binding site recognizing a broader set of sequences than the canonical CSD; S102 phosphorylation dramatically reduces ssDNA binding.","method":"Crystal structure determination, NMR structural characterization, DNA binding assays with phosphomimetic and deletion mutants","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation by mutagenesis and DNA-binding assays","pmids":["32710623"],"is_preprint":false},{"year":2020,"finding":"JAK2V617F phosphorylates YB-1 post-translationally; YBX1 inactivation in JAK2-mutated cells causes RNA mis-splicing, intron retention, and disruption of ERK signaling control; YBX1 functions as a splicing factor maintaining disease persistence in myeloproliferative neoplasms.","method":"In-depth phosphoproteome profiling, genetic inactivation (CRISPR/shRNA), in vivo mouse and primary human cell models, RNA-seq (splicing analysis)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphoproteomics identifies modification, genetic inactivation with defined splicing phenotype replicated in mouse and human primary cells","pmids":["33239784"],"is_preprint":false},{"year":2020,"finding":"YBX1 undergoes liquid-liquid phase separation (LLPS) in vitro and in cells; YBX1 condensates selectively recruit miR-223 in vitro and sort it into exosomes; point mutations inhibiting LLPS impair YBX1 incorporation into biomolecular condensates and perturb miR-223 sorting into exosomes.","method":"LLPS in vitro assays, live-cell imaging of condensates, point mutagenesis of phase-separation residues, exosome miRNA quantification","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of LLPS, mutagenesis with functional exosome sorting readout","pmids":["34766549"],"is_preprint":false},{"year":2020,"finding":"YB-1 is a global translation inhibitor that binds a wide range of mRNAs; YBX1 knockout leads to compensatory upregulation of YB-3 translation, which binds a strikingly similar set of mRNAs and substitutes for YB-1 in global translational repression.","method":"Ribo-Seq, RIP-Seq, YBX1 knockout cell lines","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — genome-wide ribosome profiling and RIP-Seq in knockout cells, orthogonal methods","pmids":["31944153"],"is_preprint":false},{"year":2020,"finding":"Ybx1 interacts with PRC2, highly overlaps PRC2 binding genome-wide, controls PRC2 distribution, and inhibits H3K27me3 levels in neural progenitor cells; Ybx1 knockout increases H3K27me3 and PRC2 enzymatic inhibition partially rescues gene expression and NPC functions.","method":"Co-immunoprecipitation (Ybx1-PRC2), ChIP-seq, Ybx1 knockout mice and NPCs, PRC2 inhibitor rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, genome-wide ChIP-seq, genetic knockout with pharmacological rescue establishing epistatic relationship","pmids":["32792512"],"is_preprint":false},{"year":2020,"finding":"YB-1 dephosphorylation at serine residues 102, 165, and 176 increases accessibility of the nuclear localization signal (NLS) by altering protein conformation, facilitating nuclear entry during late G2/M phase; live-cell imaging shows YB-1 is primarily perinuclear during G1/S and enters the nucleus at late G2/M.","method":"Confocal microscopy, live-cell imaging, mass spectrometry (phosphorylation mapping), atomistic molecular dynamics simulations","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging plus MS-based phosphorylation mapping with MD simulations, single lab","pmids":["32013098"],"is_preprint":false},{"year":2019,"finding":"Inhibition of RNA polymerase II activity results in nuclear accumulation of YB-1 accompanied by its phosphorylation at Ser102; kinase inhibition reduces YB-1 phosphorylation and nuclear accumulation; nuclear RNA is required for nuclear retention of YB-1.","method":"RNAPII inhibitor treatment, kinase inhibitors, subcellular fractionation, immunofluorescence, RNA depletion experiments","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological perturbations with defined localization readout, single lab","pmids":["31906126"],"is_preprint":false},{"year":2021,"finding":"YB-1 phosphorylation at Ser209 (by Akt kinase in vitro) inhibits YB-1 nuclear translocation and prevents S102-phosphorylation-mediated nuclear import; phosphomimetic S209E substitution blocks nuclear entry.","method":"In vitro Akt kinase assay, phosphomimetic substitutions (S209E), subcellular localization assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus phosphomimetic mutagenesis with localization readout, single lab","pmids":["35008856"],"is_preprint":false},{"year":2021,"finding":"YB-1 unwinds mRNA secondary structures without ATP consumption using its cold shock domain to destabilize RNA stem/loops and its unstructured C-terminal domain to secure RNA unwinding; at endogenous levels YB-1 facilitates stress granule disassembly, and overexpression inhibits SG assembly.","method":"In vitro RNA unwinding assays, unwinding-defective mutants, arsenite stress granule assays in HeLa cells, live-cell imaging","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of RNA unwinding with domain mutants, cellular functional validation, single lab with multiple orthogonal methods","pmids":["34469566"],"is_preprint":false},{"year":2021,"finding":"YBX1 promotes translation of oncogenic transcripts including MYC by recruitment to polysomal chains; YBX1 genetic inactivation displaces MYC and other oncogenic drivers from polysomes, depleting their protein levels and reducing leukemia cell competitive fitness.","method":"Polysome fractionation, genetic inactivation (CRISPR), in vitro and in vivo competitive assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polysome profiling with genetic inactivation, in vivo validation, single lab","pmids":["34465866"],"is_preprint":false},{"year":2018,"finding":"YB-1 acts as a potent cofactor of PARP1, stimulating its poly(ADP-ribose) polymerase activity; the C-terminal domain of YB-1 is indispensable for PARP1 stimulation; functional interactions between YB-1 and PARP1 can be mediated by poly(ADP-ribose).","method":"In vitro PARP1 activity assays with purified YB-1, domain deletion analysis, PAR binding assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with domain mapping, single lab","pmids":["29805738"],"is_preprint":false},{"year":2015,"finding":"YB-1 forms stable homo-multimers cooperatively on specific mRNAs (but not others), enabling selective translational inhibition of mRNAs on which stable multimers form; the same cooperative multimerization mechanism also operates on specific DNA structures.","method":"In vitro binding and multimerization assays, translation reporter assays, DNA binding studies","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution demonstrating cooperative multimerization with functional translation inhibition, single lab","pmids":["26271991"],"is_preprint":false},{"year":2012,"finding":"YB-1 synthesis is regulated by the mTOR signaling pathway; inhibition of mTOR with PP242 (but not rapamycin) specifically suppresses YB-1 translation; this dependence is dictated by the 5'UTR of YB-1 mRNA as shown by reporter constructs.","method":"mTOR inhibitor treatment (PP242/rapamycin), reporter constructs with YB-1 5'UTR, Western and Northern blotting","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway perturbation plus reporter construct 5'UTR mapping, single lab","pmids":["23285076"],"is_preprint":false},{"year":2020,"finding":"CircRNA-SORE binds YBX1 in the cytoplasm, preventing its interaction with E3 ubiquitin ligase PRP19 and thus blocking PRP19-mediated YBX1 degradation; this stabilizes YBX1 and confers sorafenib resistance in hepatocellular carcinoma.","method":"RNA pulldown, co-immunoprecipitation, in vitro and in vivo models, siRNA knockdown","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown and Co-IP identify the circRNA-YBX1-PRP19 relationship with functional ubiquitination readout, single lab","pmids":["33361760"],"is_preprint":false},{"year":2022,"finding":"YB-1 binds the 5'UTR of CCT4 mRNA to promote CCT4 translation; CCT4 (a CCT chaperone component) activates mTOR signaling by promoting mLST8 folding; YB-1 also autoregulates its own translation by binding its 5'UTR, sustaining mTOR activation.","method":"RNA immunoprecipitation, 5'UTR reporter assays, genetic knockdown, xenograft model with RNA decoys, co-expression analysis in patient samples","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and reporter assays establishing 5'UTR binding and translational activation, in vivo RNA decoy validation, single lab","pmids":["35239512"],"is_preprint":false},{"year":2023,"finding":"FBL (fibrillarin) interacts with YBX1 and promotes its nuclear accumulation in response to DNA damage; nuclear YBX1 binds the BRCA1 promoter to activate BRCA1 expression, supporting homologous recombination-mediated DNA repair.","method":"Co-immunoprecipitation, ChIP assay, knockdown experiments, DNA damage repair assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP establishing FBL-YBX1 interaction and promoter binding, single lab","pmids":["37489617"],"is_preprint":false},{"year":2016,"finding":"YB-1 binds to HIF-1α by co-immunoprecipitation and to hypoxia-response element (HRE) sequences (single- and double-stranded) by DNA binding assays; under hypoxia, YB-1 translocates to the nucleus and represses HIF-1α-mediated EPO transcription.","method":"Co-immunoprecipitation, DNA binding assays, siRNA depletion, reporter assays, immunofluorescence for nuclear shuttling","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and DNA binding with functional reporter assay, single lab","pmids":["27524241"],"is_preprint":false},{"year":2016,"finding":"Cytoplasmic YB-1 directly stabilizes Col1a1 mRNA to promote renal fibrosis; conversely, nuclear (S102-phosphorylated) YB-1 represses the Col1a1 promoter; forced nuclear YB-1 shuttling by small molecule HSc025 is anti-fibrotic in vivo.","method":"mRNA