{"gene":"HNRNPLL","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2008,"finding":"hnRNPLL is an inducible RNA-binding protein that directly binds CD45 (Ptprc) pre-mRNA transcripts and is both necessary and sufficient for alternative splicing of CD45 during the naïve-to-activated T cell transition, promoting CD45RO at the expense of CD45RA isoforms.","method":"shRNA interference screen, overexpression and knockdown in B/T cell lines and primary T cells, exon array analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal loss- and gain-of-function experiments, direct RNA binding demonstrated, replicated across multiple cell types and two independent labs (PMID:18669861 and PMID:19100700)","pmids":["18669861","19100700"],"is_preprint":false},{"year":2008,"finding":"A single point mutation in hnRNPLL destabilizes an RNA-recognition domain (RRM) that binds with micromolar affinity to the Ptprc exon-silencing sequence, identifying this RRM as essential for CD45 exon skipping and for T cell accumulation in peripheral lymphoid tissues.","method":"ENU mutagenesis screen, biochemical binding assay (micromolar Kd measurement), exon array analysis of mutant T cells","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro binding assay with affinity measurement combined with genetic in vivo phenotype, single rigorous study with multiple orthogonal methods","pmids":["19100700"],"is_preprint":false},{"year":2012,"finding":"hnRNPLL binds Ighg2b mRNA in plasma cells and promotes increased levels of the membrane-encoding Ighg2b isoform at the expense of the secreted isoform; it also alters splicing of CD44 mRNA, promoting exon inclusion and decreasing overall CD44 levels.","method":"shRNA screen, RNA-seq, direct RNA binding (implied by transcript isoform shift upon knockdown/overexpression), transcriptional profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA binding inferred from isoform shifts, no direct RIP shown for Ighg2b; replicated in a separate study (PMID:25825742)","pmids":["22991471"],"is_preprint":false},{"year":2014,"finding":"hnRNPLL induces selective retention of introns flanking cassette exons 4–6 in Ptprc mRNA and similar intron retention patterns in 14 other genes; retroviral restoration of Senp2 (one hnRNPLL splicing target) partially rescues the survival defect of Hnrpll-mutant T cells, placing Senp2 downstream of hnRNPLL in T cell survival.","method":"Deep RNA sequencing of polyadenylated RNA from hnRNPLL-mutant and hnRNPLL-low B cells; genetic epistasis via retroviral cDNA rescue","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq with mutant/WT comparison plus genetic rescue experiment; single lab, two orthogonal methods","pmids":["24476532"],"is_preprint":false},{"year":2015,"finding":"hnRNPLL preferentially recognizes CA dinucleotide-containing sequences in introns and 3′ UTRs, promotes exon inclusion or exclusion in a context-dependent manner, stabilizes mRNA when associated with 3′ UTRs, and mediates genome-wide RNA processing switches during B cell–to–plasma cell differentiation including loss of Bcl6 expression and increased Ig production.","method":"PAR-CLIP (genome-wide binding site mapping), RNA sequencing, primary B-cell differentiation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — PAR-CLIP provides nucleotide-resolution binding sites combined with RNA-seq of primary differentiating cells; multiple orthogonal methods in one rigorous study","pmids":["25825742"],"is_preprint":false},{"year":2017,"finding":"hnRNPLL specifically associates with cytoplasmic PABPC1 (poly(A)-binding protein 1) in T cells and plasma cells; PABPC1 promotes hnRNPLL binding to immunoglobulin mRNA and regulates the switch from membrane IgH to secreted IgH, suggesting PABPC1 recruits hnRNPLL to the 3′-end of RNA to regulate alternative polyadenylation. PABPC1 is not required for hnRNPLL-mediated CD45 alternative splicing.","method":"Co-immunoprecipitation, RNA immunoprecipitation, knockdown functional assays for mIgH/sIgH ratio","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional RIP assay plus knockdown phenotype; single lab","pmids":["28611064"],"is_preprint":false},{"year":2017,"finding":"hnRNPLL binds CD44 pre-mRNA and regulates CD44 alternative splicing during epithelial-mesenchymal transition; hnRNPLL knockdown increases the CD44 variable exon 6 (CD44v6) isoform, and a neutralising CD44v6 antibody suppresses the invasion phenotype induced by hnRNPLL knockdown, placing CD44v6 downstream of hnRNPLL in colorectal cancer invasion.","method":"Genome-wide shRNA in vivo metastasis screen, RNA immunoprecipitation, Matrigel invasion assays, antibody neutralisation epistasis","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP demonstrates direct binding, antibody rescue provides genetic epistasis; single lab, two orthogonal methods","pmids":["28360095"],"is_preprint":false},{"year":2018,"finding":"ADAR1/ADAR2-mediated A-to-I editing of an intronic exon 12A (E12A) in HNRNPLL mRNA generates an SRSF1-binding splicing enhancer, promoting inclusion of E12A and producing a distinct HNRNPLL isoform that regulates growth-related genes (CCND1, TGFBR1) independently of canonical HNRNPLL; silencing E12A impairs clonogenic ability and sensitizes cells to doxorubicin.","method":"ADAR overexpression/knockdown, splicing reporter assays, RNA-seq, colony formation and drug-sensitivity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of editing-to-splicing coupling with functional validation; single lab, multiple assays","pmids":["29769310"],"is_preprint":false},{"year":2018,"finding":"hnRNPLL binds mRNAs encoding DNA replication proteins PCNA, RFC3, and FEN1, stabilizes these mRNAs (demonstrated by reduced decay during actinomycin D treatment upon hnRNPLL overexpression), and promotes cell cycle progression; knockdown of any of these three targets individually suppresses the proliferation-promoting effect of hnRNPLL overexpression.","method":"RNA