{"gene":"PTBP1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1992,"finding":"PTBP1 (hnRNP I) is a nuclear RNA-binding protein that associates with polypyrimidine tracts on hnRNA; it is released from hnRNP complexes by micrococcal nuclease digestion more readily than most hnRNP proteins (nuclease hypersensitivity), suggesting binding to exposed regions of hnRNA-protein complexes. Immunofluorescence revealed a unique localization in the nucleoplasm plus a discrete perinucleolar structure.","method":"Micrococcal nuclease digestion of hnRNP complexes; immunofluorescence microscopy; cDNA cloning and sequencing","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical fractionation and immunofluorescence in a single focused study; multiple orthogonal methods but single lab","pmids":["1641332"],"is_preprint":false},{"year":1997,"finding":"Nuclear localization of PTBP1 (hnRNP I) is directed by a 60-amino-acid bipartite sequence at the amino terminus (designated NLD-I), which is both necessary and sufficient for nuclear import, as demonstrated by fusion to a cytoplasmic reporter protein.","method":"Transient transfection of hnRNP I domain fusions to chloramphenicol acetyltransferase reporter; subcellular localization assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct domain-deletion/fusion experiment with functional readout; single lab, single method","pmids":["9281380"],"is_preprint":false},{"year":1999,"finding":"Xenopus PTBP1 homolog VgRBP60 binds the Vg1 mRNA localization element and is required for cytoplasmic RNA localization in Xenopus oocytes; specific base changes that abolish localization in vivo also abolish VgRBP60 binding in vitro, and hnRNP I colocalizes with Vg1 RNA in the vegetal cytoplasm.","method":"In vitro RNA-binding assays with mutant localization elements; immunolocalization and in situ hybridization in Xenopus oocytes","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal in vitro binding and in vivo colocalization, two orthogonal methods, single lab","pmids":["10518224"],"is_preprint":false},{"year":2000,"finding":"The human HNRNPI gene (chromosome 19) generates three protein isoforms (hnRNP I / PTB, PTB2, PTB3) through alternative splicing of a single gene transcript; the chromosome 14 locus is a non-expressed processed pseudogene.","method":"RT-PCR, EST database analysis, genomic DNA sequencing of intron-exon boundaries","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular characterization of gene structure and isoforms; single lab, two orthogonal approaches","pmids":["11024286"],"is_preprint":false},{"year":2007,"finding":"PTB/hnRNP I is required for remodeling of the Vg1 RNP during cytoplasmic RNA transport in Xenopus oocytes; it promotes dissociation of Vg1RBP/vera from Vg1 RNA, and mutations blocking this remodeling event abolish vegetal localization.","method":"RNA-protein interaction assays; loss-of-function experiments with remodeling-blocking mutations; vegetal localization assays in Xenopus oocytes","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic/biochemical dissection of RNP remodeling in a model organism; multiple orthogonal methods, single lab","pmids":["18039852"],"is_preprint":false},{"year":2007,"finding":"PTBP1 (hnRNP I/PTB) can antagonize splicing repression imposed by SRp30c: PTB competes with SRp30c for binding to the CE9 intronic element, reduces SRp30c binding in nuclear extract, stimulates splicing to a downstream 3' splice site, and relieves CE9-mediated splicing repression in vitro and in vivo.","method":"RNA affinity chromatography; in vitro splicing assays with His-tagged PTB; in vivo splicing reporter assays","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted splicing assays plus in vivo validation, multiple orthogonal methods in one study","pmids":["17548433"],"is_preprint":false},{"year":2009,"finding":"Zebrafish hnRNP I (PTBP1 ortholog) inhibits Notch signaling by destabilizing the Notch intracellular domain (NICD); overexpression of hnRNP I promotes NICD turnover requiring the C-terminal RAM domain of NICD, and this activity is conserved from zebrafish to human.","method":"Zebrafish brom bones mutant characterization; co-immunoprecipitation; NICD stability/turnover assays; conservation assay in human cells","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in zebrafish plus biochemical domain mapping; single lab, multiple methods","pmids":["19197356"],"is_preprint":false},{"year":2009,"finding":"PTBP1 knockdown in human glioma cells slows proliferation and inhibits migration and adhesion; PTBP1 promotes exon 3 skipping of RTN4 (Nogo), and overexpression of the exon-3-containing RTN4 isoform decreases proliferation to a similar degree as PTBP1 removal, placing RTN4 splicing downstream of PTBP1 in glioma growth.","method":"siRNA knockdown; Affymetrix Exon Array; isoform overexpression; cell proliferation, migration, and adhesion assays","journal":"Brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD phenotype plus epistasis via isoform rescue; single lab, multiple orthogonal methods","pmids":["19506066"],"is_preprint":false},{"year":2012,"finding":"PTBP1 interacts with miRNAs (including let-7) and with human Argonaute 2 (hAgo2) through RNA, and genetically interacts with C. elegans let-7 pathway, indicating a conserved role for PTBP1 in modulating miRNA-mediated gene regulation.","method":"Biotinylated miRNA inhibitor affinity purification; co-immunoprecipitation; C. elegans genetic interaction assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification plus genetic epistasis in two organisms; single lab","pmids":["22427970"],"is_preprint":false},{"year":2015,"finding":"Linc-RoR interacts with PTBP1 (hnRNP I) and requires PTBP1 to bind c-Myc mRNA, thereby stabilizing c-Myc mRNA and promoting c-Myc expression; this interaction is distinct from Linc-RoR's inhibitory interaction with AUF1.","method":"RNA immunoprecipitation; RNA pulldown; c-Myc mRNA stability assays; knockdown/rescue experiments","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus RNA pulldown plus stability assays; single lab, multiple orthogonal methods","pmids":["26656491"],"is_preprint":false},{"year":2016,"finding":"PTBP1 promotes production of PKM2 (cancer-specific pyruvate kinase isoform) over PKM1 through alternative splicing of the PKM gene; miR-1 and miR-133b suppress this Warburg-effect-promoting activity by silencing PTBP1, switching isoform expression from PKM2 to PKM1 and increasing ROS.","method":"Ectopic miRNA expression; isoform-specific RT-PCR for PKM1/PKM2; in vitro and in vivo tumor models; ROS measurement","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined splicing phenotype; in vitro and in vivo; single lab","pmids":["26980745"],"is_preprint":false},{"year":2016,"finding":"PTBP1 and PTBP2 repress non-conserved cryptic exons using CU microsatellites; they also repress conserved tissue-specific exons, with repression titrated to generate transcriptome diversity needed for neuronal differentiation.","method":"RNA-seq after PTBP1/PTBP2 knockdown; bioinformatic identification of CU microsatellite binding motifs; minigene splicing assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome-wide KD analysis plus motif identification; single lab, multiple methods","pmids":["27681424"],"is_preprint":false},{"year":2016,"finding":"PTBP1 and PTBP2 display both redundant and distinct roles in neuronal pre-mRNA splicing; a PTBP1 knockin allele rescues forebrain-specific but not pan-neuronal Ptbp2 knockout, indicating functional differences not arising from differential RNA binding but potentially from different cofactor interactions.","method":"Conditional knockin mouse genetics; Ptbp2 knockout; transcriptome-wide RNA binding comparison; behavioral and developmental phenotype analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with knockin/knockout mouse models plus transcriptome-wide binding comparison; rigorous multi-method study","pmids":["27926877"],"is_preprint":false},{"year":2016,"finding":"PTBP1 directly binds MCL1 mRNA and destabilizes it; knockdown of PTBP1 stabilizes MCL1 mRNA, increases MCL1 protein, and protects cancer cells from antitubulin agent-induced apoptosis in a MCL1-dependent manner.","method":"RNA immunoprecipitation; mRNA stability assays; PTBP1 knockdown; MCL1 rescue experiments; apoptosis assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus mRNA stability plus epistasis rescue; single lab, multiple orthogonal methods","pmids":["27367564"],"is_preprint":false},{"year":2016,"finding":"PTBP1 directly binds the proximal poly(A) signal of CD5 mRNA and affects its stability or poly(A) site selection during T-cell activation, fine-tuning CD5 expression levels.","method":"siRNA depletion of PTBP1; quantification of CD5 mRNA isoforms; 3'-UTR reporter assays","journal":"European journal of immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA depletion experiment with reporter assay; limited mechanistic resolution","pmids":["27005442"],"is_preprint":false},{"year":2018,"finding":"PTBP1 is required for progression of germinal center B cells through late S phase and for affinity maturation; it directly regulates alternative splicing and abundance of transcripts induced during positive selection to promote proliferation.","method":"Conditional PTBP1 knockout in B cells; flow cytometry cell cycle analysis; RNA-seq; immunization experiments","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular phenotype plus transcriptome-wide splicing analysis; rigorous multi-method study","pmids":["29358707"],"is_preprint":false},{"year":2018,"finding":"PTBP1 enhances miR-101-guided AGO2 interaction with MCL1 mRNA, thereby facilitating miR-101-induced MCL1 repression and apoptosis; PTBP1 cooperates with miRISC on a shared target mRNA.","method":"Co-immunoprecipitation of AGO2; miR-101 overexpression; PTBP1 knockdown; apoptosis and clonogenic assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP/Co-IP plus functional apoptosis assays; single lab, multiple methods","pmids":["29748555"],"is_preprint":false},{"year":2018,"finding":"PTBP1 and PTBP2 have distinct phosphorylation patterns in their N-terminal, linker 1, and linker 2 regions, and overlapping acetylation in their RRMs with unique sites in PTBP1 RRM2 and RRM3; lysine residues in the PTBP2 nuclear localization sequence are acetylated, suggesting post-translational modifications contribute to their differential splicing activities.","method":"Mass spectrometry analysis of PTMs in in vitro splicing reaction mixtures","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-quality MS identification of PTMs; single lab, descriptive rather than functionally validated","pmids":["29851470"],"is_preprint":false},{"year":2018,"finding":"PTBP1 promotes full-length hTERT splicing and telomerase activity; knockdown of PTBP1 reduces hTERT FL splicing, shortens telomere length, and PTBP1 interacts with hTERT pre-mRNA in a NOVA1-dependent manner as shown by RNA pulldown.","method":"PTBP1 stable knockdown; RT-PCR for hTERT isoforms; RNA pulldown; telomere length measurement","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown plus functional splicing/telomere phenotype; single lab, multiple methods","pmids":["30568224"],"is_preprint":false},{"year":2018,"finding":"PTBP1 contributes to