stability assays, subcellular fractionation, YB-1 half-knockout mouse model, small molecule nuclear shuttling, fibrosis quantification in vivo","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic compartment-specific functions validated in knockout mice and with pharmacological tool, in vivo rescue","pmids":["27591085"],"is_preprint":false},{"year":2015,"finding":"YB-1 promotes microtubule-dependent trafficking and recycling of MT1-MMP to cell surface invasion sites, increasing breast cancer invasion and metastasis.","method":"YB-1/EGFP transfection, immunofluorescence localization to invadopodia, MT1-MMP endocytosis/recycling rate measurements, in vivo tumor formation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization to invadopodia with trafficking kinetics and in vivo tumor phenotype, single lab","pmids":["20599698"],"is_preprint":false},{"year":2005,"finding":"YB-1 represses AP-1-dependent transcription and directly binds to the AP-1 DNA sequence; a 49 kDa YB-1 protein was purified from cancer cells by DNA-affinity chromatography and confirmed by tandem MS and immunoblotting to bind the AP-1 sequence specifically.","method":"DNA-affinity chromatography (NAPSTER assay), tandem MS sequencing, gel mobility supershift assays, luciferase reporter transfection assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — biochemical purification and direct DNA binding with functional reporter assay, single lab","pmids":["15702969"],"is_preprint":false},{"year":2005,"finding":"YB-1 inhibits p53-dependent apoptotic gene transactivation (e.g., Bax) without affecting p53-mediated activation of CDKN1A or MDM2; nuclear YB-1 selectively alters p53 transcriptional activity; transcriptionally active p53 is required for YB-1 nuclear localization.","method":"Co-transfection reporter assays, apoptosis assays, Bax protein quantification, p53-null and p53-expressing cell comparisons","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional selectivity demonstrated with multiple promoter reporters and endogenous target proteins, single lab","pmids":["16158057"],"is_preprint":false},{"year":2017,"finding":"YB-1 directly binds the MACC1 promoter (demonstrated by ChIP) and activates MACC1 transcription, thereby activating the MACC1/c-Met signaling pathway to promote lung adenocarcinoma progression.","method":"ChIP assay, promoter reporter assays, siRNA knockdown, xenograft mouse model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay with in vivo validation, single lab","pmids":["28624808"],"is_preprint":false},{"year":2013,"finding":"YB-1 directly binds and represses the p16 (CDKN2A/INK4a) promoter as demonstrated by ChIP; YB1 overexpression decreases p16 expression and promotes cell proliferation while preventing cellular senescence.","method":"ChIP assay, overexpression in mouse embryonic fibroblasts, senescence-associated β-galactosidase assay","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence with functional proliferation/senescence readout, single lab","pmids":["24165022"],"is_preprint":false},{"year":1997,"finding":"YB-1 and dbpA bind the lower strand of the SICR (stress-inducible change region) within the grp78 core promoter element and repress stress-inducible (ER stress) transcription; YB-1 interacts with YY1 (identified by yeast two-hybrid) and inhibits YY1 binding to the core element.","method":"Expression library screening, gel shift assays, co-transfection reporter assays, yeast interaction trap (two-hybrid)","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gel shifts plus functional reporter assays plus two-hybrid identification of YY1 interaction, single lab","pmids":["8972186"],"is_preprint":false},{"year":2020,"finding":"YB-1 depletion causes cytokinesis failure and multinucleation; phosphorylation at six serine residues (including novel sites identified by mass spectrometry) is essential for cytokinesis completion; phosphorylated YB-1 orchestrates spatio-temporal distribution of microtubules, β-actin, and the chromosome passenger complex (CPC) to define the cleavage plane.","method":"siRNA knockdown in multiple cell lines, rescue experiments, confocal live-cell imaging, mass spectrometry-based phosphorylation site mapping, atomistic modelling","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic depletion with rescue, imaging of cytokinesis machinery, MS phosphosite mapping, single lab","pmids":["32882852"],"is_preprint":false},{"year":2016,"finding":"YB-1 is SUMOylated in a circadian-clock-controlled manner in zebrafish; circadian changes in YB-1 SUMOylation regulate its periodic nuclear entry; nuclear YB-1 directly binds the cyclin A2 promoter and downregulates cyclin A2 mRNA expression.","method":"SUMOylation assays, live zebrafish imaging, ChIP on cyclin A2 promoter, circadian cycle analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and direct SUMOylation detection with functional gene expression readout, zebrafish ortholog","pmids":["28008157"],"is_preprint":false},{"year":2015,"finding":"YB-1 interacts with YBX1 target DNA/mRNA structures via cooperative homo-multimerization; YB-1 promotes XPC-HR23B binding to DNA containing bulky NER lesions, and YB-1 and XPC-HR23B mutually stimulate each other's binding to damaged DNA substrates.","method":"In vitro DNA binding assays with NER substrate mimics, competition/stimulation binding assays with purified proteins","journal":"Biochemistry. Biokhimiia","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins and defined DNA substrates, single lab","pmids":["25756536"],"is_preprint":false},{"year":2016,"finding":"YBX1 and NOD2 directly interact (demonstrated by co-immunoprecipitation and sucrose gradient co-migration); GMDP (muramyl peptide) stimulates formation of higher-molecular-mass YBX1-NOD2 complexes; both YBX1 and NOD2 contribute independently to GMDP-induced NF-κB activation.","method":"Co-immunoprecipitation, sucrose gradient centrifugation, NOD2/YBX1 siRNA knockdown, NF-κB reporter assay","journal":"Innate immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with functional reporter and separate knockdown controls, single lab","pmids":["27694635"],"is_preprint":false},{"year":2022,"finding":"RSK2 phosphorylates YB-1 at Ser102, promoting formation of a YB-1/KLF5 transcriptional complex that co-regulates BLBC-specific genes (KRT16, Ly6D); YB-1 also stabilizes KLF5 mRNA in an RNA 5-methylcytosine modification-dependent manner.","method":"Co-immunoprecipitation, ChIP, luciferase reporter assays, RSK inhibitor (LJH685), mRNA stability assays, in vivo xenograft","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and mRNA stability with pharmacological inhibition and in vivo validation, single lab","pmids":["35022570"],"is_preprint":false},{"year":2024,"finding":"ZO-1 physically interacts with YB-1 in endothelial cells; arsenite treatment decreases ZO-1/YB-1 interaction and drives YB-1 into stress granules; YB-1 is essential for stress granule formation and for the cytoprotective effects of ZO-1 downregulation during angiogenesis.","method":"Co-immunoprecipitation, arsenite stress granule assays, endothelial-specific ZO-1 knockout mice, confocal imaging of YB-1 granules in retinal vasculature","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with in vivo genetic knockout model and functional angiogenesis readout, single lab","pmids":["38782923"],"is_preprint":false},{"year":2020,"finding":"YB-1 mediates TNF-induced NF-κB activation by maintaining expression of TRAF2, a central component of the TNFR1 signaling complex; YB-1-deficient cells show reduced TRAF2 expression and enhanced apoptosis in response to TNF.","method":"YB-1 knockout/knockdown cells, TNF stimulation, NF-κB reporter assays, caspase-3 activation, zVAD rescue","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic depletion with defined molecular (TRAF2) and functional (apoptosis) readout, single lab","pmids":["32764479"],"is_preprint":false},{"year":2013,"finding":"YB-1 stabilizes HIV-1 genomic RNA by binding to the stem loop 2 of the HIV-1 RNA packaging signal (mapped as the YB-1-responsive element), thereby enhancing HIV-1 protein expression and viral production.","method":"YB-1 overexpression/knockdown in producer cells, viral production quantification, RNA stability assays, deletion mapping of responsive element","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with RNA element mapping, single lab","pmids":["23589019"],"is_preprint":false}],"current_model":"YBX1 is a multifunctional cold-shock domain RNA/DNA-binding protein that operates as a context-dependent translational repressor or activator (binding mRNA 5'UTRs and 3'UTRs), a transcription factor (activating or repressing promoters depending on cofactors and phosphorylation state), a splicing factor downstream of JAK2, a stress granule regulator (suppressing SG assembly via ATP-independent mRNA unwinding and promoting G3BP1 translation), a mitochondrial mismatch-repair factor, and an extracellular Notch-3 ligand; its activities are regulated by phosphorylation (primarily at S102 by Akt/RSK2, and dephosphorylation by calcineurin), acetylation (K81 by HDAC-dependent mechanism), ubiquitination (K27-linked by HACE1 for secretion; PRP19-mediated for degradation), and SUMOylation, which together control its subcellular localization (cytoplasmic retention vs. nuclear import via transportin-1) and its selective engagement with mRNA targets, chromatin, and protein partners including PRC2, PARP1, p53, NF-κB/TRAF2, HIF-1α, and Notch-3."