immunoprecipitation, actinomycin D mRNA stability assay, RNA-seq, siRNA epistasis knockdowns, proliferation assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RIP binding plus mRNA stability assay plus genetic epistasis; single lab, multiple orthogonal methods","pmids":["29869816"],"is_preprint":false},{"year":2020,"finding":"hnRNPLL promotes exon skipping of ES cell-preferred exons in Bptf and Tbx3 during the onset of embryonic stem cell differentiation; hnRNPLL knockout causes sustained expression of ES cell-preferred isoforms of these transcription factors, leading to differentiation deficiency and developmental defects in KO mice.","method":"Bioinformatic screening, hnRNPLL knockout mouse, alternative splicing analysis, functional differentiation assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined molecular (isoform) phenotype and developmental readout; single lab","pmids":["33349972"],"is_preprint":false},{"year":2021,"finding":"The hnRNPLL thunder mutation disrupts alternative splicing of Ptprc in plasmablasts (loss of CD45 exon silencing), but this dysregulation does not affect B cell development, proliferation, or in vitro plasmablast generation; the germinal center B cell deficiency observed in Hnrnpllthu/thu mice is B cell-extrinsic.","method":"Hnrnpll hypomorphic mouse, mixed bone marrow chimeras, in vivo immunization, in vitro B cell stimulation assays, flow cytometry","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bone marrow chimera epistasis distinguishes cell-intrinsic vs extrinsic effects; single lab with multiple defined readouts","pmids":["33331104"],"is_preprint":false},{"year":2023,"finding":"The lncRNA lnc-PPP2R1B physically interacts with and stabilizes hnRNPLL protein; this interaction is required for hnRNPLL-mediated alternative splicing of PPP2R1B (retention of exons 2 and 3), which preserves PP2A trimer function and promotes Wnt/β-catenin-dependent osteogenesis in mesenchymal stem cells.","method":"RNA immunoprecipitation/pulldown (lncRNA–protein interaction), knockdown of lnc-PPP2R1B and HNRNPLL, RT-PCR isoform analysis, in vivo ectopic osteogenesis","journal":"Stem cell reviews and reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/pulldown for lncRNA-protein interaction, single lab, limited mechanistic detail in abstract","pmids":["37243830"],"is_preprint":false},{"year":2024,"finding":"hnRNPLL depletion stimulates exon 17 retention in MYOF (myoferlin) mRNA, reducing the short MYOF isoform (MYOFb); hnRNPLL or MYOFb overexpression promotes pancreatic cancer cell migration and invasion, placing MYOF alternative splicing downstream of hnRNPLL in PDAC metastasis.","method":"hnRNPLL knockdown/overexpression, RNA-seq splicing analysis, MYOFb overexpression, migration/invasion assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined molecular isoform readout and functional epistasis; single lab","pmids":["39742990"],"is_preprint":false},{"year":2011,"finding":"The hnRNPLL thunder mutation disrupts CD45 (Ptprc) exon silencing in both NKT and conventional T cells equally, yet selectively impairs survival of conventional T cells but not NKT cells, demonstrating that hnRNPLL-dependent Ptprc splicing regulation is dissociable from its pro-survival function.","method":"Hnrpll hypomorphic mouse, NKT vs T cell comparisons, flow cytometry, functional assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic dissection using hypomorphic allele comparing two cell types; single lab, defined molecular and phenotypic readouts","pmids":["22073166"],"is_preprint":false}],"current_model":"hnRNPLL is a tissue-restricted RNA-binding protein (induced in activated/memory T cells, plasma cells, and ES cells) that recognizes CA-rich sequences in introns and 3′ UTRs via its RNA-recognition domain; it acts as a global regulator of alternative splicing—promoting cassette exon skipping or inclusion in a context-dependent manner, inducing flanking intron retention as a mechanistic hallmark—and also stabilizes target mRNAs when bound to their 3′ UTRs, with its best-characterized substrates being CD45/Ptprc (T cell isoform switching), immunoglobulin heavy-chain mRNA (membrane vs. secreted Ig balance, cooperatively with PABPC1), CD44, MYOF, and DNA replication factors (PCNA, RFC3, FEN1), thereby orchestrating transcriptome reprogramming during lymphocyte differentiation, ES cell pluripotency exit, and cancer cell invasion."},"narrative":{"mechanistic_narrative":"hnRNPLL is an inducible, tissue-restricted RNA-binding protein that functions as a global regulator of alternative splicing and mRNA fate during lymphocyte differentiation, stem-cell state transitions, and cancer cell invasion [PMID:18669861, PMID:19100700, PMID:25825742]. It recognizes CA-dinucleotide-containing sequences in introns and 3′ UTRs, and promotes either exon skipping or inclusion in a context-dependent manner while stabilizing transcripts when bound to their 3′ UTRs [PMID:25825742]. Its activity depends on an RNA-recognition motif that binds the Ptprc exon-silencing element with micromolar affinity; a single point mutation destabilizing this RRM abolishes CD45 exon skipping and impairs peripheral T cell accumulation [PMID:19100700]. The best-characterized substrate is CD45/Ptprc, where hnRNPLL is necessary and sufficient to drive the naïve-to-activated isoform switch from CD45RA toward CD45RO, with selective retention of introns flanking cassette exons 4–6 as a mechanistic hallmark [PMID:18669861, PMID:19100700, PMID:24476532]. Notably, hnRNPLL-dependent Ptprc splicing is genetically dissociable from its pro-survival function in conventional T cells [PMID:22073166], and Senp2, one of its splicing targets, acts downstream to support T cell survival [PMID:24476532]. In plasma cells, hnRNPLL controls the membrane-versus-secreted immunoglobulin heavy-chain balance and broader plasma-cell differentiation programs including loss of Bcl6, acting on Ig mRNA in cooperation with