Affinage

HNRNPLL

Heterogeneous nuclear ribonucleoprotein L-like · UniProt Q8WVV9

Length
542 aa
Mass
60.1 kDa
Annotated
2026-06-10
17 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2008 High

    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

    PMID:18669861 PMID:19100700

    Open questions at the time
    • Did not define the RNA sequence determinants of recognition
    • Did not establish targets beyond CD45/Ptprc
  2. 2008 High

    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

    PMID:19100700

    Open questions at the time
    • No structural model of the RRM–RNA complex
    • Whether the same RRM mediates binding to non-Ptprc targets not addressed
  3. 2011 Medium

    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

    PMID:22073166

    Open questions at the time
    • Did not identify the splicing target responsible for the survival defect
    • Mechanism of cell-type-selective survival dependency unresolved
  4. 2012 Medium

    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

    PMID:22991471

    Open questions at the time
    • RNA binding to Ighg2b inferred from isoform shifts rather than direct RIP
    • Mechanism of membrane vs secreted isoform choice not defined
  5. 2014 Medium

    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

    PMID:24476532

    Open questions at the time
    • Why introns are retained mechanistically not resolved
    • Senp2 rescue was only partial, implying additional effectors
  6. 2015 High

    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

    PMID:25825742

    Open questions at the time
    • What dictates inclusion versus exclusion at a given CA site not fully resolved
    • Stabilization mechanism via 3′UTR not biochemically dissected here
  7. 2017 Medium

    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

    PMID:28611064

    Open questions at the time
    • Single lab; structural basis of the hnRNPLL–PABPC1 interaction unknown
    • Whether PABPC1 cooperation extends to other 3′UTR targets not tested
  8. 2017 Medium

    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

    PMID:28360095

    Open questions at the time
    • Single lab; direct mechanism of CD44v6-driven invasion not detailed
    • Whether finding generalizes beyond colorectal cancer not tested
  9. 2018 Medium

    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

    PMID:29769310

    Open questions at the time
    • Functional protein product of E12A isoform not characterized
    • Single lab
  10. 2018 Medium

    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

    PMID:29869816

    Open questions at the time
    • Molecular determinants of selective stabilization vs splicing not defined
    • Single lab
  11. 2020 Medium

    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

    PMID:33349972

    Open questions at the time
    • How hnRNPLL is itself induced/regulated during differentiation onset not addressed
    • Single lab
  12. 2021 Medium

    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

    PMID:33331104

    Open questions at the time
    • Identity of the extrinsic cell type/program driving the GC defect unknown
    • Single lab
  13. 2023 Low

    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

    PMID:37243830

    Open questions at the time
    • Single Co-IP/pulldown without reciprocal validation of the lncRNA-protein interaction
    • Mechanism by which the lncRNA stabilizes hnRNPLL protein not defined
  14. 2024 Medium