spermatogenesis by regulating spermatogonia proliferation; germ cell-specific Ptbp1 knockout mice show retarded neonatal spermatogonia proliferation and progressive decline in sperm count, and PTBP1 deletion in germline stem cells causes proliferation arrest and increased apoptosis in vitro.","method":"Cre-loxP conditional knockout mice; histology; in vitro germline stem cell culture with hydroxytamoxifen-induced deletion; flow cytometry apoptosis assay","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular phenotype in vivo and in vitro; single lab","pmids":["30416150"],"is_preprint":false},{"year":2019,"finding":"PTBP1 directly binds the 5'-UTR of AXL mRNA via its RRM1 domain and reduces AXL mRNA stability without affecting transcription rate, leading to decreased AXL expression and promoting apoptosis.","method":"RNA immunoprecipitation; mRNA stability assays; RRM1 domain mutation; transcription run-on assay; PTBP1/PTBP2 overexpression comparison","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus stability assays plus domain mutagenesis; single lab, multiple methods","pmids":["31729427"],"is_preprint":false},{"year":2019,"finding":"PTBP1 binds to and regulates the stability of SLC31A1 (copper transporter) mRNA, confirmed by RNA immunoprecipitation, dual-luciferase reporter assay, and RNA stability detection; knockdown of PTBP1 upregulates SLC31A1 and enhances cisplatin sensitivity in osteosarcoma cells.","method":"RNA immunoprecipitation; dual-luciferase reporter assay; mRNA stability assay; transcriptome sequencing; xenograft model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus reporter plus stability assays; single lab, multiple orthogonal methods","pmids":["32207235"],"is_preprint":false},{"year":2019,"finding":"PTBP1 enhances cyclin D3 (CCND3) translation by interacting with the 5'-UTR of CCND3 mRNA, facilitating cell cycle progression in hepatocellular carcinoma cells.","method":"RNA immunoprecipitation; luciferase 5'-UTR reporter; PTBP1 knockdown with CCND3 protein measurement","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus reporter assay; single lab, two orthogonal methods","pmids":["31301177"],"is_preprint":false},{"year":2019,"finding":"Ptbp1 is essential for BCR-mediated B-cell activation and antibody production; B-cell-specific Ptbp1-deficient mice have severely reduced natural antibodies, defective BCR-mediated activation, and impaired plasmablast generation in response to both T-independent and T-dependent antigens.","method":"B-cell-specific conditional knockout mice; serum antibody measurement by ELISA; immunization with NP-Ficoll and NP-CGG; flow cytometry","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined immune phenotype; single lab","pmids":["30476084"],"is_preprint":false},{"year":2019,"finding":"PTBP1 mRNA isoforms differ in their 5'- and 3'-UTRs and protein-coding region splicing; eIF3 binds differentially to each PTBP1 mRNA isoform in a cell-cycle-dependent manner, with eIF3 binding correlating with repression of PTBP1 protein during S phase, indicating translational regulation of PTBP1 levels during the cell cycle.","method":"5'/3' end mapping; ribosome profiling; eIF3 RIP; cell cycle synchronization; Western blot","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus cell-cycle-synchronized protein measurement; single lab, multiple methods","pmids":["31263002"],"is_preprint":false},{"year":2020,"finding":"PTBP1 promotes ATPase-dependent dissociation of UPF1 from potential NMD target mRNAs, protecting them from nonsense-mediated decay; this mechanism depends on UPF1's tendency to release RNA upon ATP binding/hydrolysis and is coordinated by a regulatory loop in UPF1 domain 1B. PTBP1 does not require direct competition for binding sites but displaces already-bound UPF1.","method":"In vitro helicase activity assays; UPF1 dissociation from purified mRNPs; transcriptome-wide UPF1 CLIP-seq; domain mutagenesis of UPF1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified components plus transcriptome-wide validation and mutagenesis; single lab but multiple orthogonal methods","pmids":["32571872"],"is_preprint":false},{"year":2020,"finding":"PTBP1 and HNRNPK are essential RNA-binding proteins for SINEUP lncRNA-mediated translational upregulation; they contribute to SINEUP RNA subcellular distribution and assembly of translational initiation complexes, leading to enhanced target mRNA translation.","method":"Co-transfection; subcellular fractionation; co-immunoprecipitation; translation assays in HEK293T cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus fractionation plus translation assay; single lab, multiple methods","pmids":["33130894"],"is_preprint":false},{"year":2020,"finding":"LUCAT1 lncRNA interacts with PTBP1 in colorectal cancer cells and facilitates association of DNA damage-related gene transcripts with PTBP1, leading to altered alternative splicing of those genes; ectopic PTBP1 expression rescues the effects of LUCAT1 knockdown.","method":"RNA immunoprecipitation; alternative splicing analysis by RNA-seq; PTBP1 rescue experiment; in vivo xenograft","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP plus epistasis rescue; single lab, multiple methods","pmids":["31964396"],"is_preprint":false},{"year":2021,"finding":"PTBP1 is required for germinal center B cells receiving T cell help to express the c-MYC-dependent gene program and to progress through late S phase; it directly regulates alternative splicing and transcript abundance of genes upregulated during positive selection.","method":"Conditional PTBP1 knockout; flow cytometry cell cycle analysis; RNA-seq for splicing and transcript abundance; in vivo immunization","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined proliferation phenotype plus transcriptome-wide splicing analysis; multi-method single rigorous study","pmids":["29358707"],"is_preprint":false},{"year":2021,"finding":"SON regulates PTBP1-mediated oncogenic splicing in glioblastoma: SON knockdown causes intron retention in the PTBP1 transcript, reducing PTBP1 protein and inhibiting downstream oncogenic splicing events. SON also forms a complex with hnRNP A2B1 and antagonizes RBFOX2 activity.","method":"PTBP1 RNA-seq splicing analysis; SON knockdown; RT-PCR for PTBP1 intron retention; co-immunoprecipitation; orthotopic xenograft model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splicing analysis plus Co-IP plus in vivo model; single lab, multiple methods","pmids":["34548489"],"is_preprint":false},{"year":2021,"finding":"MALAT1 lncRNA interacts with PTBP1 and promotes USP8 mRNA degradation through this interaction; reduced USP8 then regulates ubiquitination and stability of TAK1, promoting macrophage pyroptosis and inflammation in liver fibrosis.","method":"RNA pulldown; RNA immunoprecipitation; mRNA stability assay; co-immunoprecipitation; protein degradation assay; m6A methylated RIP","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown plus RIP plus mRNA stability assays; single lab, multiple orthogonal methods","pmids":["34839365"],"is_preprint":false},{"year":2021,"finding":"PTBP1 deficiency in dendritic cells increases MHC II expression, perturbs T-cell homeostasis, and regulates PKM alternative splicing and a subset of IFN response genes without affecting DC development.","method":"DC-specific Ptbp1 conditional knockout; flow cytometry; RNA-seq for splicing; antitumor and asthma models","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined immune and splicing phenotypes; single lab, multiple methods","pmids":["33421118"],"is_preprint":false},{"year":2022,"finding":"Ptbp1 deficiency in endothelial cells reverses low-disturbed-flow-induced RNA splicing patterns in the NF-κB pathway and inhibits NF-κB nuclear translocation and transcriptional activation of Icam1 and Vcam1; endothelial-specific Ptbp1 deletion reduces myeloid cell infiltration and atherosclerosis in vivo; Ptbp1 promotes inclusion of a conserved alternative exon in Ripk1, reducing Ripk1 protein.","method":"CRISPR Cas9 KO screen; endothelial-specific conditional knockout; RNA splicing analysis; NF-κB nuclear translocation assay; in vivo atherosclerosis model","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus conditional KO with defined molecular and in vivo vascular phenotype; multiple methods across in vitro and in vivo","pmids":["35858420"],"is_preprint":false},{"year":2022,"finding":"PTBP1 promotes hematopoietic stem cell self-renewal and erythroid differentiation by ensuring ribosome biogenesis and translation of mRNAs encoding ribosomal proteins; PTBP1 deficiency causes splicing defects and upregulation of a specific CDC42 isoform that partly mimics the protein-synthesis defect.","method":"Hematopoietic compartment-specific PTBP1 deletion; RNA-seq for splicing; ribosome biogenesis assays; polysome profiling; CDC42 isoform overexpression","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO plus ribosome assays plus epistasis via isoform rescue; single lab, multiple methods","pmids":["35545054"],"is_preprint":false},{"year":2022,"finding":"PTBP1 interacts with hnRNPH1 in Sertoli cells to regulate alternative pre-mRNA splicing of cell adhesion-related target genes; this interaction is required for blood-testis barrier function and normal spermatogenesis.","method":"Sertoli cell-specific hnRNPH1 knockout; co-immunoprecipitation; alternative splicing analysis by RNA-seq","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus splicing analysis in conditional KO context; single lab, multiple methods","pmids":["36718792"],"is_preprint":false},{"year":2022,"finding":"PTBP1 and PTBP2 interact with distinct sets of proteins under splicing conditions: PTBP1 interacts with many mRNA processing and splicing regulators while PTBP2 does not; both interact with chromatin remodeling and transcription proteins; potential 'writers' and 'erasers' of PTM modifications on PTBPs were identified.","method":"In vitro splicing system; mass spectrometry identification of interacting proteins","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — MS-based interactome under defined splicing conditions; single lab, descriptive","pmids":["35113929"],"is_preprint":false},{"year":2023,"finding":"Integrative structural modeling of PTBP1 bound to an EMCV IRES RNA fragment reveals strong compaction and ordering of both RNA and protein with residual conformational flexibility; PTBP1 acts as an RNA chaperone organizing the IRES RNA into a few distinct conformations with RNA stems exposed outward.","method":"NMR; mass spectrometry; small-angle scattering; integrative structural modeling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — integrative structural determination with multiple orthogonal biophysical methods; single study but rigorous multi-method approach","pmids":["37833274"],"is_preprint":false},{"year":2023,"finding":"PTBP1-associated RNA loops determined by CRIC-seq reveal positional rules: loops within individual introns promote cassette exon inclusion by accelerating asymmetric intron removal, while loops spanning across cassette exons repress splicing; cancer-related splicing QTLs can disrupt these RNA loops by reducing PTBP1 binding.","method":"Capture RIC-seq (CRIC-seq) for in situ RNA-RNA proximity ligation; bioinformatic analysis of loop positions; splicing