cytoplasmic PABPC1, which recruits hnRNPLL to the 3′ end of transcripts to regulate alternative polyadenylation [PMID:22991471, PMID:25825742, PMID:28611064]. hnRNPLL also drives exon skipping of ES cell-preferred isoforms of Bptf and Tbx3 to enable embryonic stem cell differentiation [PMID:33349972], stabilizes mRNAs encoding the DNA replication factors PCNA, RFC3, and FEN1 to promote cell-cycle progression [PMID:29869816], and controls splicing of CD44 (v6 isoform) and MYOF to govern cancer cell invasion and metastasis [PMID:28360095, PMID:39742990].","teleology":[{"year":2008,"claim":"Established hnRNPLL as the inducible factor that directly drives CD45 isoform switching during T cell activation, answering how the naïve-to-activated CD45RA-to-CD45RO transition is controlled.","evidence":"shRNA screen with reciprocal knockdown/overexpression in B/T cell lines and primary T cells, plus direct RNA binding and exon array analysis","pmids":["18669861","19100700"],"confidence":"High","gaps":["Did not define the RNA sequence determinants of recognition","Did not establish targets beyond CD45/Ptprc"]},{"year":2008,"claim":"Pinpointed the RRM as the essential binding module by showing a single destabilizing point mutation abolishes Ptprc exon-silencing binding and impairs peripheral T cell accumulation, linking molecular binding to an in vivo phenotype.","evidence":"ENU mutagenesis screen, in vitro binding assay with micromolar Kd measurement, exon array of mutant T cells","pmids":["19100700"],"confidence":"High","gaps":["No structural model of the RRM–RNA complex","Whether the same RRM mediates binding to non-Ptprc targets not addressed"]},{"year":2011,"claim":"Dissociated hnRNPLL's splicing function from its survival function by showing equal Ptprc dysregulation in NKT and conventional T cells but selective survival impairment only in conventional T cells.","evidence":"Hnrpll hypomorphic (thunder) mouse comparing NKT vs conventional T cells by flow cytometry and functional assays","pmids":["22073166"],"confidence":"Medium","gaps":["Did not identify the splicing target responsible for the survival defect","Mechanism of cell-type-selective survival dependency unresolved"]},{"year":2012,"claim":"Extended hnRNPLL's regulatory scope beyond T cells to plasma-cell immunoglobulin and CD44 splicing, indicating a broad role in B-lineage isoform control.","evidence":"shRNA screen, RNA-seq, and transcriptional profiling in plasma cells","pmids":["22991471"],"confidence":"Medium","gaps":["RNA binding to Ighg2b inferred from isoform shifts rather than direct RIP","Mechanism of membrane vs secreted isoform choice not defined"]},{"year":2014,"claim":"Identified flanking-intron retention as a mechanistic hallmark of hnRNPLL action and placed a specific target (Senp2) downstream in T cell survival via genetic rescue.","evidence":"Deep RNA-seq of mutant/low B cells plus retroviral cDNA rescue of Senp2 in Hnrpll-mutant T cells","pmids":["24476532"],"confidence":"Medium","gaps":["Why introns are retained mechanistically not resolved","Senp2 rescue was only partial, implying additional effectors"]},{"year":2015,"claim":"Defined the genome-wide binding preference (CA-rich motifs in introns/3′UTRs) and dual activities of hnRNPLL (context-dependent splicing plus 3′UTR-mediated mRNA stabilization) during B-to-plasma-cell differentiation.","evidence":"PAR-CLIP nucleotide-resolution binding maps and RNA-seq in primary differentiating B cells","pmids":["25825742"],"confidence":"High","gaps":["What dictates inclusion versus exclusion at a given CA site not fully resolved","Stabilization mechanism via 3′UTR not biochemically dissected here"]},{"year":2017,"claim":"Identified PABPC1 as a direct cytoplasmic partner that recruits hnRNPLL to 3′ transcript ends to regulate Ig alternative polyadenylation, distinguishing this from PABPC1-independent CD45 splicing.","evidence":"Reciprocal co-IP, RNA immunoprecipitation, and knockdown assays of mIgH/sIgH ratio","pmids":["28611064"],"confidence":"Medium","gaps":["Single lab; structural basis of the hnRNPLL–PABPC1 interaction unknown","Whether PABPC1 cooperation extends to other 3′UTR targets not tested"]},{"year":2017,"claim":"Linked hnRNPLL to cancer invasion by showing it controls CD44v6 splicing, with antibody neutralization placing CD44v6 downstream in colorectal cancer invasion.","evidence":"Genome-wide in vivo shRNA metastasis screen, RIP, Matrigel invasion, and CD44v6 antibody neutralization epistasis","pmids":["28360095"],"confidence":"Medium","gaps":["Single lab; direct mechanism of CD44v6-driven invasion not detailed","Whether finding generalizes beyond colorectal cancer not tested"]},{"year":2018,"claim":"Revealed an A-to-I editing-to-splicing feedback loop producing a distinct HNRNPLL isoform (E12A-included) that regulates growth genes independently of canonical HNRNPLL.","evidence":"ADAR overexpression/knockdown, splicing reporter assays, RNA-seq, and clonogenic/drug-sensitivity assays","pmids":["29769310"],"confidence":"Medium","gaps":["Functional protein product of E12A isoform not characterized","Single lab"]},{"year":2018,"claim":"Demonstrated a 3′UTR-mediated mRNA-stabilization role by showing hnRNPLL binds and stabilizes PCNA, RFC3, and FEN1 mRNAs to promote cell-cycle progression.","evidence":"RIP, actinomycin D mRNA stability assay, RNA-seq, and siRNA epistasis with proliferation readouts","pmids":["29869816"],"confidence":"Medium","gaps":["Molecular determinants of selective stabilization vs splicing not defined","Single lab"]},{"year":2020,"claim":"Established hnRNPLL as a regulator of stem-cell exit by driving exon skipping of ES-preferred Bptf and Tbx3 isoforms required for proper differentiation in vivo.","evidence":"hnRNPLL knockout mouse with alternative splicing analysis and differentiation/developmental assays","pmids":["33349972"],"confidence":"Medium","gaps":["How hnRNPLL is itself induced/regulated during differentiation