    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

    PMID:39742990

    Open questions at the time
    • Mechanism by which MYOFb promotes invasion not detailed
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0140110 transcription regulator activity 3
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-8953854 Metabolism of RNA 2 R-HSA-1266738 Developmental Biology 1
Partners
PABPC1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 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. shRNA interference screen, overexpression and knockdown in B/T cell lines and primary T cells, exon array analysis Science High 18669861 19100700
2008 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. ENU mutagenesis screen, biochemical binding assay (micromolar Kd measurement), exon array analysis of mutant T cells Immunity High 19100700
2012 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. shRNA screen, RNA-seq, direct RNA binding (implied by transcript isoform shift upon knockdown/overexpression), transcriptional profiling Proceedings of the National Academy of Sciences of the United States of America Medium 22991471
2014 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. Deep RNA sequencing of polyadenylated RNA from hnRNPLL-mutant and hnRNPLL-low B cells; genetic epistasis via retroviral cDNA rescue Genome biology Medium 24476532
2015 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. PAR-CLIP (genome-wide binding site mapping), RNA sequencing, primary B-cell differentiation assays Proceedings of the National Academy of Sciences of the United States of America High 25825742
2017 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. Co-immunoprecipitation, RNA immunoprecipitation, knockdown functional assays for mIgH/sIgH ratio The Journal of biological chemistry Medium 28611064
2017 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. Genome-wide shRNA in vivo metastasis screen, RNA immunoprecipitation, Matrigel invasion assays, antibody neutralisation epistasis Gut Medium 28360095
2018 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. ADAR overexpression/knockdown, splicing reporter assays, RNA-seq, colony formation and drug-sensitivity assays The Journal of biological chemistry Medium 29769310
2018 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. RNA immunoprecipitation, actinomycin D mRNA stability assay, RNA-seq, siRNA epistasis knockdowns, proliferation assays Cancer science Medium 29869816
2020 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. Bioinformatic screening, hnRNPLL knockout mouse, alternative splicing analysis, functional differentiation assays The EMBO journal Medium 33349972
2021 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. Hnrnpll hypomorphic mouse, mixed bone marrow chimeras, in vivo immunization, in vitro B cell stimulation assays, flow cytometry Immunology and cell biology Medium 33331104
2023 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. RNA immunoprecipitation/pulldown (lncRNA–protein interaction), knockdown of lnc-PPP2R1B and HNRNPLL, RT-PCR isoform analysis, in vivo ectopic osteogenesis Stem cell reviews and reports Low 37243830
2024 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. hnRNPLL knockdown/overexpression, RNA-seq splicing analysis, MYOFb overexpression, migration/invasion assays Cancer letters Medium 39742990
2011 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. Hnrpll hypomorphic mouse, NKT vs T cell comparisons, flow cytometry, functional assays PloS one Medium 22073166

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL. Science (New York, N.Y.) 171 18669861
2008 Memory T cell RNA rearrangement programmed by heterogeneous nuclear ribonucleoprotein hnRNPLL. Immunity 73 19100700
2017 HNRNPLL, a newly identified colorectal cancer metastasis suppressor, modulates alternative splicing of CD44 during epithelial-mesenchymal transition. Gut 63 28360095
2015 RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 50 25825742
2014 The RNA-binding protein hnRNPLL induces a T cell alternative splicing program delineated by differential intron retention in polyadenylated RNA. Genome biology 46 24476532
2012 Heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) and elongation factor, RNA polymerase II, 2 (ELL2) are regulators of mRNA processing in plasma cells. Proceedings of the National Academy of Sciences of the United States of America 35 22991471
2017 Cytoplasmic poly(A)-binding protein 1 (PABPC1) interacts with the RNA-binding protein hnRNPLL and thereby regulates immunoglobulin secretion in plasma cells. The Journal of biological chemistry 29 28611064
2018 Tumor-associated intronic editing of HNRPLL generates a novel splicing variant linked to cell proliferation. The Journal of biological chemistry 20 29769310
2020 hnRNPLL controls pluripotency exit of embryonic stem cells by modulating alternative splicing of Tbx3 and Bptf. The EMBO journal 15 33349972
2018 HNRNPLL stabilizes mRNA for DNA replication proteins and promotes cell cycle progression in colorectal cancer cells. Cancer science 13 29869816
2016 RNA-binding protein hnRNPLL as a critical regulator of lymphocyte homeostasis and differentiation. Wiley interdisciplinary reviews. RNA 12 26821996
2023 Lnc-PPP2R1B Mediates the Alternative Splicing of PPP2R1B by Interacting and Stabilizing HNRNPLL and Promotes Osteogenesis of MSCs. Stem cell reviews and reports 8 37243830
2021 Loss of hnRNPLL-dependent splicing of Ptprc has no impact on B-cell development, activation and terminal differentiation into antibody-secreting cells. Immunology and cell biology 8 33331104
2011 Differential requirement for the CD45 splicing regulator hnRNPLL for accumulation of NKT and conventional T cells. PloS one 8 22073166
2024 hnRNPLL regulates MYOF alternative splicing and correlates with early metastasis in pancreatic ductal adenocarcinoma. Cancer letters 6 39742990
2020 Behavioural phenotyping of thunder mice with a hypomorphic mutation of heterogeneous nuclear ribonuclear protein L-like (hnRNPLL) and reduced T cell function. Neuroscience letters 2 33152455
2026 Integrative Multi-Omics Analysis Reveals HNRNPLL as a Potential Biomarker Associated with Hepatocellular Carcinoma Progression. Metabolites 0 42042880

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