outcome prediction","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — novel transcriptome-wide structural method with mechanistic validation and disease-relevant findings; single rigorous study with multiple orthogonal approaches","pmids":["36958328"],"is_preprint":false},{"year":2023,"finding":"PTBP1 activates co-transcriptional splicing of hundreds of introns in pluripotent stem cells; retention of a PTBP1-dependent intron in DNMT3B triggers NMD of DNMT3B transcripts, reducing DNMT3B levels in developing neurons and protecting differentiation-specific genes from ectopic methylation.","method":"Acute PTBP1 depletion (dTAG system); analysis of chromatin- and RNA Pol II-associated nascent transcripts; RNA-seq; bisulfite sequencing for methylation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — acute depletion with nascent transcript analysis plus epigenetic readout; multiple orthogonal methods in a rigorous single study","pmids":["36626906"],"is_preprint":false},{"year":2023,"finding":"In adult peripheral sensory neurons, PTBP1 is co-expressed with PTBP2 (PTBP2 restricted to nucleus, PTBP1 also axonal); axonal PTBP1 levels increase after peripheral nerve injury, where it associates with mRNAs for importin β1 (KPNB1) and RHOA; PTBP1 perturbation affects local axonal translation, nociceptor regeneration, and thermal/mechanical sensation.","method":"Immunofluorescence and subcellular fractionation; axonal mRNA co-IP; local translation assays; sensory phenotyping after PTBP1 perturbation","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization plus RIP plus functional sensory phenotype; single lab, multiple methods","pmids":["37506203"],"is_preprint":false},{"year":2023,"finding":"PTBP1 directly binds the 5'-UTR of NCOA4 mRNA and promotes NCOA4 translation, thereby mediating ferroptosis in liver cancer cells; the PTBP1-binding region was mapped to the 5'-UTR by RNA pulldown, and PTBP1 silencing decreases NCOA4-mediated ferritinophagy.","method":"RNA pulldown; dual-luciferase assay; cycloheximide chase (PTBP1 KD did not affect NCOA4 protein stability); xenograft model","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown plus reporter plus in vivo; single lab, multiple methods","pmids":["36660932"],"is_preprint":false},{"year":2023,"finding":"PTBP1 interacts with RALY to regulate exon 5 splicing of DNMT3B (from DNMT3B-S to DNMT3B-L isoform); DNMT3B-L then induces promoter methylation of DUSP2, suppressing DUSP2 expression and increasing radioresistance in prostate cancer cells.","method":"Co-immunoprecipitation; splicing analysis by RT-PCR; PTBP1/RALY knockdown; bisulfite sequencing; in vitro and in vivo irradiation models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus splicing analysis plus epigenetic readout; single lab, multiple methods","pmids":["39287090"],"is_preprint":false},{"year":2023,"finding":"MIR99AHG lncRNA binds and stabilizes PTBP1, and the complex promotes inclusion of exon 13 in SMARCA1 pre-mRNA (producing SMARCA1-L isoform) by altering PTBP1 binding to splice sites on intron 12; SMARCA1-L, unlike SMARCA1, promotes invadopodia formation and invasion in colorectal cancer.","method":"RNA pulldown; RNA immunoprecipitation; splicing minigene assays; MIR99AHG knockdown; invasion assays; patient CRC tissue analysis","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown plus RIP plus splicing analysis; single lab, multiple methods","pmids":["37725664"],"is_preprint":false},{"year":2024,"finding":"PTBP1 inhibits NDUFS2 third exon skipping in cardiomyocytes by directly binding to PTBP1 in the nucleus; loss of DCRT lncRNA releases PTBP1 to promote NDUFS2 exon skipping, and the resulting NDUFS2 isoform impairs mitochondrial complex I activity and antioxidant function, causing dilated cardiomyopathy.","method":"CRISPR-Cas9 DCRT knockout mice; RNA immunoprecipitation; chromatin co-IP; isoform sequencing; mitochondrial complex I activity assay","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus RIP plus functional mitochondrial assays plus isoform sequencing; rigorous multi-method study","pmids":["38841852"],"is_preprint":false},{"year":2024,"finding":"PTBP1 K266 crotonylation (by KAT2B) enhances PTBP1 interaction with hnRNPA1/A2 and promotes PKM alternative splicing toward PKM2, increasing glycolysis and colorectal cancer progression; K266 crotonylation also enhances RNA-binding capacity.","method":"Crotonylation proteomics; immunoprecipitation; RNA immunoprecipitation; point mutagenesis (K266); in vitro/in vivo CRC models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM identification plus mutagenesis plus RIP plus splicing analysis; single lab, multiple methods","pmids":["39497094"],"is_preprint":false},{"year":2024,"finding":"PTBP1 deficiency in endothelial cells leads to left ventricular noncompaction by reducing endothelial cell migration via altered alternative splicing of β-arrestin-1 (Arrb1), which disrupts cardiomyocyte proliferation during cardiac development.","method":"Endothelial-specific Ptbp1 conditional knockout; RNA splicing analysis; migration assays; cardiac morphology/histology","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cardiac phenotype plus splicing mechanism; single lab, multiple methods","pmids":["37002228"],"is_preprint":false},{"year":2024,"finding":"PSMD14 (a deubiquitinating enzyme) directly interacts with PTBP1, promotes its deubiquitination and stabilization, and thereby sustains PTBP1 protein levels to promote gastric cancer progression.","method":"Co-immunoprecipitation; ubiquitination assay; Western blot; PSMD14/PTBP1 knockdown and rescue","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus rescue experiment; single lab, multiple methods","pmids":["35405117"],"is_preprint":false},{"year":2025,"finding":"PTBP1 K436 lactylation (with SIRT1 as eraser) stabilizes PTBP1 protein by attenuating interaction with TRIM21 E3 ligase and inhibiting proteasomal degradation; K436 lactylation also enhances PTBP1 RNA-binding capacity and promotes PFKFB4 mRNA stabilization, further increasing glycolysis in glioma stem cells.","method":"Lactylation proteomics; site-directed mutagenesis (K436); Co-IP of PTBP1/TRIM21; RNA immunoprecipitation for PFKFB4; SIRT1 delactylation assay; GSC functional assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM mapping plus mutagenesis plus Co-IP plus RIP; single lab, multiple orthogonal methods","pmids":["39570804"],"is_preprint":false},{"year":2024,"finding":"PTBP1 stabilizes TXNIP mRNA by direct binding; PTBP1 knockdown promotes TXNIP mRNA stability, increasing TXNIP-mediated oxidative stress that impairs lysosomal function and blocks autophagic flux in gastric cancer cells.","method":"RNA immunoprecipitation sequencing (si-PTBP1 RIP-seq); mRNA stability assay; ROS and autophagy flux assays; xenograft","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq plus stability assay plus functional autophagy readout; single lab, multiple methods","pmids":["39153986"],"is_preprint":false},{"year":2024,"finding":"Lkb1 regulates PTBP1 expression and through PTBP1 controls alternative splicing of PKM isoforms 1 and 2 in vascular smooth muscle cells; loss of Lkb1 increases PKM2/PKM1 ratio and aerobic glycolysis, driving VSMC transdifferentiation and aortic aneurysm; treatment with PKM2 activator rescues the phenotype.","method":"Smooth muscle cell-specific Lkb1 conditional knockout; single-cell RNA-seq; isoform-specific RT-PCR; PKM2 activator rescue; lineage tracing","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO plus scRNA-seq plus pharmacological rescue; single lab, multiple methods","pmids":["39189621"],"is_preprint":false},{"year":2017,"finding":"PTBP1 directly interacts with c-Myc protein and stabilizes c-Myc by preventing its proteasomal degradation; this is mediated by PTBP1 upregulating USP28 and limiting FBW7-mediated ubiquitination of c-Myc in gastric cancer cells.","method":"Co-immunoprecipitation; ubiquitination assay; Western blot; PTBP1/c-Myc knockdown and rescue","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus rescue; single lab, multiple methods","pmids":["36635500"],"is_preprint":false}],"current_model":"PTBP1 (hnRNP I) is a multifunctional RNA-binding protein that binds polypyrimidine/CU-rich sequences on pre-mRNAs and mRNAs to regulate alternative splicing (promoting or repressing exon inclusion depending on binding position relative to cassette exons, as defined by RNA-loop positional rules), mRNA stability, translation, cytoplasmic mRNA localization, co-transcriptional splicing, and protection from nonsense-mediated decay (by displacing UPF1 in an ATPase-dependent manner); its protein stability and activity are regulated by post-translational modifications including phosphorylation, acetylation, lactylation (K436, inhibiting TRIM21-mediated degradation), and crotonylation (K266, enhancing hnRNPA1/A2 cooperation for PKM splicing), as well as by deubiquitinases (PSMD14) and ubiquitin ligases; in neurons and stem cells, PTBP1 switches from nuclear/cytoplasmic to axonal localization upon injury, where it regulates local translation of regeneration-associated mRNAs; in immune cells, it is required for germinal center B-cell proliferation, BCR-mediated antibody production, and endothelial NF-κB priming; and it controls cardiac, vascular, hematopoietic, and spermatogonial development through tissue-specific splicing programs."},"narrative":{"mechanistic_narrative":"PTBP1 (hnRNP I) is a polypyrimidine/CU-rich-tract-binding RNA protein that governs alternative splicing and a broader post-transcriptional program controlling cell proliferation, differentiation, and tissue development [PMID:1641332, PMID:27681424, PMID:36958328]. As a splicing regulator it represses cryptic and tissue-specific cassette exons through CU microsatellite elements [PMID:27681424], with the splicing outcome dictated by positional rules: PTBP1-associated RNA loops within a single intron accelerate asymmetric intron removal to promote exon inclusion, whereas loops spanning a cassette exon repress it [PMID:36958328]. It can also antagonize repression by competing with other splicing factors for intronic elements [PMID:17548433], and acts as an RNA chaperone that compacts and orders structured RNAs such as viral IRES elements [PMID:37833274]. Beyond splicing, PTBP1 controls mRNA fate in the cytoplasm: it binds 5'-UTRs to modulate stability or translation of targets including AXL, CCND3, and NCOA4 [PMID:31729427, PMID:31301177, PMID:36660932], destabilizes transcripts such as MCL1 [PMID:27367564], and protects mRNAs from nonsense-mediated decay by promoting ATPase-dependent displacement of UPF1 [PMID:32571872]. PTBP1 directs cell-type-specific programs across many tissues — germinal center B-cell proliferation and antibody production [PMID:29358707, PMID:30476084], endothelial NF-κB priming and atherosclerosis through Ripk1 splicing [PMID:35858420], hematopoietic stem cell self-renewal via ribosomal protein translation [PMID:35545054], spermatogonial proliferation [PMID:30416150], and cardiac development, where misregulated NDUFS2 exon skipping impairs mitochondrial complex I and causes dilated cardiomyopathy [PMID:38841852]. A recurrent oncogenic theme is PTBP1-driven PKM splicing toward the PKM2 isoform to promote glycolysis [PMID:26980745, PMID:39189621]. PTBP1 protein abundance and RNA-binding activity are themselves tuned by post-translational modifications including K266 crotonylation and K436 lactylation, and by ubiquitin-system enzymes such as the deubiquitinase PSMD14 and the E3 ligase TRIM21 [PMID:39497094, PMID:35405117, PMID:39570804].","teleology":[{"year":1992,"claim":"Established PTBP1 as a nuclear hnRNP that binds polypyrimidine tracts on nascent transcripts, defining its founding biochemical activity.","evidence":"Micrococcal nuclease fractionation of hnRNP complexes and immunofluorescence","pmids":["1641332"],"confidence":"Medium","gaps":["No splicing or downstream functional readout in this study","Perinucleolar localization left mechanistically unexplained"]},{"year":1997,"claim":"Mapped an N-terminal bipartite nuclear localization domain, explaining how PTBP1 reaches its site of action.","evidence":"Domain-fusion to a cytoplasmic reporter and subcellular localization assay","pmids":["9281380"],"confidence":"Medium","gaps":["Does not address regulated nuclear/cytoplasmic shuttling","No link to function of cytoplasmic pools"]},{"year":1999,"claim":"Linked PTBP1 to cytoplasmic mRNA localization, showing it binds a localization element required for vegetal RNA transport.","evidence":"Reciprocal in vitro RNA binding and in vivo colocalization in Xenopus oocytes","pmids":["10518224","18039852"],"confidence":"Medium","gaps":["Mechanism of RNP remodeling not resolved at this stage","Generality to mammalian mRNA localization untested"]},{"year":2007,"claim":"Demonstrated PTBP1 acts as a positional splicing regulator that can both repress and, by competing with other factors, activate splice-site usage.","evidence":"RNA affinity chromatography with in vitro and in vivo splicing reporters","pmids":["17548433"],"confidence":"High","gaps":["Single element studied; positional logic not yet generalized","Cofactor competition not structurally defined"]},{"year":2009,"claim":"Connected PTBP1 to disease-relevant phenotypes by showing it controls oncogenic exon choices (RTN4) and can destabilize signaling effectors (NICD).","evidence":"Exon array after siRNA knockdown, isoform rescue, and zebrafish genetics","pmids":["19506066","19197356"],"confidence":"Medium","gaps":["NICD destabilization mechanism distinct from RNA binding not fully defined","Direct binding sites not mapped for all targets"]},{"year":2016,"claim":"Defined transcriptome-wide repression of cryptic and tissue-specific exons via CU microsatellites and distinguished PTBP1 from PTBP2 by cofactor usage rather than RNA-binding specificity.","evidence":"RNA-seq after PTBP1/PTBP2 knockdown, motif analysis, and knockin/knockout mouse genetics","pmids":["27681424","27926877"],"confidence":"High","gaps":["Identity of the distinguishing cofactors not established here","Quantitative rules linking binding to outcome not yet derived"]},{"year":2016,"claim":"Extended PTBP1 function into cytoplasmic mRNA stability control, showing direct binding destabilizes targets such as MCL1 with consequences for apoptosis.","evidence":"RIP, mRNA stability assays, and MCL1 rescue with apoptosis readouts","pmids":["27367564","26980745"],"confidence":"Medium","gaps":["Decay machinery recruited by PTBP1 not identified","Relationship between stability and splicing roles unresolved"]},{"year":2018,"claim":"Established PTBP1 as a developmental and immune regulator, required for germinal center B-cell cell-cycle progression and spermatogonial proliferation.","evidence":"Conditional knockout mice with cell-cycle, immunization, and histology analyses","pmids":["29358707","30416150","30476084"],"confidence":"High","gaps":["Direct splicing targets driving each tissue phenotype only partially defined","Tissue-specific cofactor context not resolved"]},{"year":2018,"claim":"Showed PTBP1 activity and levels are regulated by post-translational modifications and by interactions with miRNA/lncRNA machinery.","evidence":"Mass spectrometry of PTMs in splicing reactions; AGO2 Co-IP and miRNA cooperation assays","pmids":["29851470","29748555","22427970"],"confidence":"Medium","gaps":["Functional consequence of individual PTM sites not validated at this stage","Writer/eraser enzymes not yet assigned"]},{"year":2020,"claim":"Resolved a mechanism by which PTBP1 protects mRNAs from NMD, displacing UPF1 in an ATPase-dependent manner without direct site competition.","evidence":"In vitro helicase/dissociation assays with purified components and transcriptome-wide UPF1 CLIP-seq","pmids":["32571872"],"confidence":"High","gaps":["Which endogenous transcripts are physiologically protected not enumerated","Coordination with co-transcriptional splicing not addressed here"]},{"year":2022,"claim":"Demonstrated PTBP1 drives vascular and hematopoietic programs through specific splicing events (Ripk1, ribosomal protein translation) with in vivo disease consequences.","evidence":"CRISPR screen, endothelial- and hematopoietic-specific conditional knockouts, splicing and ribosome assays, atherosclerosis model","pmids":["35858420","35545054"],"confidence":"High","gaps":["Full set of effector splice events per phenotype incomplete","Crosstalk between translation and splicing roles unresolved"]},{"year":2023,"claim":"Derived the structural and positional logic of PTBP1 splicing regulation via RNA loops, and showed it activates co-transcriptional splicing with epigenetic downstream effects through DNMT3B.","evidence":"CRIC-seq RNA-RNA proximity ligation; acute dTAG depletion with nascent transcript and bisulfite sequencing; integrative structural modeling of an IRES complex","pmids":["36958328","36626906","37833274"],"confidence":"High","gaps":["Determinants of loop formation in vivo not fully defined","Generality of the chaperone model beyond viral IRES untested"]},{"year":2024,"claim":"Showed PTBP1 protein stability and RNA-binding are tuned by metabolic-linked PTMs and ubiquitin-system enzymes, and that PTBP1 controls cardiac and metabolic phenotypes through specific isoform switches.","evidence":"Crotonylation/lactylation proteomics with K266/K436 mutagenesis; PSMD14/TRIM21 Co-IP and ubiquitination assays; conditional knockouts for NDUFS2 and Arrb1 splicing","pmids":["39497094","39570804","35405117","38841852","37002228"],"confidence":"High","gaps":["Hierarchy among competing PTMs not established","How metabolic state feeds back to PTBP1 modification in vivo unclear"]},{"year":null,"claim":"The integrated rules connecting PTBP1 binding position, RNA structure, cofactor identity, and post-translational modification state to a defined splicing or stability outcome in a given cell type remain to be unified into a predictive model.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No single framework links positional loop logic, PTM state, and tissue cofactors","Causal mechanism distinguishing PTBP1 from PTBP2 outcomes not molecularly resolved","Mendelian disease association in humans not established in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,11,13,20,25,37]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[5,11,37,38]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[36]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[22,24,26,40]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[25]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,1,43]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[25,39]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,11,25,37,38]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[38]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[33,43,45]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,23,28,31]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,32,43,49]}],"complexes":[],"partners":["UPF1","AGO2","HNRNPA1","HNRNPH1","RALY","PSMD14","TRIM21","MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P26599","full_name":"Polypyrimidine tract-binding protein 1","aliases":["57 kDa RNA-binding protein PPTB-1","Heterogeneous nuclear ribonucleoprotein I","hnRNP I"],"length_aa":557,"mass_kda":59.6,"function":"Plays a role in pre-mRNA splicing and in the regulation of alternative splicing events. Activates exon skipping of its own pre-mRNA during muscle cell differentiation. Binds to the polypyrimidine tract of introns. May promote RNA looping when bound to two separate polypyrimidine tracts in the same pre-mRNA. May promote the binding of U2 snRNP to pre-mRNA. Cooperates with RAVER1 to modulate switching between mutually exclusive exons during maturation of the TPM1 pre-mRNA. Represses the splicing of MAPT/Tau exon 10 (PubMed:15009664). Binds to polypyrimidine-rich controlling element (PCE) of CFTR and promotes exon skipping of CFTR exon 9, thereby antagonizing TIA1 and its role in exon inclusion of CFTR exon 9 (PubMed:14966131). Plays a role in the splicing of pyruvate kinase PKM by binding repressively to a polypyrimidine tract flanking PKM exon 9, inhibiting exon 9 inclusion and resulting in exon 10 inclusion and production of the PKM M2 isoform (PubMed:20010808). In case of infection by picornaviruses, binds to the viral internal ribosome entry site (IRES) and stimulates the IRES-mediated translation (PubMed:21518806)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P26599/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTBP1","classification":"Not Classified","n_dependent_lines":677,"n_total_lines":1208,"dependency_fraction":0.5604304635761589},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPB2","stoichiometry":0.2},{"gene":"HNRNPL","stoichiometry":0.2},{"gene":"IGF2BP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PTBP1","total_profiled":1310},"omim":[{"mim_id":"621495","title":"STAD SYNDROME; STADS","url":"https://www.omim.org/entry/621495"},{"mim_id":"616328","title":"LONG INTERGENIC NONCODING RNA PINKY","url":"https://www.omim.org/entry/616328"},{"mim_id":"615906","title":"ORC UBIQUITIN LIGASE 1; OBI1","url":"https://www.omim.org/entry/615906"},{"mim_id":"615719","title":"TCL1 UPSTREAM NEURAL DIFFERENTIATION-ASSOCIATED RNA; TUNAR","url":"https://www.omim.org/entry/615719"},{"mim_id":"615240","title":"POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 15; KCTD15","url":"https://www.omim.org/entry/615240"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTBP1"},"hgnc":{"alias_symbol":["HNRPI","HNRNP-I","PTB2","PTB3","PTB-1","PTB4","pPTB"],"prev_symbol":["PTB"]},"alphafold":{"accession":"P26599","domains":[{"cath_id":"3.30.70.330","chopping":"59-155","consensus_level":"high","plddt":81.1723,"start":59,"end":155},{"cath_id":"3.30.70.330","chopping":"182-273","consensus_level":"high","plddt":87.2835,"start":182,"end":273},{"cath_id":"3.30.70.330","chopping":"337-441","consensus_level":"high","plddt":86.2866,"start":337,"end":441},{"cath_id":"3.30.70.330","chopping":"450-525","consensus_level":"high","plddt":89.9341,"start":450,"end":525}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P26599","model_url":"https://alphafold.ebi.ac.uk/files/AF-P26599-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P26599-F1-predicted_aligned_error_v6.png","plddt_mean":70.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTBP1","jax_strain_url":"https://www.jax.org/strain/search?query=PTBP1"},"sequence":{"accession":"P26599","fasta_url":"https://rest.uniprot.org/uniprotkb/P26599.