},"narrative":{"mechanistic_narrative":"YBX1 is a multifunctional cold-shock-domain protein that governs gene expression at both the RNA and DNA levels, operating as a global translational regulator, a sequence-specific transcription factor, and a stress-response coordinator [PMID:11574481, PMID:31944153, PMID:32710623]. In the cytoplasm it binds mRNA at or near the cap, stabilizing transcripts and displacing eIF4E [PMID:11574481], and acts as a broad translational repressor whose loss is compensated by upregulation of the paralog YB-3 [PMID:31944153]; it forms cooperative homo-multimers on selected mRNAs and DNA structures to confer target selectivity [PMID:26271991]. At specific 5'UTRs it switches to translational activation, driving production of G3BP1, NFE2L2, HIF1A, and CCT4, the last of which feeds back to sustain mTOR signaling alongside YBX1 autoregulation [PMID:25800057, PMID:31668005, PMID:35239512]. Through G3BP1 control and ATP-independent unwinding of mRNA secondary structure via its cold-shock and disordered C-terminal domains, YBX1 modulates stress granule assembly and disassembly [PMID:25800057, PMID:34469566], and it phase-separates into condensates that sort miR-223 into exosomes [PMID:34766549]. In the nucleus YBX1 binds promoter elements to either repress (class II MHC Y-box, AP-1, p16/CDKN2A, grp78, p53 apoptotic targets, HIF-1α-driven EPO) or activate (CCL5, MACC1, BRCA1) transcription depending on cofactors and modification state [PMID:8163940, PMID:15702969, PMID:24165022, PMID:8972186, PMID:16158057, PMID:27524241, PMID:24947514, PMID:28624808, PMID:37489617]. Its CSD plus C-terminal extension forms a rigid module that recognizes a broad set of DNA sequences, and phosphorylation at S102 destabilizes the fold and reduces ssDNA binding [PMID:32710623]. Nucleocytoplasmic partitioning is the master control point: nuclear import proceeds through transportin-1 recognition of an NLS [PMID:27794479], and is gated by phosphorylation (S102 promotes import; calcineurin dephosphorylation and S209 phosphorylation oppose it), SUMOylation, cell-cycle stage, and partner interactions with HSP60 and FBL [PMID:24947514, PMID:35008856, PMID:32013098, PMID:28008157, PMID:19470374, PMID:37489617]. YBX1 stability and secretion are set by ubiquitination, with HACE1-mediated K27-linked chains routing it through TSG101 for extracellular release and PRP19-mediated chains targeting it for degradation [PMID:26343856, PMID:33361760]. Additional activities include mitochondrial mismatch repair [PMID:19272840], stimulation of PARP1 and assistance of XPC-HR23B in DNA repair [PMID:29805738, PMID:25756536], JAK2-dependent splicing control in myeloproliferative neoplasms [PMID:33239784], PRC2-coupled regulation of H3K27me3 [PMID:32792512], and roles in cytokinesis, microtubule-dependent MT1-MMP trafficking, NF-κB signaling, and as an extracellular Notch-3 ligand [PMID:32882852, PMID:20599698, PMID:32764479, PMID:19640841].","teleology":[{"year":1994,"claim":"Established that YBX1 is a sequence-specific transcriptional repressor, binding the inverted CCAAT (Y) element to silence inducible immune genes.","evidence":"Co-transfection of YB-1 with promoter-reporter constructs and endogenous MHC II gene readout","pmids":["8163940"],"confidence":"High","gaps":["Did not identify the modifications or cofactors that gate this repression","No structural basis for Y-element recognition"]},{"year":2001,"claim":"Defined the dual cytoplasmic function of YBX1 as a cap-dependent mRNA stabilizer and an activation-by-cleavage transcription factor, linking mRNA release to nuclear translocation.","evidence":"In vitro mRNA stability and cap-competition assays; biochemical fractionation and thrombin-induced proteolysis with reporter assays","pmids":["11574481","11390977"],"confidence":"High","gaps":["Physiological protease and trigger for cleavage in non-thrombin contexts unresolved","Relationship between cap binding and eIF4E displacement at endogenous loci not mapped"]},{"year":2002,"claim":"Showed YBX1 recognizes oxidatively damaged RNA, implicating it in RNA quality control under oxidative stress.","evidence":"In vitro binding to 8-oxoguanine RNA with deletion mutants and bacterial oxidative-stress resistance assay","pmids":["12379116"],"confidence":"High","gaps":["Fate of bound oxidized RNA in mammalian cells unknown","Whether this binding alters translation of damaged transcripts untested"]},{"year":2009,"claim":"Extended YBX1 function beyond the nucleus/cytoplasm to mitochondrial mismatch repair and to extracellular Notch-3 ligand activity, revealing a remarkably broad localization repertoire.","evidence":"Mitochondrial fractionation with MMR assays and mtDNA mutagenesis quantification; co-IP and Notch reporter assays distinguishing Notch-3 from Notch-1","pmids":["19272840","19640841"],"confidence":"Medium","gaps":["Mitochondrial import mechanism and partner repair factors unidentified","Notch-3 ligand role rests on a single lab without independent confirmation"]},{"year":2015,"claim":"Resolved how YBX1 achieves mRNA-target selectivity and how it controls stress granule biogenesis, linking translational control to RNA homeostasis.","evidence":"Cooperative multimerization and translation reporter assays; 5'UTR binding/translational activation of G3BP1; tRF-mediated displacement of 3'UTRs from YBX1 (RIP, LNA, synthetic mimetics)","pmids":["26271991","25800057","25957686"],"confidence":"High","gaps":["Structural basis distinguishing multimerizing from non-multimerizing targets unclear","How tRF abundance is set physiologically not addressed"]},{"year":2016,"claim":"Identified transportin-1 as the import receptor and converging phosphorylation/SUMOylation inputs as the switch controlling YBX1 nuclear access and compartment-specific transcriptional outputs.","evidence":"In vitro nuclear import assays with NLS mutagenesis and M9M inhibition; S102/calcineurin co-IP and ChIP; HIF-1α co-IP and HRE binding; circadian SUMOylation with cyclin A2 ChIP in zebrafish","pmids":["27794479","24947514","27524241","28008157"],"confidence":"High","gaps":["Integration of competing phospho/SUMO signals into a single localization decision not unified","Stimulus specificity of each input incompletely mapped"]},{"year":2016,"claim":"Demonstrated compartment-segregated, opposing functions of YBX1 on the same target gene (cytoplasmic mRNA stabilization vs nuclear promoter repression), providing a clean in vivo model of localization-dependent activity.","evidence":"mRNA stability assays, half-knockout mice, and small-molecule nuclear shuttling in a renal fibrosis model","pmids":["27591085"],"confidence":"High","gaps":["Whether this compartmental antagonism generalizes beyond Col1a1 untested"]},{"year":2018,"claim":"Connected YBX1 to DNA repair pathways as a PARP1 cofactor and an XPC-HR23B partner, broadening its DNA-associated roles beyond transcription.","evidence":"In vitro PARP1 activity assays with domain deletions; NER substrate binding/stimulation assays with purified proteins","pmids":["29805738","25756536"],"confidence":"Medium","gaps":["In vitro reconstitution awaits cellular validation of repair contribution","C-terminal domain mechanism of PARP1 stimulation not structurally defined"]},{"year":2019,"claim":"Pinpointed K81 acetylation as a regulatory switch that disables 5'UTR binding and translational activation of oncogenic targets, defining a druggable post-translational control point.","evidence":"Acetylomics, MS-275 treatment, K81A rescue mutant, mRNA binding and in vivo metastasis assays","pmids":["31668005"],"confidence":"High","gaps":["Acetyltransferase responsible for K81 not identified","Interplay between acetylation and phosphorylation at adjacent sites unresolved"]},{"year":2020,"claim":"Provided the structural and mechanistic foundation for YBX1 as a global translation repressor, an ATP-independent RNA chaperone, a PRC2-coupled chromatin regulator, and a JAK2-dependent splicing factor, with the CSDex defining its DNA-binding breadth.","evidence":"Crystal/NMR structure with phosphomimetic DNA-binding assays; Ribo-Seq/RIP-Seq in knockouts; in vitro unwinding with domain mutants; Co-IP/ChIP-seq with PRC2; phosphoproteomics and RNA-seq in JAK2V617F models","pmids":["32710623","31944153","34469566","32792512","33239784"],"confidence":"High","gaps":["How a single protein partitions between repression, unwinding, splicing, and chromatin roles in one cell is unresolved","Direct structural model of YBX1-PRC2 contact lacking"]},{"year":2020,"claim":"Established phase separation as the mechanism for selective miR-223 sorting into exosomes and refined the multi-site phospho-code controlling cell-cycle-timed nuclear entry and cytokinesis.","evidence":"In vitro LLPS with phase-separation mutants and exosome miRNA quantification; live-cell imaging with MS phosphosite mapping and MD simulations across cell-cycle and cytokinesis studies","pmids":["34766549","32013098","32882852"],"confidence":"Medium","gaps":["Determinants of selective miRNA recruitment into condensates incompletely defined","Kinases for individual cell-cycle phosphosites not all assigned"]},{"year":2020,"claim":"Mapped ubiquitin-dependent control of YBX1 fate, with K27-linked chains (HACE1) driving secretion via TSG101 and PRP19-mediated chains driving degradation, the latter blockable by a stabilizing circRNA.","evidence":"Ubiquitination/co-IP and secretion assays for HACE1-K27-TSG101; RNA pulldown/co-IP and ubiquitination readout for circRNA-SORE/PRP19","pmids":["26343856","33361760"],"confidence":"Medium","gaps":["Signals selecting between secretory and degradative ubiquitination unknown","Both findings rest on single labs"]},{"year":2021,"claim":"Showed YBX1 directly promotes polysomal translation of MYC and other oncogenic drivers, tying its translational activity to malignant fitness.","evidence":"Polysome fractionation with CRISPR inactivation and competitive in vivo assays","pmids":["34465866"],"confidence":"Medium","gaps":["Distinction from global repressor role on the same transcripts not mechanistically reconciled","Recruitment determinants to polysomes undefined"]},{"year":2024,"claim":"Connected YBX1 to endothelial stress-granule biology through ZO-1 sequestration, defining a stress-released pool that drives cytoprotective