onset not addressed","Single lab"]},{"year":2021,"claim":"Showed that hnRNPLL-dependent Ptprc dysregulation is dispensable for B cell development, with germinal center deficiency being B cell-extrinsic, refining the in vivo significance of its splicing activity.","evidence":"Hnrnpll hypomorphic mouse, mixed bone marrow chimeras, in vivo immunization, and flow cytometry","pmids":["33331104"],"confidence":"Medium","gaps":["Identity of the extrinsic cell type/program driving the GC defect unknown","Single lab"]},{"year":2023,"claim":"Proposed that the lncRNA lnc-PPP2R1B stabilizes hnRNPLL protein to enable PPP2R1B splicing supporting PP2A function and Wnt-dependent osteogenesis.","evidence":"RNA pulldown/RIP for lncRNA-protein interaction, knockdowns, RT-PCR isoform analysis, and in vivo ectopic osteogenesis","pmids":["37243830"],"confidence":"Low","gaps":["Single Co-IP/pulldown without reciprocal validation of the lncRNA-protein interaction","Mechanism by which the lncRNA stabilizes hnRNPLL protein not defined"]},{"year":2024,"claim":"Extended hnRNPLL's invasion-regulatory role to pancreatic cancer via control of MYOF exon 17 splicing, placing the MYOFb isoform downstream of hnRNPLL in metastasis.","evidence":"hnRNPLL knockdown/overexpression, RNA-seq splicing analysis, MYOFb overexpression, and migration/invasion assays","pmids":["39742990"],"confidence":"Medium","gaps":["Mechanism by which MYOFb promotes invasion not detailed","Single lab"]},{"year":null,"claim":"How hnRNPLL selects between competing outcomes — exon inclusion, exon skipping, intron retention, alternative polyadenylation, and mRNA stabilization — at a given CA-rich site, and which cofactors dictate each choice, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating RRM binding with outcome selection","Combinatorial cofactor logic beyond PABPC1 largely uncharacterized","Determinants of tissue-restricted target repertoire unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,4,5,6,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9]}],"complexes":[],"partners":["PABPC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WVV9","full_name":"Heterogeneous nuclear ribonucleoprotein L-like","aliases":["Stromal RNA-regulating factor"],"length_aa":542,"mass_kda":60.1,"function":"RNA-binding protein that functions as a regulator of alternative splicing for multiple target mRNAs, including PTPRC/CD45 and STAT5A. Required for alternative splicing of PTPRC","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8WVV9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPLL","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HNRNPLL","total_profiled":1310},"omim":[{"mim_id":"611208","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN L-LIKE; HNRNPLL","url":"https://www.omim.org/entry/611208"},{"mim_id":"151460","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, C; PTPRC","url":"https://www.omim.org/entry/151460"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HNRNPLL"},"hgnc":{"alias_symbol":[],"prev_symbol":["HNRPLL"]},"alphafold":{"accession":"Q8WVV9","domains":[{"cath_id":"3.30.70.330","chopping":"76-146","consensus_level":"high","plddt":89.3001,"start":76,"end":146},{"cath_id":"3.30.70.330","chopping":"167-257","consensus_level":"high","plddt":88.7749,"start":167,"end":257},{"cath_id":"3.30.70.330","chopping":"335-439","consensus_level":"high","plddt":93.234,"start":335,"end":439},{"cath_id":"3.30.70.330","chopping":"450-535","consensus_level":"high","plddt":92.1448,"start":450,"end":535}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WVV9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WVV9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WVV9-F1-predicted_aligned_error_v6.png","plddt_mean":75.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HNRNPLL","jax_strain_url":"https://www.jax.org/strain/search?query=HNRNPLL"},"sequence":{"accession":"Q8WVV9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WVV9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WVV9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WVV9"}},"corpus_meta":[{"pmid":"18669861","id":"PMC_18669861","title":"Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL.","date":"2008","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18669861","citation_count":171,"is_preprint":false},{"pmid":"19100700","id":"PMC_19100700","title":"Memory T cell RNA rearrangement programmed by heterogeneous nuclear ribonucleoprotein hnRNPLL.","date":"2008","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/19100700","citation_count":73,"is_preprint":false},{"pmid":"28360095","id":"PMC_28360095","title":"HNRNPLL, a newly identified colorectal cancer metastasis suppressor, modulates alternative splicing of CD44 during epithelial-mesenchymal transition.","date":"2017","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/28360095","citation_count":63,"is_preprint":false},{"pmid":"25825742","id":"PMC_25825742","title":"RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25825742","citation_count":50,"is_preprint":false},{"pmid":"24476532","id":"PMC_24476532","title":"The RNA-binding protein hnRNPLL induces a T cell alternative splicing program delineated by differential intron retention in polyadenylated RNA.","date":"2014","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/24476532","citation_count":46,"is_preprint":false},{"pmid":"22991471","id":"PMC_22991471","title":"Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22991471","citation_count":35,"is_preprint":false},{"pmid":"28611064","id":"PMC_28611064","title":"Cytoplasmic poly(A)-binding protein 1 (PABPC1) interacts with the RNA-binding protein hnRNPLL and thereby regulates immunoglobulin secretion in plasma cells.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28611064","citation_count":29,"is_preprint":false},{"pmid":"29769310","id":"PMC_29769310","title":"Tumor-associated intronic editing of HNRPLL generates a novel splicing variant linked to cell proliferation.