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P26599/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P26599"}},"corpus_meta":[{"pmid":"1641332","id":"PMC_1641332","title":"hnRNP I, the polypyrimidine tract-binding protein: distinct nuclear localization and association with hnRNAs.","date":"1992","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1641332","citation_count":302,"is_preprint":false},{"pmid":"10518224","id":"PMC_10518224","title":"A Xenopus protein related to hnRNP I has a role in cytoplasmic RNA localization.","date":"1999","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/10518224","citation_count":202,"is_preprint":false},{"pmid":"31964396","id":"PMC_31964396","title":"Hypoxia induced LUCAT1/PTBP1 axis modulates cancer cell viability and chemotherapy response.","date":"2020","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31964396","citation_count":136,"is_preprint":false},{"pmid":"34839365","id":"PMC_34839365","title":"The METTL3/MALAT1/PTBP1/USP8/TAK1 axis promotes pyroptosis and M1 polarization of macrophages and contributes to liver fibrosis.","date":"2021","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34839365","citation_count":128,"is_preprint":false},{"pmid":"19506066","id":"PMC_19506066","title":"Splicing factors PTBP1 and PTBP2 promote proliferation and migration of glioma cell lines.","date":"2009","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/19506066","citation_count":127,"is_preprint":false},{"pmid":"32115910","id":"PMC_32115910","title":"Roles of PTBP1 in alternative splicing, glycolysis, and oncogensis.","date":"2020","source":"Journal of Zhejiang University. 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is a nuclear RNA-binding protein that associates with polypyrimidine tracts on hnRNA; it is released from hnRNP complexes by micrococcal nuclease digestion more readily than most hnRNP proteins (nuclease hypersensitivity), suggesting binding to exposed regions of hnRNA-protein complexes. Immunofluorescence revealed a unique localization in the nucleoplasm plus a discrete perinucleolar structure.\",\n      \"method\": \"Micrococcal nuclease digestion of hnRNP complexes; immunofluorescence microscopy; cDNA cloning and sequencing\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical fractionation and immunofluorescence in a single focused study; multiple orthogonal methods but single lab\",\n      \"pmids\": [\"1641332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Nuclear localization of PTBP1 (hnRNP I) is directed by a 60-amino-acid bipartite sequence at the amino terminus (designated NLD-I), which is both necessary and sufficient for nuclear import, as demonstrated by fusion to a cytoplasmic reporter protein.\",\n      \"method\": \"Transient transfection of hnRNP I domain fusions to chloramphenicol acetyltransferase reporter; subcellular localization assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct domain-deletion/fusion experiment with functional readout; single lab, single method\",\n      \"pmids\": [\"9281380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Xenopus PTBP1 homolog VgRBP60 binds the Vg1 mRNA localization element and is required for cytoplasmic RNA localization in Xenopus oocytes; specific base changes that abolish localization in vivo also abolish VgRBP60 binding in vitro, and hnRNP I colocalizes with Vg1 RNA in the vegetal cytoplasm.\",\n      \"method\": \"In vitro RNA-binding assays with mutant localization elements; immunolocalization and in situ hybridization in Xenopus oocytes\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vitro binding and in vivo colocalization, two orthogonal methods, single lab\",\n      \"pmids\": [\"10518224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The human HNRNPI gene (chromosome 19) generates three protein isoforms (hnRNP I / PTB, PTB2, PTB3) through alternative splicing of a single gene transcript; the chromosome 14 locus is a non-expressed processed pseudogene.\",\n      \"method\": \"RT-PCR, EST database analysis, genomic DNA sequencing of intron-exon boundaries\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular characterization of gene structure and isoforms; single lab, two orthogonal approaches\",\n      \"pmids\": [\"11024286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTB/hnRNP I is required for remodeling of the Vg1 RNP during cytoplasmic RNA transport in Xenopus oocytes; it promotes dissociation of Vg1RBP/vera from Vg1 RNA, and mutations blocking this remodeling event abolish vegetal localization.\",\n      \"method\": \"RNA-protein interaction assays; loss-of-function experiments with remodeling-blocking mutations; vegetal localization assays in Xenopus oocytes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic/biochemical dissection of RNP remodeling in a model organism; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18039852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTBP1 (hnRNP I/PTB) can antagonize splicing repression imposed by SRp30c: PTB competes with SRp30c for binding to the CE9 intronic element, reduces SRp30c binding in nuclear extract, stimulates splicing to a downstream 3' splice site, and relieves CE9-mediated splicing repression in vitro and in vivo.\",\n      \"method\": \"RNA affinity chromatography; in vitro splicing assays with His-tagged PTB; in vivo splicing reporter assays\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted splicing assays plus in vivo validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17548433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Zebrafish hnRNP I (PTBP1 ortholog) inhibits Notch signaling by destabilizing the Notch intracellular domain (NICD); overexpression of hnRNP I promotes NICD turnover requiring the C-terminal RAM domain of NICD, and this activity is conserved from zebrafish to human.\",\n      \"method\": \"Zebrafish brom bones mutant characterization; co-immunoprecipitation; NICD stability/turnover assays; conservation assay in human cells\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in zebrafish plus biochemical domain mapping; single lab, multiple methods\",\n      \"pmids\": [\"19197356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PTBP1 knockdown in human glioma cells slows proliferation and inhibits migration and adhesion; PTBP1 promotes exon 3 skipping of RTN4 (Nogo), and overexpression of the exon-3-containing RTN4 isoform decreases proliferation to a similar degree as PTBP1 removal, placing RTN4 splicing downstream of PTBP1 in glioma growth.\",\n      \"method\": \"siRNA knockdown; Affymetrix Exon Array; isoform overexpression; cell proliferation, migration, and adhesion assays\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD phenotype plus epistasis via isoform rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19506066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTBP1 interacts with miRNAs (including let-7) and with human Argonaute 2 (hAgo2) through RNA, and genetically interacts with C. elegans let-7 pathway, indicating a conserved role for PTBP1 in modulating miRNA-mediated gene regulation.\",\n      \"method\": \"Biotinylated miRNA inhibitor affinity purification; co-immunoprecipitation; C. elegans genetic interaction assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification plus genetic epistasis in two organisms; single lab\",\n      \"pmids\": [\"22427970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Linc-RoR interacts with PTBP1 (hnRNP I) and requires PTBP1 to bind c-Myc mRNA, thereby stabilizing c-Myc mRNA and promoting c-Myc expression; this interaction is distinct from Linc-RoR's inhibitory interaction with AUF1.\",\n      \"method\": \"RNA immunoprecipitation; RNA pulldown; c-Myc mRNA stability assays; knockdown/rescue experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus RNA pulldown plus stability assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26656491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PTBP1 promotes production of PKM2 (cancer-specific pyruvate kinase isoform) over PKM1 through alternative splicing of the PKM gene; miR-1 and miR-133b suppress this Warburg-effect-promoting activity by silencing PTBP1, switching isoform expression from PKM2 to PKM1 and increasing ROS.\",\n      \"method\": \"Ectopic miRNA expression; isoform-specific RT-PCR for PKM1/PKM2; in vitro and in vivo tumor models; ROS measurement\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined splicing phenotype; in vitro and in vivo; single lab\",\n      \"pmids\": [\"26980745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PTBP1 and PTBP2 repress non-conserved cryptic exons using CU microsatellites; they also repress conserved tissue-specific exons, with repression titrated to generate transcriptome diversity needed for neuronal differentiation.\",\n      \"method\": \"RNA-seq after PTBP1/PTBP2 knockdown; bioinformatic identification of CU microsatellite binding motifs; minigene splicing assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome-wide KD analysis plus motif identification; single lab, multiple methods\",\n      \"pmids\": [\"27681424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PTBP1 and PTBP2 display both redundant and distinct roles in neuronal pre-mRNA splicing; a PTBP1 knockin allele rescues forebrain-specific but not pan-neuronal Ptbp2 knockout, indicating functional differences not arising from differential RNA binding but potentially from different cofactor interactions.\",\n      \"method\": \"Conditional knockin mouse genetics; Ptbp2 knockout; transcriptome-wide RNA binding comparison; behavioral and developmental phenotype analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with knockin/knockout mouse models plus transcriptome-wide binding comparison; rigorous multi-method study\",\n      \"pmids\": [\"27926877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PTBP1 directly binds MCL1 mRNA and destabilizes it; knockdown of PTBP1 stabilizes MCL1 mRNA, increases MCL1 protein, and protects cancer cells from antitubulin agent-induced apoptosis in a MCL1-dependent manner.\",\n      \"method\": \"RNA immunoprecipitation; mRNA stability assays; PTBP1 knockdown; MCL1 rescue experiments; apoptosis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus mRNA stability plus epistasis rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27367564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PTBP1 directly binds the proximal poly(A) signal of CD5 mRNA and affects its stability or poly(A) site selection during T-cell activation, fine-tuning CD5 expression levels.\",\n      \"method\": \"siRNA depletion of PTBP1; quantification of CD5 mRNA isoforms; 3'-UTR reporter assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA depletion experiment with reporter assay; limited mechanistic resolution\",\n      \"pmids\": [\"27005442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTBP1 is required for progression of germinal center B cells through late S phase and for affinity maturation; it directly regulates alternative splicing and abundance of transcripts induced during positive selection to promote proliferation.