granule formation in vivo.","evidence":"Co-IP, arsenite stress granule assays, and endothelial ZO-1 knockout mice with retinal vasculature imaging","pmids":["38782923"],"confidence":"Medium","gaps":["Reciprocal regulation of ZO-1 by YBX1 not established","Single-lab finding awaiting independent confirmation"]},{"year":null,"claim":"How YBX1's many activities are coordinated within a single cell—which modifications, partners, and condensate states select among translation repression/activation, transcription, splicing, repair, and secretion—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking post-translational code to functional state selection","Quantitative partitioning of YBX1 pools across compartments and condensates unmeasured","Endogenous physiological triggers for many in vitro activities undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,8,9,17,22,25,28,45]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,14,25,30,33,35,36,37,40]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,12,29,30,33,34,35,36,37,42]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,9,13,17,23,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[24,18,44]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7,32,38]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,6,22,31]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,11,12,14,20,29,30,31,34,36,39]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5,10]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7,32,38]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[18,29,33,35,36,37]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,12,29,30,33,34,35,36,37,42]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,15,16,17,25]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,9,22,43]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4,24,29,40]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[41,44]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,12,35,42,44]}],"complexes":[],"partners":["PARP1","PRC2","HIF1A","NOD2","TRAF2","FBL","HSP60","TJP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P67809","full_name":"Y-box-binding protein 1","aliases":["CCAAT-binding transcription factor I subunit A","CBF-A","DNA-binding protein B","DBPB","Enhancer factor I subunit A","EFI-A","Nuclease-sensitive element-binding protein 1","Y-box transcription factor"],"length_aa":324,"mass_kda":35.9,"function":"DNA- and RNA-binding protein involved in various processes, such as translational repression, RNA stabilization, mRNA splicing, DNA repair and transcription regulation (PubMed:10817758, PubMed:11698476, PubMed:14718551, PubMed:18809583, PubMed:31358969, PubMed:8188694). Predominantly acts as a RNA-binding protein: binds preferentially to the 5'-[CU]CUGCG-3' RNA motif and specifically recognizes mRNA transcripts modified by C5-methylcytosine (m5C) (PubMed:19561594, PubMed:31358969). Promotes mRNA stabilization: acts by binding to m5C-containing mRNAs and recruiting the mRNA stability maintainer ELAVL1, thereby preventing mRNA decay (PubMed:10817758, PubMed:11698476, PubMed:31358969). Component of the CRD-mediated complex that promotes MYC mRNA stability (PubMed:19029303). Contributes to the regulation of translation by modulating the interaction between the mRNA and eukaryotic initiation factors (By similarity). Plays a key role in RNA composition of extracellular exosomes by defining the sorting of small non-coding RNAs, such as tRNAs, Y RNAs, Vault RNAs and miRNAs (PubMed:27559612, PubMed:29073095). Probably sorts RNAs in exosomes by recognizing and binding C5-methylcytosine (m5C)-containing RNAs (PubMed:28341602, PubMed:29073095). Acts as a key effector of epidermal progenitors by preventing epidermal progenitor senescence: acts by regulating the translation of a senescence-associated subset of cytokine mRNAs, possibly by binding to m5C-containing mRNAs (PubMed:29712925). Also involved in pre-mRNA alternative splicing regulation: binds to splice sites in pre-mRNA and regulates splice site selection (PubMed:12604611). Binds to TSC22D1 transcripts, thereby inhibiting their translation and negatively regulating TGF-beta-mediated transcription of COL1A2 (By similarity). Also able to bind DNA: regulates transcription of the multidrug resistance gene MDR1 is enhanced in presence of the APEX1 acetylated form at 'Lys-6' and 'Lys-7' (PubMed:18809583). Binds to promoters that contain a Y-box (5'-CTGATTGGCCAA-3'), such as MDR1 and HLA class II genes (PubMed:18809583, PubMed:8188694). Promotes separation of DNA strands that contain mismatches or are modified by cisplatin (PubMed:14718551). Has endonucleolytic activity and can introduce nicks or breaks into double-stranded DNA, suggesting a role in DNA repair (PubMed:14718551). The secreted form acts as an extracellular mitogen and stimulates cell migration and proliferation (PubMed:19483673)","subcellular_location":"Cytoplasm; Nucleus; Cytoplasmic granule; Secreted; Secreted, extracellular exosome; Cytoplasm, P-body","url":"https://www.uniprot.org/uniprotkb/P67809/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/YBX1","classification":"Common Essential","n_dependent_lines":1193,"n_total_lines":1208,"dependency_fraction":0.9875827814569537},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX21","stoichiometry":10.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"DDX6","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"IGF2BP1","stoichiometry":0.2},{"gene":"LSM14A","stoichiometry":0.2},{"gene":"LSM14B","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YBX1","total_profiled":1310},"omim":[{"mim_id":"621228","title":"LONG INTERGENIC NONCODING RNA 1013; LINC01013","url":"https://www.omim.org/entry/621228"},{"mim_id":"620544","title":"PPP1R13B DIVERGENT TRANSCRIPT, NONCODING; PPP1R13BDT","url":"https://www.omim.org/entry/620544"},{"mim_id":"619668","title":"DEOXYRIBOSE-PHOSPHATE ALDOLASE; DERA","url":"https://www.omim.org/entry/619668"},{"mim_id":"611894","title":"MICRO RNA 140; MIR140","url":"https://www.omim.org/entry/611894"},{"mim_id":"601231","title":"MECHANISTIC TARGET OF RAPAMYCIN; MTOR","url":"https://www.omim.org/entry/601231"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":1910.6}],"url":"https://www.proteinatlas.org/search/YBX1"},"hgnc":{"alias_symbol":["YB-1","YB1","DBPB","NSEP-1","MDR-NF1","BP-8","CSDB","CSDA2"],"prev_symbol":["NSEP1"]},"alphafold":{"accession":"P67809","domains":[{"cath_id":"2.40.50.140","chopping":"53-125","consensus_level":"high","plddt":93.7607,"start":53,"end":125}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P67809","model_url":"https://alphafold.ebi.ac.uk/files/AF-P67809-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P67809-F1-predicted_aligned_error_v6.png","plddt_mean":61.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=YBX1","jax_strain_url":"https://www.jax.org/strain/search?query=YBX1"},"sequence":{"accession":"P67809","fasta_url":"https://rest.uniprot.org/uniprotkb/P67809.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P67809/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P67809"}},"corpus_meta":[{"pmid":"25957686","id":"PMC_25957686","title":"Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25957686","citation_count":736,"is_preprint":false},{"pmid":"12815724","id":"PMC_12815724","title":"The pleiotropic functions of the Y-box-binding protein, YB-1.","date":"2003","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/12815724","citation_count":432,"is_preprint":false},{"pmid":"33361760","id":"PMC_33361760","title":"CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1.","date":"2020","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33361760","citation_count":371,"is_preprint":false},{"pmid":"24217978","id":"PMC_24217978","title":"YB-1 protein: functions and regulation.","date":"2013","source":"Wiley interdisciplinary reviews. 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cytosolic retention is mediated by region 247–267 which is cleaved during activation.\",\n      \"method\": \"Biochemical fractionation, oligo(dT) affinity chromatography, immunoprecipitation, RNase treatment, reporter gene assays, nuclear localization imaging\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical methods in one study establishing mechanism of mRNA-release-dependent nuclear translocation\",\n      \"pmids\": [\"11390977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"YB-1 binds specifically to RNA containing 8-oxoguanine (oxidized RNA) but not normal RNA; domain deletion mapping identified the regions required for this binding; expression of YB-1 in E. coli confers resistance to oxidative stress in a binding-activity-dependent manner.\",\n      \"method\": \"In vitro RNA-binding assays with purified protein, deletion mutant analysis, bacterial oxidative-stress resistance assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — purified protein in vitro binding with mutagenesis, functional validation in bacterial model\",\n      \"pmids\": [\"12379116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"YB-1 represses IFN-γ-induced transcription of class II MHC genes (HLA-DR) and the Invariant chain gene by binding the Y element (inverted CCAAT box) in their promoters.\",\n      \"method\": \"Co-transfection of YB-1 expression vector with promoter-reporter constructs, transient transfection with >70% efficiency, mRNA and antigen expression analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter assays with exogenous YB-1 plus endogenous gene expression readout, two complementary approaches\",\n      \"pmids\": [\"8163940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"YB-1 localizes to human mitochondria, contributes to mitochondrial mismatch-binding and mismatch-repair activity, and its depletion increases mitochondrial DNA mutagenesis; mitochondrial MMR is distinct from nuclear MMR and does not require canonical nuclear MMR factors such as MSH2.