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29769310","citation_count":20,"is_preprint":false},{"pmid":"33349972","id":"PMC_33349972","title":"hnRNPLL controls pluripotency exit of embryonic stem cells by modulating alternative splicing of Tbx3 and Bptf.","date":"2020","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/33349972","citation_count":15,"is_preprint":false},{"pmid":"29869816","id":"PMC_29869816","title":"HNRNPLL stabilizes mRNA for DNA replication proteins and promotes cell cycle progression in colorectal cancer cells.","date":"2018","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/29869816","citation_count":13,"is_preprint":false},{"pmid":"26821996","id":"PMC_26821996","title":"RNA-binding protein hnRNPLL as a critical regulator of lymphocyte homeostasis and differentiation.","date":"2016","source":"Wiley interdisciplinary reviews. RNA","url":"https://pubmed.ncbi.nlm.nih.gov/26821996","citation_count":12,"is_preprint":false},{"pmid":"37243830","id":"PMC_37243830","title":"Lnc-PPP2R1B Mediates the Alternative Splicing of PPP2R1B by Interacting and Stabilizing HNRNPLL and Promotes Osteogenesis of MSCs.","date":"2023","source":"Stem cell reviews and reports","url":"https://pubmed.ncbi.nlm.nih.gov/37243830","citation_count":8,"is_preprint":false},{"pmid":"33331104","id":"PMC_33331104","title":"Loss of hnRNPLL-dependent splicing of Ptprc has no impact on B-cell development, activation and terminal differentiation into antibody-secreting cells.","date":"2021","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33331104","citation_count":8,"is_preprint":false},{"pmid":"22073166","id":"PMC_22073166","title":"Differential requirement for the CD45 splicing regulator hnRNPLL for accumulation of NKT and conventional T cells.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22073166","citation_count":8,"is_preprint":false},{"pmid":"39742990","id":"PMC_39742990","title":"hnRNPLL regulates MYOF alternative splicing and correlates with early metastasis in pancreatic ductal adenocarcinoma.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/39742990","citation_count":6,"is_preprint":false},{"pmid":"33152455","id":"PMC_33152455","title":"Behavioural phenotyping of thunder mice with a hypomorphic mutation of heterogeneous nuclear ribonuclear protein L-like (hnRNPLL) and reduced T cell function.","date":"2020","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/33152455","citation_count":2,"is_preprint":false},{"pmid":"42042880","id":"PMC_42042880","title":"Integrative Multi-Omics Analysis Reveals HNRNPLL as a Potential Biomarker Associated with Hepatocellular Carcinoma Progression.","date":"2026","source":"Metabolites","url":"https://pubmed.ncbi.nlm.nih.gov/42042880","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10630,"output_tokens":3650,"usd":0.04332,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11423,"output_tokens":4519,"usd":0.085045,"stage2_stop_reason":"end_turn"},"total_usd":0.128365,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"hnRNPLL is an inducible RNA-binding protein that directly binds CD45 (Ptprc) pre-mRNA transcripts and is both necessary and sufficient for alternative splicing of CD45 during the naïve-to-activated T cell transition, promoting CD45RO at the expense of CD45RA isoforms.\",\n      \"method\": \"shRNA interference screen, overexpression and knockdown in B/T cell lines and primary T cells, exon array analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal loss- and gain-of-function experiments, direct RNA binding demonstrated, replicated across multiple cell types and two independent labs (PMID:18669861 and PMID:19100700)\",\n      \"pmids\": [\"18669861\", \"19100700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A single point mutation in hnRNPLL destabilizes an RNA-recognition domain (RRM) that binds with micromolar affinity to the Ptprc exon-silencing sequence, identifying this RRM as essential for CD45 exon skipping and for T cell accumulation in peripheral lymphoid tissues.\",\n      \"method\": \"ENU mutagenesis screen, biochemical binding assay (micromolar Kd measurement), exon array analysis of mutant T cells\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro binding assay with affinity measurement combined with genetic in vivo phenotype, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"19100700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"hnRNPLL binds Ighg2b mRNA in plasma cells and promotes increased levels of the membrane-encoding Ighg2b isoform at the expense of the secreted isoform; it also alters splicing of CD44 mRNA, promoting exon inclusion and decreasing overall CD44 levels.\",\n      \"method\": \"shRNA screen, RNA-seq, direct RNA binding (implied by transcript isoform shift upon knockdown/overexpression), transcriptional profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA binding inferred from isoform shifts, no direct RIP shown for Ighg2b; replicated in a separate study (PMID:25825742)\",\n      \"pmids\": [\"22991471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"hnRNPLL induces selective retention of introns flanking cassette exons 4–6 in Ptprc mRNA and similar intron retention patterns in 14 other genes; retroviral restoration of Senp2 (one hnRNPLL splicing target) partially rescues the survival defect of Hnrpll-mutant T cells, placing Senp2 downstream of hnRNPLL in T cell survival.\",\n      \"method\": \"Deep RNA sequencing of polyadenylated RNA from hnRNPLL-mutant and hnRNPLL-low B cells; genetic epistasis via retroviral cDNA rescue\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq with mutant/WT comparison plus genetic rescue experiment; single lab, two orthogonal methods\",\n      \"pmids\": [\"24476532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"hnRNPLL preferentially recognizes CA dinucleotide-containing sequences in introns and 3′ UTRs, promotes exon inclusion or exclusion in a context-dependent manner, stabilizes mRNA when associated with 3′ UTRs, and mediates genome-wide RNA processing switches during B cell–to–plasma cell differentiation including loss of Bcl6 expression and increased Ig production.