\",\n      \"method\": \"Conditional PTBP1 knockout in B cells; flow cytometry cell cycle analysis; RNA-seq; immunization experiments\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular phenotype plus transcriptome-wide splicing analysis; rigorous multi-method study\",\n      \"pmids\": [\"29358707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTBP1 enhances miR-101-guided AGO2 interaction with MCL1 mRNA, thereby facilitating miR-101-induced MCL1 repression and apoptosis; PTBP1 cooperates with miRISC on a shared target mRNA.\",\n      \"method\": \"Co-immunoprecipitation of AGO2; miR-101 overexpression; PTBP1 knockdown; apoptosis and clonogenic assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP/Co-IP plus functional apoptosis assays; single lab, multiple methods\",\n      \"pmids\": [\"29748555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTBP1 and PTBP2 have distinct phosphorylation patterns in their N-terminal, linker 1, and linker 2 regions, and overlapping acetylation in their RRMs with unique sites in PTBP1 RRM2 and RRM3; lysine residues in the PTBP2 nuclear localization sequence are acetylated, suggesting post-translational modifications contribute to their differential splicing activities.\",\n      \"method\": \"Mass spectrometry analysis of PTMs in in vitro splicing reaction mixtures\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-quality MS identification of PTMs; single lab, descriptive rather than functionally validated\",\n      \"pmids\": [\"29851470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTBP1 promotes full-length hTERT splicing and telomerase activity; knockdown of PTBP1 reduces hTERT FL splicing, shortens telomere length, and PTBP1 interacts with hTERT pre-mRNA in a NOVA1-dependent manner as shown by RNA pulldown.\",\n      \"method\": \"PTBP1 stable knockdown; RT-PCR for hTERT isoforms; RNA pulldown; telomere length measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown plus functional splicing/telomere phenotype; single lab, multiple methods\",\n      \"pmids\": [\"30568224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTBP1 contributes to spermatogenesis by regulating spermatogonia proliferation; germ cell-specific Ptbp1 knockout mice show retarded neonatal spermatogonia proliferation and progressive decline in sperm count, and PTBP1 deletion in germline stem cells causes proliferation arrest and increased apoptosis in vitro.\",\n      \"method\": \"Cre-loxP conditional knockout mice; histology; in vitro germline stem cell culture with hydroxytamoxifen-induced deletion; flow cytometry apoptosis assay\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular phenotype in vivo and in vitro; single lab\",\n      \"pmids\": [\"30416150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTBP1 directly binds the 5'-UTR of AXL mRNA via its RRM1 domain and reduces AXL mRNA stability without affecting transcription rate, leading to decreased AXL expression and promoting apoptosis.\",\n      \"method\": \"RNA immunoprecipitation; mRNA stability assays; RRM1 domain mutation; transcription run-on assay; PTBP1/PTBP2 overexpression comparison\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus stability assays plus domain mutagenesis; single lab, multiple methods\",\n      \"pmids\": [\"31729427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTBP1 binds to and regulates the stability of SLC31A1 (copper transporter) mRNA, confirmed by RNA immunoprecipitation, dual-luciferase reporter assay, and RNA stability detection; knockdown of PTBP1 upregulates SLC31A1 and enhances cisplatin sensitivity in osteosarcoma cells.\",\n      \"method\": \"RNA immunoprecipitation; dual-luciferase reporter assay; mRNA stability assay; transcriptome sequencing; xenograft model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus reporter plus stability assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32207235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTBP1 enhances cyclin D3 (CCND3) translation by interacting with the 5'-UTR of CCND3 mRNA, facilitating cell cycle progression in hepatocellular carcinoma cells.\",\n      \"method\": \"RNA immunoprecipitation; luciferase 5'-UTR reporter; PTBP1 knockdown with CCND3 protein measurement\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus reporter assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"31301177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ptbp1 is essential for BCR-mediated B-cell activation and antibody production; B-cell-specific Ptbp1-deficient mice have severely reduced natural antibodies, defective BCR-mediated activation, and impaired plasmablast generation in response to both T-independent and T-dependent antigens.\",\n      \"method\": \"B-cell-specific conditional knockout mice; serum antibody measurement by ELISA; immunization with NP-Ficoll and NP-CGG; flow cytometry\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined immune phenotype; single lab\",\n      \"pmids\": [\"30476084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTBP1 mRNA isoforms differ in their 5'- and 3'-UTRs and protein-coding region splicing; eIF3 binds differentially to each PTBP1 mRNA isoform in a cell-cycle-dependent manner, with eIF3 binding correlating with repression of PTBP1 protein during S phase, indicating translational regulation of PTBP1 levels during the cell cycle.\",\n      \"method\": \"5'/3' end mapping; ribosome profiling; eIF3 RIP; cell cycle synchronization; Western blot\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus cell-cycle-synchronized protein measurement; single lab, multiple methods\",\n      \"pmids\": [\"31263002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTBP1 promotes ATPase-dependent dissociation of UPF1 from potential NMD target mRNAs, protecting them from nonsense-mediated decay; this mechanism depends on UPF1's tendency to release RNA upon ATP binding/hydrolysis and is coordinated by a regulatory loop in UPF1 domain 1B. PTBP1 does not require direct competition for binding sites but displaces already-bound UPF1.\",\n      \"method\": \"In vitro helicase activity assays; UPF1 dissociation from purified mRNPs; transcriptome-wide UPF1 CLIP-seq; domain mutagenesis of UPF1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified components plus transcriptome-wide validation and mutagenesis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32571872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTBP1 and HNRNPK are essential RNA-binding proteins for SINEUP lncRNA-mediated translational upregulation; they contribute to SINEUP RNA subcellular distribution and assembly of translational initiation complexes, leading to enhanced target mRNA translation.\",\n      \"method\": \"Co-transfection; subcellular fractionation; co-immunoprecipitation; translation assays in HEK293T cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus fractionation plus translation assay; single lab, multiple methods\",\n      \"pmids\": [\"33130894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LUCAT1 lncRNA interacts with PTBP1 in colorectal cancer cells and facilitates association of DNA damage-related gene transcripts with PTBP1, leading to altered alternative splicing of those genes; ectopic PTBP1 expression rescues the effects of LUCAT1 knockdown.\",\n      \"method\": \"RNA immunoprecipitation; alternative splicing analysis by RNA-seq; PTBP1 rescue experiment; in vivo xenograft\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP plus epistasis rescue; single lab, multiple methods\",\n      \"pmids\": [\"31964396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTBP1 is required for germinal center B cells receiving T cell help to express the c-MYC-dependent gene program and to progress through late S phase; it directly regulates alternative splicing and transcript abundance of genes upregulated during positive selection.\",\n      \"method\": \"Conditional PTBP1 knockout; flow cytometry cell cycle analysis; RNA-seq for splicing and transcript abundance; in vivo immunization\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined proliferation phenotype plus transcriptome-wide splicing analysis; multi-method single rigorous study\",\n      \"pmids\": [\"29358707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SON regulates PTBP1-mediated oncogenic splicing in glioblastoma: SON knockdown causes intron retention in the PTBP1 transcript, reducing PTBP1 protein and inhibiting downstream oncogenic splicing events. SON also forms a complex with hnRNP A2B1 and antagonizes RBFOX2 activity.\",\n      \"method\": \"PTBP1 RNA-seq splicing analysis; SON knockdown; RT-PCR for PTBP1 intron retention; co-immunoprecipitation; orthotopic xenograft model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splicing analysis plus Co-IP plus in vivo model; single lab, multiple methods\",\n      \"pmids\": [\"34548489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MALAT1 lncRNA interacts with PTBP1 and promotes USP8 mRNA degradation through this interaction; reduced USP8 then regulates ubiquitination and stability of TAK1, promoting macrophage pyroptosis and inflammation in liver fibrosis.\",\n      \"method\": \"RNA pulldown; RNA immunoprecipitation; mRNA stability assay; co-immunoprecipitation; protein degradation assay; m6A methylated RIP\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown plus RIP plus mRNA stability assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34839365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTBP1 deficiency in dendritic cells increases MHC II expression, perturbs T-cell homeostasis, and regulates PKM alternative splicing and a subset of IFN response genes without affecting DC development.\",\n      \"method\": \"DC-specific Ptbp1 conditional knockout; flow cytometry; RNA-seq for splicing; antitumor and asthma models\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined immune and splicing phenotypes; single lab, multiple methods\",\n      \"pmids\": [\"33421118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ptbp1 deficiency in endothelial cells reverses low-disturbed-flow-induced RNA splicing patterns in the NF-κB pathway and inhibits NF-κB nuclear translocation and transcriptional activation of Icam1 and Vcam1; endothelial-specific Ptbp1 deletion reduces myeloid cell infiltration and atherosclerosis in vivo; Ptbp1 promotes inclusion of a conserved alternative exon in Ripk1, reducing Ripk1 protein.\",\n      \"method\": \"CRISPR Cas9 KO screen; endothelial-specific conditional knockout; RNA splicing analysis; NF-κB nuclear translocation assay; in vivo atherosclerosis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus conditional KO with defined molecular and in vivo vascular phenotype; multiple methods across in vitro and in vivo\",\n      \"pmids\": [\"35858420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTBP1 promotes hematopoietic stem cell self-renewal and erythroid differentiation by ensuring ribosome biogenesis and translation of mRNAs encoding ribosomal proteins; PTBP1 deficiency causes splicing defects and upregulation of a specific CDC42 isoform that partly mimics the protein-synthesis defect.