\",\n      \"method\": \"Subcellular fractionation, mitochondrial extract MMR assays, siRNA depletion, mitochondrial DNA mutagenesis quantification\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fractionation combined with functional biochemical repair assay and genetic depletion with defined readout\",\n      \"pmids\": [\"19272840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Extracellular secreted YB-1 acts as a ligand for Notch-3 receptor (but not Notch-1), interacting with its extracellular domain; this interaction activates Notch-3 signaling, leading to nuclear translocation of the Notch-3 intracellular domain and upregulation of Notch target genes.\",\n      \"method\": \"Co-immunoprecipitation, co-localization at cell membranes (GFP fusion), reporter assays for Notch target genes, binding specificity assays comparing Notch-1 vs Notch-3\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and localization data with functional Notch reporter readout, single lab\",\n      \"pmids\": [\"19640841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HSP60 binds to YB-1 at the YB-NLS region in the cytoplasm, and this interaction regulates YB-1 polysome association and subcellular distribution; HSP60 overexpression decreases YB-1 in heavy-sedimenting polysome fractions and suppresses YB-NLS-mediated nuclear import.\",\n      \"method\": \"Co-immunoprecipitation, sucrose gradient sedimentation, overexpression/knockdown of HSP60, nuclear localization assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding mapped to YB-NLS with functional consequence on polysome association and nuclear import, single lab\",\n      \"pmids\": [\"19470374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"YB-1 interacts with tubulin and microtubules and stimulates microtubule assembly in vitro; high-resolution microscopy shows YB-1 coats the outer microtubule wall; tubulin binding interferes with RNA:YB-1 complexes.\",\n      \"method\": \"In vitro microtubule assembly assays, electron microscopy, atomic force microscopy, co-sedimentation assays, RNA competition assays\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with structural imaging, single lab\",\n      \"pmids\": [\"18793384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"tRNA-derived fragments (tRFs) from tRNA(Glu), tRNA(Asp), tRNA(Gly), and tRNA(Tyr) suppress the stability of oncogenic transcripts by displacing their 3'UTRs from YBX1; these tRFs share a common motif matching the YBX1 recognition sequence, demonstrating sequence-specific displacement of mRNAs from YBX1.\",\n      \"method\": \"RNA-binding protein immunoprecipitation, LNA loss-of-function, synthetic RNA mimetics gain-of-function, in vitro displacement assays, invasion/metastasis assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (RIP, LNA, synthetic mimetics), mechanistic model validated in vitro and in vivo\",\n      \"pmids\": [\"25957686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YB-1 directly binds to and translationally activates the 5'UTR of G3BP1 mRNA, controlling G3BP1 protein availability for stress granule (SG) nucleation; YB-1 inactivation dramatically reduces G3BP1 protein and SG formation.\",\n      \"method\": \"Direct RNA binding assays (5'UTR), translational reporter assays, YB-1 siRNA knockdown, in vivo xenograft SG formation analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct 5'UTR binding demonstrated, translational activation validated with multiple methods including in vivo\",\n      \"pmids\": [\"25800057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HACE1 E3 ubiquitin ligase polyubiquitinates YB-1 via non-canonical K27-linked ubiquitin chains; this ubiquitination promotes YB-1 interaction with TSG101 (a component of the MVB pathway) and is required for YB-1 extracellular secretion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, secretion assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific E3 ligase identified with K27-linkage characterization and TSG101 interaction, single lab\",\n      \"pmids\": [\"26343856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Transportin-1 mediates YB-1 nuclear import; YB-1 and transportin-1 form a complex in HeLa cell extracts; nuclear import is abolished by a transportin-1 competitor substrate, the transportin-1 inhibitor M9M, and inactivating mutations in the transportin-1-dependent NLS (P201A/Y202A).\",\n      \"method\": \"In vitro nuclear import assay, co-immunoprecipitation from cell extracts, site-directed mutagenesis of NLS, pharmacological inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro transport assay with mutagenesis of NLS and pharmacological inhibition, multiple orthogonal approaches\",\n      \"pmids\": [\"27794479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YB-1 phosphorylation at serine 102 promotes its nuclear translocation and CCL5 promoter binding; calcineurin (CN) dephosphorylates YB-1 at S102, reducing its CCL5 transcriptional activation; YB-1/CN interact directly by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, reporter assays, calcineurin inhibitor (cyclosporine A) treatment in vivo and in vitro, phospho-specific antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, ChIP, functional promoter assays, in vivo pharmacological validation across multiple systems\",\n      \"pmids\": [\"24947514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Class I HDAC inhibitor MS-275 promotes YB-1 acetylation at lysine-81, blocking its binding to 5'UTRs of NFE2L2 (NRF2), HIF1A, and G3BP1 mRNAs and thereby reducing their translation; an MS-275-resistant YB-1(K81A) mutant restores translational activation of these targets and metastatic capacity.\",\n      \"method\": \"Global acetylomics, in vivo metastasis assays, MS-275-resistant point mutant (K81A), mRNA binding assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — acetylomics identifies modification site, mutagenesis (K81A) functionally validates it, in vivo rescue experiment\",\n      \"pmids\": [\"31668005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YB-1 CSD with C-terminal extension (CSDex) adopts a rigid structure (not disordered); phosphorylation of S102 destabilizes the protein and causes partial unfolding; CSDex provides a unique DNA binding site recognizing a broader set of sequences than the canonical CSD; S102 phosphorylation dramatically reduces ssDNA binding.\",\n      \"method\": \"Crystal structure determination, NMR structural characterization, DNA binding assays with phosphomimetic and deletion mutants\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation by mutagenesis and DNA-binding assays\",\n      \"pmids\": [\"32710623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JAK2V617F phosphorylates YB-1 post-translationally; YBX1 inactivation in JAK2-mutated cells causes RNA mis-splicing, intron retention, and disruption of ERK signaling control; YBX1 functions as a splicing factor maintaining disease persistence in myeloproliferative neoplasms.\",\n      \"method\": \"In-depth phosphoproteome profiling, genetic inactivation (CRISPR/shRNA), in vivo mouse and primary human cell models, RNA-seq (splicing analysis)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphoproteomics identifies modification, genetic inactivation with defined splicing phenotype replicated in mouse and human primary cells\",\n      \"pmids\": [\"33239784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YBX1 undergoes liquid-liquid phase separation (LLPS) in vitro and in cells; YBX1 condensates selectively recruit miR-223 in vitro and sort it into exosomes; point mutations inhibiting LLPS impair YBX1 incorporation into biomolecular condensates and perturb miR-223 sorting into exosomes.\",\n      \"method\": \"LLPS in vitro assays, live-cell imaging of condensates, point mutagenesis of phase-separation residues, exosome miRNA quantification\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of LLPS, mutagenesis with functional exosome sorting readout\",\n      \"pmids\": [\"34766549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YB-1 is a global translation inhibitor that binds a wide range of mRNAs; YBX1 knockout leads to compensatory upregulation of YB-3 translation, which binds a strikingly similar set of mRNAs and substitutes for YB-1 in global translational repression.\",\n      \"method\": \"Ribo-Seq, RIP-Seq, YBX1 knockout cell lines\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — genome-wide ribosome profiling and RIP-Seq in knockout cells, orthogonal methods\",\n      \"pmids\": [\"31944153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ybx1 interacts with PRC2, highly overlaps PRC2 binding genome-wide, controls PRC2 distribution, and inhibits H3K27me3 levels in neural progenitor cells; Ybx1 knockout increases H3K27me3 and PRC2 enzymatic inhibition partially rescues gene expression and NPC functions.\",\n      \"method\": \"Co-immunoprecipitation (Ybx1-PRC2), ChIP-seq, Ybx1 knockout mice and NPCs, PRC2 inhibitor rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, genome-wide ChIP-seq, genetic knockout with pharmacological rescue establishing epistatic relationship\",\n      \"pmids\": [\"32792512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YB-1 dephosphorylation at serine residues 102, 165, and 176 increases accessibility of the nuclear localization signal (NLS) by altering protein conformation, facilitating nuclear entry during late G2/M phase; live-cell imaging shows YB-1 is primarily perinuclear during G1/S and enters the nucleus at late G2/M.\",\n      \"method\": \"Confocal microscopy, live-cell imaging, mass spectrometry (phosphorylation mapping), atomistic molecular dynamics simulations\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging plus MS-based phosphorylation mapping with MD simulations, single lab\",\n      \"pmids\": [\"32013098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Inhibition of RNA polymerase II activity results in nuclear accumulation of YB-1 accompanied by its phosphorylation at Ser102; kinase inhibition reduces YB-1 phosphorylation and nuclear accumulation; nuclear RNA is required for nuclear retention of YB-1.