\",\n      \"method\": \"PAR-CLIP (genome-wide binding site mapping), RNA sequencing, primary B-cell differentiation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — PAR-CLIP provides nucleotide-resolution binding sites combined with RNA-seq of primary differentiating cells; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"25825742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPLL specifically associates with cytoplasmic PABPC1 (poly(A)-binding protein 1) in T cells and plasma cells; PABPC1 promotes hnRNPLL binding to immunoglobulin mRNA and regulates the switch from membrane IgH to secreted IgH, suggesting PABPC1 recruits hnRNPLL to the 3′-end of RNA to regulate alternative polyadenylation. PABPC1 is not required for hnRNPLL-mediated CD45 alternative splicing.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, knockdown functional assays for mIgH/sIgH ratio\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional RIP assay plus knockdown phenotype; single lab\",\n      \"pmids\": [\"28611064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"hnRNPLL binds CD44 pre-mRNA and regulates CD44 alternative splicing during epithelial-mesenchymal transition; hnRNPLL knockdown increases the CD44 variable exon 6 (CD44v6) isoform, and a neutralising CD44v6 antibody suppresses the invasion phenotype induced by hnRNPLL knockdown, placing CD44v6 downstream of hnRNPLL in colorectal cancer invasion.\",\n      \"method\": \"Genome-wide shRNA in vivo metastasis screen, RNA immunoprecipitation, Matrigel invasion assays, antibody neutralisation epistasis\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP demonstrates direct binding, antibody rescue provides genetic epistasis; single lab, two orthogonal methods\",\n      \"pmids\": [\"28360095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAR1/ADAR2-mediated A-to-I editing of an intronic exon 12A (E12A) in HNRNPLL mRNA generates an SRSF1-binding splicing enhancer, promoting inclusion of E12A and producing a distinct HNRNPLL isoform that regulates growth-related genes (CCND1, TGFBR1) independently of canonical HNRNPLL; silencing E12A impairs clonogenic ability and sensitizes cells to doxorubicin.\",\n      \"method\": \"ADAR overexpression/knockdown, splicing reporter assays, RNA-seq, colony formation and drug-sensitivity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of editing-to-splicing coupling with functional validation; single lab, multiple assays\",\n      \"pmids\": [\"29769310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"hnRNPLL binds mRNAs encoding DNA replication proteins PCNA, RFC3, and FEN1, stabilizes these mRNAs (demonstrated by reduced decay during actinomycin D treatment upon hnRNPLL overexpression), and promotes cell cycle progression; knockdown of any of these three targets individually suppresses the proliferation-promoting effect of hnRNPLL overexpression.\",\n      \"method\": \"RNA immunoprecipitation, actinomycin D mRNA stability assay, RNA-seq, siRNA epistasis knockdowns, proliferation assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RIP binding plus mRNA stability assay plus genetic epistasis; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29869816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"hnRNPLL promotes exon skipping of ES cell-preferred exons in Bptf and Tbx3 during the onset of embryonic stem cell differentiation; hnRNPLL knockout causes sustained expression of ES cell-preferred isoforms of these transcription factors, leading to differentiation deficiency and developmental defects in KO mice.\",\n      \"method\": \"Bioinformatic screening, hnRNPLL knockout mouse, alternative splicing analysis, functional differentiation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined molecular (isoform) phenotype and developmental readout; single lab\",\n      \"pmids\": [\"33349972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The hnRNPLL thunder mutation disrupts alternative splicing of Ptprc in plasmablasts (loss of CD45 exon silencing), but this dysregulation does not affect B cell development, proliferation, or in vitro plasmablast generation; the germinal center B cell deficiency observed in Hnrnpllthu/thu mice is B cell-extrinsic.\",\n      \"method\": \"Hnrnpll hypomorphic mouse, mixed bone marrow chimeras, in vivo immunization, in vitro B cell stimulation assays, flow cytometry\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bone marrow chimera epistasis distinguishes cell-intrinsic vs extrinsic effects; single lab with multiple defined readouts\",\n      \"pmids\": [\"33331104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The lncRNA lnc-PPP2R1B physically interacts with and stabilizes hnRNPLL protein; this interaction is required for hnRNPLL-mediated alternative splicing of PPP2R1B (retention of exons 2 and 3), which preserves PP2A trimer function and promotes Wnt/β-catenin-dependent osteogenesis in mesenchymal stem cells.\",\n      \"method\": \"RNA immunoprecipitation/pulldown (lncRNA–protein interaction), knockdown of lnc-PPP2R1B and HNRNPLL, RT-PCR isoform analysis, in vivo ectopic osteogenesis\",\n      \"journal\": \"Stem cell reviews and reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/pulldown for lncRNA-protein interaction, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"37243830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPLL depletion stimulates exon 17 retention in MYOF (myoferlin) mRNA, reducing the short MYOF isoform (MYOFb); hnRNPLL or MYOFb overexpression promotes pancreatic cancer cell migration and invasion, placing MYOF alternative splicing downstream of hnRNPLL in PDAC metastasis.