\",\n      \"method\": \"Hematopoietic compartment-specific PTBP1 deletion; RNA-seq for splicing; ribosome biogenesis assays; polysome profiling; CDC42 isoform overexpression\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus ribosome assays plus epistasis via isoform rescue; single lab, multiple methods\",\n      \"pmids\": [\"35545054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTBP1 interacts with hnRNPH1 in Sertoli cells to regulate alternative pre-mRNA splicing of cell adhesion-related target genes; this interaction is required for blood-testis barrier function and normal spermatogenesis.\",\n      \"method\": \"Sertoli cell-specific hnRNPH1 knockout; co-immunoprecipitation; alternative splicing analysis by RNA-seq\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus splicing analysis in conditional KO context; single lab, multiple methods\",\n      \"pmids\": [\"36718792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTBP1 and PTBP2 interact with distinct sets of proteins under splicing conditions: PTBP1 interacts with many mRNA processing and splicing regulators while PTBP2 does not; both interact with chromatin remodeling and transcription proteins; potential 'writers' and 'erasers' of PTM modifications on PTBPs were identified.\",\n      \"method\": \"In vitro splicing system; mass spectrometry identification of interacting proteins\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — MS-based interactome under defined splicing conditions; single lab, descriptive\",\n      \"pmids\": [\"35113929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Integrative structural modeling of PTBP1 bound to an EMCV IRES RNA fragment reveals strong compaction and ordering of both RNA and protein with residual conformational flexibility; PTBP1 acts as an RNA chaperone organizing the IRES RNA into a few distinct conformations with RNA stems exposed outward.\",\n      \"method\": \"NMR; mass spectrometry; small-angle scattering; integrative structural modeling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — integrative structural determination with multiple orthogonal biophysical methods; single study but rigorous multi-method approach\",\n      \"pmids\": [\"37833274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTBP1-associated RNA loops determined by CRIC-seq reveal positional rules: loops within individual introns promote cassette exon inclusion by accelerating asymmetric intron removal, while loops spanning across cassette exons repress splicing; cancer-related splicing QTLs can disrupt these RNA loops by reducing PTBP1 binding.\",\n      \"method\": \"Capture RIC-seq (CRIC-seq) for in situ RNA-RNA proximity ligation; bioinformatic analysis of loop positions; splicing outcome prediction\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — novel transcriptome-wide structural method with mechanistic validation and disease-relevant findings; single rigorous study with multiple orthogonal approaches\",\n      \"pmids\": [\"36958328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTBP1 activates co-transcriptional splicing of hundreds of introns in pluripotent stem cells; retention of a PTBP1-dependent intron in DNMT3B triggers NMD of DNMT3B transcripts, reducing DNMT3B levels in developing neurons and protecting differentiation-specific genes from ectopic methylation.\",\n      \"method\": \"Acute PTBP1 depletion (dTAG system); analysis of chromatin- and RNA Pol II-associated nascent transcripts; RNA-seq; bisulfite sequencing for methylation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — acute depletion with nascent transcript analysis plus epigenetic readout; multiple orthogonal methods in a rigorous single study\",\n      \"pmids\": [\"36626906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In adult peripheral sensory neurons, PTBP1 is co-expressed with PTBP2 (PTBP2 restricted to nucleus, PTBP1 also axonal); axonal PTBP1 levels increase after peripheral nerve injury, where it associates with mRNAs for importin β1 (KPNB1) and RHOA; PTBP1 perturbation affects local axonal translation, nociceptor regeneration, and thermal/mechanical sensation.\",\n      \"method\": \"Immunofluorescence and subcellular fractionation; axonal mRNA co-IP; local translation assays; sensory phenotyping after PTBP1 perturbation\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization plus RIP plus functional sensory phenotype; single lab, multiple methods\",\n      \"pmids\": [\"37506203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTBP1 directly binds the 5'-UTR of NCOA4 mRNA and promotes NCOA4 translation, thereby mediating ferroptosis in liver cancer cells; the PTBP1-binding region was mapped to the 5'-UTR by RNA pulldown, and PTBP1 silencing decreases NCOA4-mediated ferritinophagy.\",\n      \"method\": \"RNA pulldown; dual-luciferase assay; cycloheximide chase (PTBP1 KD did not affect NCOA4 protein stability); xenograft model\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown plus reporter plus in vivo; single lab, multiple methods\",\n      \"pmids\": [\"36660932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTBP1 interacts with RALY to regulate exon 5 splicing of DNMT3B (from DNMT3B-S to DNMT3B-L isoform); DNMT3B-L then induces promoter methylation of DUSP2, suppressing DUSP2 expression and increasing radioresistance in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation; splicing analysis by RT-PCR; PTBP1/RALY knockdown; bisulfite sequencing; in vitro and in vivo irradiation models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus splicing analysis plus epigenetic readout; single lab, multiple methods\",\n      \"pmids\": [\"39287090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MIR99AHG lncRNA binds and stabilizes PTBP1, and the complex promotes inclusion of exon 13 in SMARCA1 pre-mRNA (producing SMARCA1-L isoform) by altering PTBP1 binding to splice sites on intron 12; SMARCA1-L, unlike SMARCA1, promotes invadopodia formation and invasion in colorectal cancer.\",\n      \"method\": \"RNA pulldown; RNA immunoprecipitation; splicing minigene assays; MIR99AHG knockdown; invasion assays; patient CRC tissue analysis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown plus RIP plus splicing analysis; single lab, multiple methods\",\n      \"pmids\": [\"37725664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTBP1 inhibits NDUFS2 third exon skipping in cardiomyocytes by directly binding to PTBP1 in the nucleus; loss of DCRT lncRNA releases PTBP1 to promote NDUFS2 exon skipping, and the resulting NDUFS2 isoform impairs mitochondrial complex I activity and antioxidant function, causing dilated cardiomyopathy.\",\n      \"method\": \"CRISPR-Cas9 DCRT knockout mice; RNA immunoprecipitation; chromatin co-IP; isoform sequencing; mitochondrial complex I activity assay\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus RIP plus functional mitochondrial assays plus isoform sequencing; rigorous multi-method study\",\n      \"pmids\": [\"38841852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTBP1 K266 crotonylation (by KAT2B) enhances PTBP1 interaction with hnRNPA1/A2 and promotes PKM alternative splicing toward PKM2, increasing glycolysis and colorectal cancer progression; K266 crotonylation also enhances RNA-binding capacity.\",\n      \"method\": \"Crotonylation proteomics; immunoprecipitation; RNA immunoprecipitation; point mutagenesis (K266); in vitro/in vivo CRC models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM identification plus mutagenesis plus RIP plus splicing analysis; single lab, multiple methods\",\n      \"pmids\": [\"39497094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTBP1 deficiency in endothelial cells leads to left ventricular noncompaction by reducing endothelial cell migration via altered alternative splicing of β-arrestin-1 (Arrb1), which disrupts cardiomyocyte proliferation during cardiac development.\",\n      \"method\": \"Endothelial-specific Ptbp1 conditional knockout; RNA splicing analysis; migration assays; cardiac morphology/histology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cardiac phenotype plus splicing mechanism; single lab, multiple methods\",\n      \"pmids\": [\"37002228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSMD14 (a deubiquitinating enzyme) directly interacts with PTBP1, promotes its deubiquitination and stabilization, and thereby sustains PTBP1 protein levels to promote gastric cancer progression.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; Western blot; PSMD14/PTBP1 knockdown and rescue\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus rescue experiment; single lab, multiple methods\",\n      \"pmids\": [\"35405117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTBP1 K436 lactylation (with SIRT1 as eraser) stabilizes PTBP1 protein by attenuating interaction with TRIM21 E3 ligase and inhibiting proteasomal degradation; K436 lactylation also enhances PTBP1 RNA-binding capacity and promotes PFKFB4 mRNA stabilization, further increasing glycolysis in glioma stem cells.\",\n      \"method\": \"Lactylation proteomics; site-directed mutagenesis (K436); Co-IP of PTBP1/TRIM21; RNA immunoprecipitation for PFKFB4; SIRT1 delactylation assay; GSC functional assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM mapping plus mutagenesis plus Co-IP plus RIP; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39570804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTBP1 stabilizes TXNIP mRNA by direct binding; PTBP1 knockdown promotes TXNIP mRNA stability, increasing TXNIP-mediated oxidative stress that impairs lysosomal function and blocks autophagic flux in gastric cancer cells.\",\n      \"method\": \"RNA immunoprecipitation sequencing (si-PTBP1 RIP-seq); mRNA stability assay; ROS and autophagy flux assays; xenograft\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq plus stability assay plus functional autophagy readout; single lab, multiple methods\",\n      \"pmids\": [\"39153986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lkb1 regulates PTBP1 expression and through PTBP1 controls alternative splicing of PKM isoforms 1 and 2 in vascular smooth muscle cells; loss of Lkb1 increases PKM2/PKM1 ratio and aerobic glycolysis, driving VSMC transdifferentiation and aortic aneurysm; treatment with PKM2 activator rescues the phenotype.