\",\n      \"method\": \"RNAPII inhibitor treatment, kinase inhibitors, subcellular fractionation, immunofluorescence, RNA depletion experiments\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological perturbations with defined localization readout, single lab\",\n      \"pmids\": [\"31906126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YB-1 phosphorylation at Ser209 (by Akt kinase in vitro) inhibits YB-1 nuclear translocation and prevents S102-phosphorylation-mediated nuclear import; phosphomimetic S209E substitution blocks nuclear entry.\",\n      \"method\": \"In vitro Akt kinase assay, phosphomimetic substitutions (S209E), subcellular localization assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus phosphomimetic mutagenesis with localization readout, single lab\",\n      \"pmids\": [\"35008856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YB-1 unwinds mRNA secondary structures without ATP consumption using its cold shock domain to destabilize RNA stem/loops and its unstructured C-terminal domain to secure RNA unwinding; at endogenous levels YB-1 facilitates stress granule disassembly, and overexpression inhibits SG assembly.\",\n      \"method\": \"In vitro RNA unwinding assays, unwinding-defective mutants, arsenite stress granule assays in HeLa cells, live-cell imaging\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of RNA unwinding with domain mutants, cellular functional validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34469566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YBX1 promotes translation of oncogenic transcripts including MYC by recruitment to polysomal chains; YBX1 genetic inactivation displaces MYC and other oncogenic drivers from polysomes, depleting their protein levels and reducing leukemia cell competitive fitness.\",\n      \"method\": \"Polysome fractionation, genetic inactivation (CRISPR), in vitro and in vivo competitive assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polysome profiling with genetic inactivation, in vivo validation, single lab\",\n      \"pmids\": [\"34465866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"YB-1 acts as a potent cofactor of PARP1, stimulating its poly(ADP-ribose) polymerase activity; the C-terminal domain of YB-1 is indispensable for PARP1 stimulation; functional interactions between YB-1 and PARP1 can be mediated by poly(ADP-ribose).\",\n      \"method\": \"In vitro PARP1 activity assays with purified YB-1, domain deletion analysis, PAR binding assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with domain mapping, single lab\",\n      \"pmids\": [\"29805738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YB-1 forms stable homo-multimers cooperatively on specific mRNAs (but not others), enabling selective translational inhibition of mRNAs on which stable multimers form; the same cooperative multimerization mechanism also operates on specific DNA structures.\",\n      \"method\": \"In vitro binding and multimerization assays, translation reporter assays, DNA binding studies\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution demonstrating cooperative multimerization with functional translation inhibition, single lab\",\n      \"pmids\": [\"26271991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"YB-1 synthesis is regulated by the mTOR signaling pathway; inhibition of mTOR with PP242 (but not rapamycin) specifically suppresses YB-1 translation; this dependence is dictated by the 5'UTR of YB-1 mRNA as shown by reporter constructs.\",\n      \"method\": \"mTOR inhibitor treatment (PP242/rapamycin), reporter constructs with YB-1 5'UTR, Western and Northern blotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway perturbation plus reporter construct 5'UTR mapping, single lab\",\n      \"pmids\": [\"23285076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CircRNA-SORE binds YBX1 in the cytoplasm, preventing its interaction with E3 ubiquitin ligase PRP19 and thus blocking PRP19-mediated YBX1 degradation; this stabilizes YBX1 and confers sorafenib resistance in hepatocellular carcinoma.\",\n      \"method\": \"RNA pulldown, co-immunoprecipitation, in vitro and in vivo models, siRNA knockdown\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown and Co-IP identify the circRNA-YBX1-PRP19 relationship with functional ubiquitination readout, single lab\",\n      \"pmids\": [\"33361760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YB-1 binds the 5'UTR of CCT4 mRNA to promote CCT4 translation; CCT4 (a CCT chaperone component) activates mTOR signaling by promoting mLST8 folding; YB-1 also autoregulates its own translation by binding its 5'UTR, sustaining mTOR activation.\",\n      \"method\": \"RNA immunoprecipitation, 5'UTR reporter assays, genetic knockdown, xenograft model with RNA decoys, co-expression analysis in patient samples\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and reporter assays establishing 5'UTR binding and translational activation, in vivo RNA decoy validation, single lab\",\n      \"pmids\": [\"35239512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBL (fibrillarin) interacts with YBX1 and promotes its nuclear accumulation in response to DNA damage; nuclear YBX1 binds the BRCA1 promoter to activate BRCA1 expression, supporting homologous recombination-mediated DNA repair.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, knockdown experiments, DNA damage repair assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP establishing FBL-YBX1 interaction and promoter binding, single lab\",\n      \"pmids\": [\"37489617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YB-1 binds to HIF-1α by co-immunoprecipitation and to hypoxia-response element (HRE) sequences (single- and double-stranded) by DNA binding assays; under hypoxia, YB-1 translocates to the nucleus and represses HIF-1α-mediated EPO transcription.\",\n      \"method\": \"Co-immunoprecipitation, DNA binding assays, siRNA depletion, reporter assays, immunofluorescence for nuclear shuttling\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and DNA binding with functional reporter assay, single lab\",\n      \"pmids\": [\"27524241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cytoplasmic YB-1 directly stabilizes Col1a1 mRNA to promote renal fibrosis; conversely, nuclear (S102-phosphorylated) YB-1 represses the Col1a1 promoter; forced nuclear YB-1 shuttling by small molecule HSc025 is anti-fibrotic in vivo.\",\n      \"method\": \"mRNA stability assays, subcellular fractionation, YB-1 half-knockout mouse model, small molecule nuclear shuttling, fibrosis quantification in vivo\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic compartment-specific functions validated in knockout mice and with pharmacological tool, in vivo rescue\",\n      \"pmids\": [\"27591085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YB-1 promotes microtubule-dependent trafficking and recycling of MT1-MMP to cell surface invasion sites, increasing breast cancer invasion and metastasis.\",\n      \"method\": \"YB-1/EGFP transfection, immunofluorescence localization to invadopodia, MT1-MMP endocytosis/recycling rate measurements, in vivo tumor formation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization to invadopodia with trafficking kinetics and in vivo tumor phenotype, single lab\",\n      \"pmids\": [\"20599698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"YB-1 represses AP-1-dependent transcription and directly binds to the AP-1 DNA sequence; a 49 kDa YB-1 protein was purified from cancer cells by DNA-affinity chromatography and confirmed by tandem MS and immunoblotting to bind the AP-1 sequence specifically.\",\n      \"method\": \"DNA-affinity chromatography (NAPSTER assay), tandem MS sequencing, gel mobility supershift assays, luciferase reporter transfection assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical purification and direct DNA binding with functional reporter assay, single lab\",\n      \"pmids\": [\"15702969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"YB-1 inhibits p53-dependent apoptotic gene transactivation (e.g., Bax) without affecting p53-mediated activation of CDKN1A or MDM2; nuclear YB-1 selectively alters p53 transcriptional activity; transcriptionally active p53 is required for YB-1 nuclear localization.\",\n      \"method\": \"Co-transfection reporter assays, apoptosis assays, Bax protein quantification, p53-null and p53-expressing cell comparisons\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional selectivity demonstrated with multiple promoter reporters and endogenous target proteins, single lab\",\n      \"pmids\": [\"16158057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"YB-1 directly binds the MACC1 promoter (demonstrated by ChIP) and activates MACC1 transcription, thereby activating the MACC1/c-Met signaling pathway to promote lung adenocarcinoma progression.\",\n      \"method\": \"ChIP assay, promoter reporter assays, siRNA knockdown, xenograft mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay with in vivo validation, single lab\",\n      \"pmids\": [\"28624808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YB-1 directly binds and represses the p16 (CDKN2A/INK4a) promoter as demonstrated by ChIP; YB1 overexpression decreases p16 expression and promotes cell proliferation while preventing cellular senescence.