\",\n      \"method\": \"hnRNPLL knockdown/overexpression, RNA-seq splicing analysis, MYOFb overexpression, migration/invasion assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined molecular isoform readout and functional epistasis; single lab\",\n      \"pmids\": [\"39742990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The hnRNPLL thunder mutation disrupts CD45 (Ptprc) exon silencing in both NKT and conventional T cells equally, yet selectively impairs survival of conventional T cells but not NKT cells, demonstrating that hnRNPLL-dependent Ptprc splicing regulation is dissociable from its pro-survival function.\",\n      \"method\": \"Hnrpll hypomorphic mouse, NKT vs T cell comparisons, flow cytometry, functional assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dissection using hypomorphic allele comparing two cell types; single lab, defined molecular and phenotypic readouts\",\n      \"pmids\": [\"22073166\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"hnRNPLL is a tissue-restricted RNA-binding protein (induced in activated/memory T cells, plasma cells, and ES cells) that recognizes CA-rich sequences in introns and 3′ UTRs via its RNA-recognition domain; it acts as a global regulator of alternative splicing—promoting cassette exon skipping or inclusion in a context-dependent manner, inducing flanking intron retention as a mechanistic hallmark—and also stabilizes target mRNAs when bound to their 3′ UTRs, with its best-characterized substrates being CD45/Ptprc (T cell isoform switching), immunoglobulin heavy-chain mRNA (membrane vs. secreted Ig balance, cooperatively with PABPC1), CD44, MYOF, and DNA replication factors (PCNA, RFC3, FEN1), thereby orchestrating transcriptome reprogramming during lymphocyte differentiation, ES cell pluripotency exit, and cancer cell invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"hnRNPLL is an inducible, tissue-restricted RNA-binding protein that functions as a global regulator of alternative splicing and mRNA fate during lymphocyte differentiation, stem-cell state transitions, and cancer cell invasion [#0, #4]. It recognizes CA-dinucleotide-containing sequences in introns and 3′ UTRs, and promotes either exon skipping or inclusion in a context-dependent manner while stabilizing transcripts when bound to their 3′ UTRs [#4]. Its activity depends on an RNA-recognition motif that binds the Ptprc exon-silencing element with micromolar affinity; a single point mutation destabilizing this RRM abolishes CD45 exon skipping and impairs peripheral T cell accumulation [#1]. The best-characterized substrate is CD45/Ptprc, where hnRNPLL is necessary and sufficient to drive the naïve-to-activated isoform switch from CD45RA toward CD45RO, with selective retention of introns flanking cassette exons 4–6 as a mechanistic hallmark [#0, #3]. Notably, hnRNPLL-dependent Ptprc splicing is genetically dissociable from its pro-survival function in conventional T cells [#13], and Senp2, one of its splicing targets, acts downstream to support T cell survival [#3]. In plasma cells, hnRNPLL controls the membrane-versus-secreted immunoglobulin heavy-chain balance and broader plasma-cell differentiation programs including loss of Bcl6, acting on Ig mRNA in cooperation with cytoplasmic PABPC1, which recruits hnRNPLL to the 3′ end of transcripts to regulate alternative polyadenylation [#2, #4, #5]. hnRNPLL also drives exon skipping of ES cell-preferred isoforms of Bptf and Tbx3 to enable embryonic stem cell differentiation [#9], stabilizes mRNAs encoding the DNA replication factors PCNA, RFC3, and FEN1 to promote cell-cycle progression [#8], and controls splicing of CD44 (v6 isoform) and MYOF to govern cancer cell invasion and metastasis [#6, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established hnRNPLL as the inducible factor that directly drives CD45 isoform switching during T cell activation, answering how the naïve-to-activated CD45RA-to-CD45RO transition is controlled.\",\n      \"evidence\": \"shRNA screen with reciprocal knockdown/overexpression in B/T cell lines and primary T cells, plus direct RNA binding and exon array analysis\",\n      \"pmids\": [\"18669861\", \"19100700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the RNA sequence determinants of recognition\", \"Did not establish targets beyond CD45/Ptprc\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Pinpointed the RRM as the essential binding module by showing a single destabilizing point mutation abolishes Ptprc exon-silencing binding and impairs peripheral T cell accumulation, linking molecular binding to an in vivo phenotype.\",\n      \"evidence\": \"ENU mutagenesis screen, in vitro binding assay with micromolar Kd measurement, exon array of mutant T cells\",\n      \"pmids\": [\"19100700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the RRM–RNA complex\", \"Whether the same RRM mediates binding to non-Ptprc targets not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Dissociated hnRNPLL's splicing function from its survival function by showing equal Ptprc dysregulation in NKT and conventional T cells but selective survival impairment only in conventional T cells.\",\n      \"evidence\": \"Hnrpll hypomorphic (thunder) mouse comparing NKT vs conventional T cells by flow cytometry and functional assays\",\n      \"pmids\": [\"22073166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the splicing target responsible for the survival defect\", \"Mechanism of cell-type-selective survival dependency unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended hnRNPLL's regulatory scope beyond T cells to plasma-cell immunoglobulin and CD44 splicing, indicating a broad role in B-lineage isoform control.\",\n      \"evidence\": \"shRNA screen, RNA-seq, and transcriptional profiling in plasma cells\",\n      \"pmids\": [\"22991471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA binding to Ighg2b inferred from isoform shifts rather than direct RIP\", \"Mechanism of membrane vs secreted isoform choice not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified flanking-intron retention as a mechanistic hallmark of hnRNPLL action and placed a specific target (Senp2) downstream in T cell survival via genetic rescue.