\",\n      \"method\": \"Smooth muscle cell-specific Lkb1 conditional knockout; single-cell RNA-seq; isoform-specific RT-PCR; PKM2 activator rescue; lineage tracing\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus scRNA-seq plus pharmacological rescue; single lab, multiple methods\",\n      \"pmids\": [\"39189621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTBP1 directly interacts with c-Myc protein and stabilizes c-Myc by preventing its proteasomal degradation; this is mediated by PTBP1 upregulating USP28 and limiting FBW7-mediated ubiquitination of c-Myc in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; Western blot; PTBP1/c-Myc knockdown and rescue\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus rescue; single lab, multiple methods\",\n      \"pmids\": [\"36635500\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTBP1 (hnRNP I) is a multifunctional RNA-binding protein that binds polypyrimidine/CU-rich sequences on pre-mRNAs and mRNAs to regulate alternative splicing (promoting or repressing exon inclusion depending on binding position relative to cassette exons, as defined by RNA-loop positional rules), mRNA stability, translation, cytoplasmic mRNA localization, co-transcriptional splicing, and protection from nonsense-mediated decay (by displacing UPF1 in an ATPase-dependent manner); its protein stability and activity are regulated by post-translational modifications including phosphorylation, acetylation, lactylation (K436, inhibiting TRIM21-mediated degradation), and crotonylation (K266, enhancing hnRNPA1/A2 cooperation for PKM splicing), as well as by deubiquitinases (PSMD14) and ubiquitin ligases; in neurons and stem cells, PTBP1 switches from nuclear/cytoplasmic to axonal localization upon injury, where it regulates local translation of regeneration-associated mRNAs; in immune cells, it is required for germinal center B-cell proliferation, BCR-mediated antibody production, and endothelial NF-κB priming; and it controls cardiac, vascular, hematopoietic, and spermatogonial development through tissue-specific splicing programs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTBP1 (hnRNP I) is a polypyrimidine/CU-rich-tract-binding RNA protein that governs alternative splicing and a broader post-transcriptional program controlling cell proliferation, differentiation, and tissue development [#0, #11, #37]. As a splicing regulator it represses cryptic and tissue-specific cassette exons through CU microsatellite elements [#11], with the splicing outcome dictated by positional rules: PTBP1-associated RNA loops within a single intron accelerate asymmetric intron removal to promote exon inclusion, whereas loops spanning a cassette exon repress it [#37]. It can also antagonize repression by competing with other splicing factors for intronic elements [#5], and acts as an RNA chaperone that compacts and orders structured RNAs such as viral IRES elements [#36]. Beyond splicing, PTBP1 controls mRNA fate in the cytoplasm: it binds 5'-UTRs to modulate stability or translation of targets including AXL, CCND3, and NCOA4 [#20, #22, #40], destabilizes transcripts such as MCL1 [#13], and protects mRNAs from nonsense-mediated decay by promoting ATPase-dependent displacement of UPF1 [#25]. PTBP1 directs cell-type-specific programs across many tissues — germinal center B-cell proliferation and antibody production [#15, #23], endothelial NF-\\u03baB priming and atherosclerosis through Ripk1 splicing [#32], hematopoietic stem cell self-renewal via ribosomal protein translation [#33], spermatogonial proliferation [#19], and cardiac development, where misregulated NDUFS2 exon skipping impairs mitochondrial complex I and causes dilated cardiomyopathy [#43]. A recurrent oncogenic theme is PTBP1-driven PKM splicing toward the PKM2 isoform to promote glycolysis [#10, #49]. PTBP1 protein abundance and RNA-binding activity are themselves tuned by post-translational modifications including K266 crotonylation and K436 lactylation, and by ubiquitin-system enzymes such as the deubiquitinase PSMD14 and the E3 ligase TRIM21 [#44, #46, #47].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established PTBP1 as a nuclear hnRNP that binds polypyrimidine tracts on nascent transcripts, defining its founding biochemical activity.\",\n      \"evidence\": \"Micrococcal nuclease fractionation of hnRNP complexes and immunofluorescence\",\n      \"pmids\": [\"1641332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No splicing or downstream functional readout in this study\", \"Perinucleolar localization left mechanistically unexplained\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapped an N-terminal bipartite nuclear localization domain, explaining how PTBP1 reaches its site of action.\",\n      \"evidence\": \"Domain-fusion to a cytoplasmic reporter and subcellular localization assay\",\n      \"pmids\": [\"9281380\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address regulated nuclear/cytoplasmic shuttling\", \"No link to function of cytoplasmic pools\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Linked PTBP1 to cytoplasmic mRNA localization, showing it binds a localization element required for vegetal RNA transport.\",\n      \"evidence\": \"Reciprocal in vitro RNA binding and in vivo colocalization in Xenopus oocytes\",\n      \"pmids\": [\"10518224\", \"18039852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of RNP remodeling not resolved at this stage\", \"Generality to mammalian mRNA localization untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated PTBP1 acts as a positional splicing regulator that can both repress and, by competing with other factors, activate splice-site usage.\",\n      \"evidence\": \"RNA affinity chromatography with in vitro and in vivo splicing reporters\",\n      \"pmids\": [\"17548433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single element studied; positional logic not yet generalized\", \"Cofactor competition not structurally defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected PTBP1 to disease-relevant phenotypes by showing it controls oncogenic exon choices (RTN4) and can destabilize signaling effectors (NICD).\",\n      \"evidence\": \"Exon array after siRNA knockdown, isoform rescue, and zebrafish genetics\",\n      \"pmids\": [\"19506066\", \"19197356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NICD destabilization mechanism distinct from RNA binding not fully defined\", \"Direct binding sites not mapped for all targets\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined transcriptome-wide repression of cryptic and tissue-specific exons via CU microsatellites and distinguished PTBP1 from PTBP2 by cofactor usage rather than RNA-binding specificity.\",\n      \"evidence\": \"RNA-seq after PTBP1/PTBP2 knockdown, motif analysis, and knockin/knockout mouse genetics\",\n      \"pmids\": [\"27681424\", \"27926877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the distinguishing cofactors not established here\", \"Quantitative rules linking binding to outcome not yet derived\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended PTBP1 function into cytoplasmic mRNA stability control, showing direct binding destabilizes targets such as MCL1 with consequences for apoptosis.\",\n      \"evidence\": \"RIP, mRNA stability assays, and MCL1 rescue with apoptosis readouts\",\n      \"pmids\": [\"27367564\", \"26980745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Decay machinery recruited by PTBP1 not identified\", \"Relationship between stability and splicing roles unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established PTBP1 as a developmental and immune regulator, required for germinal center B-cell cell-cycle progression and spermatogonial proliferation.\",\n      \"evidence\": \"Conditional knockout mice with cell-cycle, immunization, and histology analyses\",\n      \"pmids\": [\"29358707\", \"30416150\", \"30476084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct splicing targets driving each tissue phenotype only partially defined\", \"Tissue-specific cofactor context not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed PTBP1 activity and levels are regulated by post-translational modifications and by interactions with miRNA/lncRNA machinery.\",\n      \"evidence\": \"Mass spectrometry of PTMs in splicing reactions; AGO2 Co-IP and miRNA cooperation assays\",\n      \"pmids\": [\"29851470\", \"29748555\", \"22427970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of individual PTM sites not validated at this stage\", \"Writer/eraser enzymes not yet assigned\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved a mechanism by which PTBP1 protects mRNAs from NMD, displacing UPF1 in an ATPase-dependent manner without direct site competition.\",\n      \"evidence\": \"In vitro helicase/dissociation assays with purified components and transcriptome-wide UPF1 CLIP-seq\",\n      \"pmids\": [\"32571872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which endogenous transcripts are physiologically protected not enumerated\", \"Coordination with co-transcriptional splicing not addressed here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated PTBP1 drives vascular and hematopoietic programs through specific splicing events (Ripk1, ribosomal protein translation) with in vivo disease consequences.\",\n      \"evidence\": \"CRISPR screen, endothelial- and hematopoietic-specific conditional knockouts, splicing and ribosome assays, atherosclerosis model\",\n      \"pmids\": [\"35858420\", \"35545054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of effector splice events per phenotype incomplete\", \"Crosstalk between translation and splicing roles unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Derived the structural and positional logic of PTBP1 splicing regulation via RNA loops, and showed it activates co-transcriptional splicing with epigenetic downstream effects through DNMT3B.\",\n      \"evidence\": \"CRIC-seq RNA-RNA proximity ligation; acute dTAG depletion with nascent transcript and bisulfite sequencing; integrative structural modeling of an IRES complex\",\n      \"pmids\": [\"36958328\", \"36626906\", \"37833274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of loop formation in vivo not fully defined\", \"Generality of the chaperone model beyond viral IRES untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed PTBP1 protein stability and RNA-binding are tuned by metabolic-linked PTMs and ubiquitin-system enzymes, and that PTBP1 controls cardiac and metabolic phenotypes through specific isoform switches.\",\n      \"evidence\": \"Crotonylation/lactylation proteomics with K266/K436 mutagenesis; PSMD14/TRIM21 Co-IP and ubiquitination assays; conditional knockouts for NDUFS2 and Arrb1 splicing\",\n      \"pmids\": [\"39497094\", \"39570804\", \"35405117\", \"38841852\", \"37002228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among competing PTMs not established\", \"How metabolic state feeds back to PTBP1 modification in vivo unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The integrated rules connecting PTBP1 binding position, RNA structure, cofactor identity, and post-translational modification state to a defined splicing or stability outcome in a given cell type remain to be unified into a predictive model.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No single framework links positional loop logic, PTM state, and tissue cofactors\", \"Causal mechanism distinguishing PTBP1 from PTBP2 outcomes not molecularly resolved\", \"Mendelian disease association in humans not established in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 11, 13, 20, 25, 37]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [5, 11, 37, 38]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [36]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [22, 24, 26, 40]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 1, 43]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [25, 39]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 11, 25, 37, 38]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [38]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [33, 43, 45]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 23, 28, 31]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 32, 43, 49]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"UPF1\", \"AGO2\", \"hnRNPA1\", \"hnRNPH1\", \"RALY\", \"PSMD14\", \"TRIM21\", \"MYC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}