\",\n      \"method\": \"ChIP assay, overexpression in mouse embryonic fibroblasts, senescence-associated β-galactosidase assay\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence with functional proliferation/senescence readout, single lab\",\n      \"pmids\": [\"24165022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"YB-1 and dbpA bind the lower strand of the SICR (stress-inducible change region) within the grp78 core promoter element and repress stress-inducible (ER stress) transcription; YB-1 interacts with YY1 (identified by yeast two-hybrid) and inhibits YY1 binding to the core element.\",\n      \"method\": \"Expression library screening, gel shift assays, co-transfection reporter assays, yeast interaction trap (two-hybrid)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gel shifts plus functional reporter assays plus two-hybrid identification of YY1 interaction, single lab\",\n      \"pmids\": [\"8972186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YB-1 depletion causes cytokinesis failure and multinucleation; phosphorylation at six serine residues (including novel sites identified by mass spectrometry) is essential for cytokinesis completion; phosphorylated YB-1 orchestrates spatio-temporal distribution of microtubules, β-actin, and the chromosome passenger complex (CPC) to define the cleavage plane.\",\n      \"method\": \"siRNA knockdown in multiple cell lines, rescue experiments, confocal live-cell imaging, mass spectrometry-based phosphorylation site mapping, atomistic modelling\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion with rescue, imaging of cytokinesis machinery, MS phosphosite mapping, single lab\",\n      \"pmids\": [\"32882852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YB-1 is SUMOylated in a circadian-clock-controlled manner in zebrafish; circadian changes in YB-1 SUMOylation regulate its periodic nuclear entry; nuclear YB-1 directly binds the cyclin A2 promoter and downregulates cyclin A2 mRNA expression.\",\n      \"method\": \"SUMOylation assays, live zebrafish imaging, ChIP on cyclin A2 promoter, circadian cycle analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and direct SUMOylation detection with functional gene expression readout, zebrafish ortholog\",\n      \"pmids\": [\"28008157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"YB-1 interacts with YBX1 target DNA/mRNA structures via cooperative homo-multimerization; YB-1 promotes XPC-HR23B binding to DNA containing bulky NER lesions, and YB-1 and XPC-HR23B mutually stimulate each other's binding to damaged DNA substrates.\",\n      \"method\": \"In vitro DNA binding assays with NER substrate mimics, competition/stimulation binding assays with purified proteins\",\n      \"journal\": \"Biochemistry. Biokhimiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins and defined DNA substrates, single lab\",\n      \"pmids\": [\"25756536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YBX1 and NOD2 directly interact (demonstrated by co-immunoprecipitation and sucrose gradient co-migration); GMDP (muramyl peptide) stimulates formation of higher-molecular-mass YBX1-NOD2 complexes; both YBX1 and NOD2 contribute independently to GMDP-induced NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, sucrose gradient centrifugation, NOD2/YBX1 siRNA knockdown, NF-κB reporter assay\",\n      \"journal\": \"Innate immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with functional reporter and separate knockdown controls, single lab\",\n      \"pmids\": [\"27694635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RSK2 phosphorylates YB-1 at Ser102, promoting formation of a YB-1/KLF5 transcriptional complex that co-regulates BLBC-specific genes (KRT16, Ly6D); YB-1 also stabilizes KLF5 mRNA in an RNA 5-methylcytosine modification-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, luciferase reporter assays, RSK inhibitor (LJH685), mRNA stability assays, in vivo xenograft\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and mRNA stability with pharmacological inhibition and in vivo validation, single lab\",\n      \"pmids\": [\"35022570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZO-1 physically interacts with YB-1 in endothelial cells; arsenite treatment decreases ZO-1/YB-1 interaction and drives YB-1 into stress granules; YB-1 is essential for stress granule formation and for the cytoprotective effects of ZO-1 downregulation during angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, arsenite stress granule assays, endothelial-specific ZO-1 knockout mice, confocal imaging of YB-1 granules in retinal vasculature\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with in vivo genetic knockout model and functional angiogenesis readout, single lab\",\n      \"pmids\": [\"38782923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YB-1 mediates TNF-induced NF-κB activation by maintaining expression of TRAF2, a central component of the TNFR1 signaling complex; YB-1-deficient cells show reduced TRAF2 expression and enhanced apoptosis in response to TNF.\",\n      \"method\": \"YB-1 knockout/knockdown cells, TNF stimulation, NF-κB reporter assays, caspase-3 activation, zVAD rescue\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic depletion with defined molecular (TRAF2) and functional (apoptosis) readout, single lab\",\n      \"pmids\": [\"32764479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"YB-1 stabilizes HIV-1 genomic RNA by binding to the stem loop 2 of the HIV-1 RNA packaging signal (mapped as the YB-1-responsive element), thereby enhancing HIV-1 protein expression and viral production.\",\n      \"method\": \"YB-1 overexpression/knockdown in producer cells, viral production quantification, RNA stability assays, deletion mapping of responsive element\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with RNA element mapping, single lab\",\n      \"pmids\": [\"23589019\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YBX1 is a multifunctional cold-shock domain RNA/DNA-binding protein that operates as a context-dependent translational repressor or activator (binding mRNA 5'UTRs and 3'UTRs), a transcription factor (activating or repressing promoters depending on cofactors and phosphorylation state), a splicing factor downstream of JAK2, a stress granule regulator (suppressing SG assembly via ATP-independent mRNA unwinding and promoting G3BP1 translation), a mitochondrial mismatch-repair factor, and an extracellular Notch-3 ligand; its activities are regulated by phosphorylation (primarily at S102 by Akt/RSK2, and dephosphorylation by calcineurin), acetylation (K81 by HDAC-dependent mechanism), ubiquitination (K27-linked by HACE1 for secretion; PRP19-mediated for degradation), and SUMOylation, which together control its subcellular localization (cytoplasmic retention vs. nuclear import via transportin-1) and its selective engagement with mRNA targets, chromatin, and protein partners including PRC2, PARP1, p53, NF-κB/TRAF2, HIF-1α, and Notch-3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YBX1 is a multifunctional cold-shock-domain protein that governs gene expression at both the RNA and DNA levels, operating as a global translational regulator, a sequence-specific transcription factor, and a stress-response coordinator [#0, #17, #14]. In the cytoplasm it binds mRNA at or near the cap, stabilizing transcripts and displacing eIF4E [#0], and acts as a broad translational repressor whose loss is compensated by upregulation of the paralog YB-3 [#17]; it forms cooperative homo-multimers on selected mRNAs and DNA structures to confer target selectivity [#25]. At specific 5'UTRs it switches to translational activation, driving production of G3BP1, NFE2L2, HIF1A, and CCT4, the last of which feeds back to sustain mTOR signaling alongside YBX1 autoregulation [#9, #13, #28]. Through G3BP1 control and ATP-independent unwinding of mRNA secondary structure via its cold-shock and disordered C-terminal domains, YBX1 modulates stress granule assembly and disassembly [#9, #22], and it phase-separates into condensates that sort miR-223 into exosomes [#16]. In the nucleus YBX1 binds promoter elements to either repress (class II MHC Y-box, AP-1, p16/CDKN2A, grp78, p53 apoptotic targets, HIF-1\\u03b1-driven EPO) or activate (CCL5, MACC1, BRCA1) transcription depending on cofactors and modification state [#3, #33, #36, #37, #34, #30, #12, #35, #29]. Its CSD plus C-terminal extension forms a rigid module that recognizes a broad set of DNA sequences, and phosphorylation at S102 destabilizes the fold and reduces ssDNA binding [#14]. Nucleocytoplasmic partitioning is the master control point: nuclear import proceeds through transportin-1 recognition of an NLS [#11], and is gated by phosphorylation (S102 promotes import; calcineurin dephosphorylation and S209 phosphorylation oppose it), SUMOylation, cell-cycle stage, and partner interactions with HSP60 and FBL [#12, #21, #19, #39, #6, #29]. YBX1 stability and secretion are set by ubiquitination, with HACE1-mediated K27-linked chains routing it through TSG101 for extracellular release and PRP19-mediated chains targeting it for degradation [#10, #27]. Additional activities include mitochondrial mismatch repair [#4], stimulation of PARP1 and assistance of XPC-HR23B in DNA repair [#24, #40], JAK2-dependent splicing control in myeloproliferative neoplasms [#15], PRC2-coupled regulation of H3K27me3 [#18], and roles in cytokinesis, microtubule-dependent MT1-MMP trafficking, NF-\\u03baB signaling, and as an extracellular Notch-3 ligand [#38, #32, #44, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that YBX1 is a sequence-specific transcriptional repressor, binding the inverted CCAAT (Y) element to silence inducible immune genes.\",\n      \"evidence\": \"Co-transfection of YB-1 with promoter-reporter constructs and endogenous MHC II gene readout\",\n      \"pmids\": [\"8163940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the modifications or cofactors that gate this repression\", \"No structural basis for Y-element recognition\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the dual cytoplasmic function of YBX1 as a cap-dependent mRNA stabilizer and an activation-by-cleavage transcription factor, linking mRNA release to nuclear translocation.