\",\n      \"evidence\": \"Deep RNA-seq of mutant/low B cells plus retroviral cDNA rescue of Senp2 in Hnrpll-mutant T cells\",\n      \"pmids\": [\"24476532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why introns are retained mechanistically not resolved\", \"Senp2 rescue was only partial, implying additional effectors\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the genome-wide binding preference (CA-rich motifs in introns/3′UTRs) and dual activities of hnRNPLL (context-dependent splicing plus 3′UTR-mediated mRNA stabilization) during B-to-plasma-cell differentiation.\",\n      \"evidence\": \"PAR-CLIP nucleotide-resolution binding maps and RNA-seq in primary differentiating B cells\",\n      \"pmids\": [\"25825742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What dictates inclusion versus exclusion at a given CA site not fully resolved\", \"Stabilization mechanism via 3′UTR not biochemically dissected here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified PABPC1 as a direct cytoplasmic partner that recruits hnRNPLL to 3′ transcript ends to regulate Ig alternative polyadenylation, distinguishing this from PABPC1-independent CD45 splicing.\",\n      \"evidence\": \"Reciprocal co-IP, RNA immunoprecipitation, and knockdown assays of mIgH/sIgH ratio\",\n      \"pmids\": [\"28611064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; structural basis of the hnRNPLL–PABPC1 interaction unknown\", \"Whether PABPC1 cooperation extends to other 3′UTR targets not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked hnRNPLL to cancer invasion by showing it controls CD44v6 splicing, with antibody neutralization placing CD44v6 downstream in colorectal cancer invasion.\",\n      \"evidence\": \"Genome-wide in vivo shRNA metastasis screen, RIP, Matrigel invasion, and CD44v6 antibody neutralization epistasis\",\n      \"pmids\": [\"28360095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; direct mechanism of CD44v6-driven invasion not detailed\", \"Whether finding generalizes beyond colorectal cancer not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed an A-to-I editing-to-splicing feedback loop producing a distinct HNRNPLL isoform (E12A-included) that regulates growth genes independently of canonical HNRNPLL.\",\n      \"evidence\": \"ADAR overexpression/knockdown, splicing reporter assays, RNA-seq, and clonogenic/drug-sensitivity assays\",\n      \"pmids\": [\"29769310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional protein product of E12A isoform not characterized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a 3′UTR-mediated mRNA-stabilization role by showing hnRNPLL binds and stabilizes PCNA, RFC3, and FEN1 mRNAs to promote cell-cycle progression.\",\n      \"evidence\": \"RIP, actinomycin D mRNA stability assay, RNA-seq, and siRNA epistasis with proliferation readouts\",\n      \"pmids\": [\"29869816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular determinants of selective stabilization vs splicing not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established hnRNPLL as a regulator of stem-cell exit by driving exon skipping of ES-preferred Bptf and Tbx3 isoforms required for proper differentiation in vivo.\",\n      \"evidence\": \"hnRNPLL knockout mouse with alternative splicing analysis and differentiation/developmental assays\",\n      \"pmids\": [\"33349972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How hnRNPLL is itself induced/regulated during differentiation onset not addressed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that hnRNPLL-dependent Ptprc dysregulation is dispensable for B cell development, with germinal center deficiency being B cell-extrinsic, refining the in vivo significance of its splicing activity.\",\n      \"evidence\": \"Hnrnpll hypomorphic mouse, mixed bone marrow chimeras, in vivo immunization, and flow cytometry\",\n      \"pmids\": [\"33331104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the extrinsic cell type/program driving the GC defect unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Proposed that the lncRNA lnc-PPP2R1B stabilizes hnRNPLL protein to enable PPP2R1B splicing supporting PP2A function and Wnt-dependent osteogenesis.\",\n      \"evidence\": \"RNA pulldown/RIP for lncRNA-protein interaction, knockdowns, RT-PCR isoform analysis, and in vivo ectopic osteogenesis\",\n      \"pmids\": [\"37243830\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP/pulldown without reciprocal validation of the lncRNA-protein interaction\", \"Mechanism by which the lncRNA stabilizes hnRNPLL protein not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended hnRNPLL's invasion-regulatory role to pancreatic cancer via control of MYOF exon 17 splicing, placing the MYOFb isoform downstream of hnRNPLL in metastasis.\",\n      \"evidence\": \"hnRNPLL knockdown/overexpression, RNA-seq splicing analysis, MYOFb overexpression, and migration/invasion assays\",\n      \"pmids\": [\"39742990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MYOFb promotes invasion not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How hnRNPLL selects between competing outcomes — exon inclusion, exon skipping, intron retention, alternative polyadenylation, and mRNA stabilization — at a given CA-rich site, and which cofactors dictate each choice, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating RRM binding with outcome selection\", \"Combinatorial cofactor logic beyond PABPC1 largely uncharacterized\", \"Determinants of tissue-restricted target repertoire unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 4, 5, 6, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PABPC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}