\",\n      \"evidence\": \"In vitro mRNA stability and cap-competition assays; biochemical fractionation and thrombin-induced proteolysis with reporter assays\",\n      \"pmids\": [\"11574481\", \"11390977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological protease and trigger for cleavage in non-thrombin contexts unresolved\", \"Relationship between cap binding and eIF4E displacement at endogenous loci not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed YBX1 recognizes oxidatively damaged RNA, implicating it in RNA quality control under oxidative stress.\",\n      \"evidence\": \"In vitro binding to 8-oxoguanine RNA with deletion mutants and bacterial oxidative-stress resistance assay\",\n      \"pmids\": [\"12379116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fate of bound oxidized RNA in mammalian cells unknown\", \"Whether this binding alters translation of damaged transcripts untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended YBX1 function beyond the nucleus/cytoplasm to mitochondrial mismatch repair and to extracellular Notch-3 ligand activity, revealing a remarkably broad localization repertoire.\",\n      \"evidence\": \"Mitochondrial fractionation with MMR assays and mtDNA mutagenesis quantification; co-IP and Notch reporter assays distinguishing Notch-3 from Notch-1\",\n      \"pmids\": [\"19272840\", \"19640841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial import mechanism and partner repair factors unidentified\", \"Notch-3 ligand role rests on a single lab without independent confirmation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how YBX1 achieves mRNA-target selectivity and how it controls stress granule biogenesis, linking translational control to RNA homeostasis.\",\n      \"evidence\": \"Cooperative multimerization and translation reporter assays; 5'UTR binding/translational activation of G3BP1; tRF-mediated displacement of 3'UTRs from YBX1 (RIP, LNA, synthetic mimetics)\",\n      \"pmids\": [\"26271991\", \"25800057\", \"25957686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis distinguishing multimerizing from non-multimerizing targets unclear\", \"How tRF abundance is set physiologically not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified transportin-1 as the import receptor and converging phosphorylation/SUMOylation inputs as the switch controlling YBX1 nuclear access and compartment-specific transcriptional outputs.\",\n      \"evidence\": \"In vitro nuclear import assays with NLS mutagenesis and M9M inhibition; S102/calcineurin co-IP and ChIP; HIF-1\\u03b1 co-IP and HRE binding; circadian SUMOylation with cyclin A2 ChIP in zebrafish\",\n      \"pmids\": [\"27794479\", \"24947514\", \"27524241\", \"28008157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of competing phospho/SUMO signals into a single localization decision not unified\", \"Stimulus specificity of each input incompletely mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated compartment-segregated, opposing functions of YBX1 on the same target gene (cytoplasmic mRNA stabilization vs nuclear promoter repression), providing a clean in vivo model of localization-dependent activity.\",\n      \"evidence\": \"mRNA stability assays, half-knockout mice, and small-molecule nuclear shuttling in a renal fibrosis model\",\n      \"pmids\": [\"27591085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this compartmental antagonism generalizes beyond Col1a1 untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected YBX1 to DNA repair pathways as a PARP1 cofactor and an XPC-HR23B partner, broadening its DNA-associated roles beyond transcription.\",\n      \"evidence\": \"In vitro PARP1 activity assays with domain deletions; NER substrate binding/stimulation assays with purified proteins\",\n      \"pmids\": [\"29805738\", \"25756536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro reconstitution awaits cellular validation of repair contribution\", \"C-terminal domain mechanism of PARP1 stimulation not structurally defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pinpointed K81 acetylation as a regulatory switch that disables 5'UTR binding and translational activation of oncogenic targets, defining a druggable post-translational control point.\",\n      \"evidence\": \"Acetylomics, MS-275 treatment, K81A rescue mutant, mRNA binding and in vivo metastasis assays\",\n      \"pmids\": [\"31668005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase responsible for K81 not identified\", \"Interplay between acetylation and phosphorylation at adjacent sites unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the structural and mechanistic foundation for YBX1 as a global translation repressor, an ATP-independent RNA chaperone, a PRC2-coupled chromatin regulator, and a JAK2-dependent splicing factor, with the CSDex defining its DNA-binding breadth.\",\n      \"evidence\": \"Crystal/NMR structure with phosphomimetic DNA-binding assays; Ribo-Seq/RIP-Seq in knockouts; in vitro unwinding with domain mutants; Co-IP/ChIP-seq with PRC2; phosphoproteomics and RNA-seq in JAK2V617F models\",\n      \"pmids\": [\"32710623\", \"31944153\", \"34469566\", \"32792512\", \"33239784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single protein partitions between repression, unwinding, splicing, and chromatin roles in one cell is unresolved\", \"Direct structural model of YBX1-PRC2 contact lacking\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established phase separation as the mechanism for selective miR-223 sorting into exosomes and refined the multi-site phospho-code controlling cell-cycle-timed nuclear entry and cytokinesis.\",\n      \"evidence\": \"In vitro LLPS with phase-separation mutants and exosome miRNA quantification; live-cell imaging with MS phosphosite mapping and MD simulations across cell-cycle and cytokinesis studies\",\n      \"pmids\": [\"34766549\", \"32013098\", \"32882852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of selective miRNA recruitment into condensates incompletely defined\", \"Kinases for individual cell-cycle phosphosites not all assigned\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped ubiquitin-dependent control of YBX1 fate, with K27-linked chains (HACE1) driving secretion via TSG101 and PRP19-mediated chains driving degradation, the latter blockable by a stabilizing circRNA.\",\n      \"evidence\": \"Ubiquitination/co-IP and secretion assays for HACE1-K27-TSG101; RNA pulldown/co-IP and ubiquitination readout for circRNA-SORE/PRP19\",\n      \"pmids\": [\"26343856\", \"33361760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals selecting between secretory and degradative ubiquitination unknown\", \"Both findings rest on single labs\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed YBX1 directly promotes polysomal translation of MYC and other oncogenic drivers, tying its translational activity to malignant fitness.\",\n      \"evidence\": \"Polysome fractionation with CRISPR inactivation and competitive in vivo assays\",\n      \"pmids\": [\"34465866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Distinction from global repressor role on the same transcripts not mechanistically reconciled\", \"Recruitment determinants to polysomes undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected YBX1 to endothelial stress-granule biology through ZO-1 sequestration, defining a stress-released pool that drives cytoprotective granule formation in vivo.\",\n      \"evidence\": \"Co-IP, arsenite stress granule assays, and endothelial ZO-1 knockout mice with retinal vasculature imaging\",\n      \"pmids\": [\"38782923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal regulation of ZO-1 by YBX1 not established\", \"Single-lab finding awaiting independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How YBX1's many activities are coordinated within a single cell\\u2014which modifications, partners, and condensate states select among translation repression/activation, transcription, splicing, repair, and secretion\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking post-translational code to functional state selection\", \"Quantitative partitioning of YBX1 pools across compartments and condensates unmeasured\", \"Endogenous physiological triggers for many in vitro activities undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 8, 9, 17, 22, 25, 28, 45]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 14, 25, 30, 33, 35, 36, 37, 40]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 12, 29, 30, 33, 34, 35, 36, 37, 42]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 9, 13, 17, 23, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [24, 18, 44]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 32, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 6, 22, 31]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 11, 12, 14, 20, 29, 30, 31, 34, 36, 39]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7, 32, 38]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [18, 29, 33, 35, 36, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 12, 29, 30, 33, 34, 35, 36, 37, 42]},\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": [0, 9, 17, 22, 23, 28]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 15, 16, 17, 25]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 9, 22, 43]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4, 24, 29, 40]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [41, 44]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 12, 35, 42, 44]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PARP1\", \"PRC2\", \"HIF1A\", \"NOD2\", \"TRAF2\", \"FBL\", \"HSP60\", \"TJP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}