Affinage

HNRNPDL

Heterogeneous nuclear ribonucleoprotein D-like · UniProt O14979

Length
420 aa
Mass
46.4 kDa
Annotated
2026-06-10
18 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HNRNPDL (JKTBP) is a nucleocytoplasmic shuttling heterogeneous nuclear ribonucleoprotein that binds RNA and regulates alternative splicing, and whose loss of function causes limb-girdle muscular dystrophy (PMID:24647604, PMID:31995753). It binds poly(A)+ RNA and recognizes a specific consensus motif (ACUAGC) with nanomolar affinity, requiring both RNA-binding domains together with the N-terminal segment of the adjacent glycine-rich domain; individual RBDs are insufficient (PMID:12406575, PMID:24647604). Steady-state localization is governed by a C-terminal shuttling sequence analogous to hnRNP A1 M9, with nuclear import mediated by transportin 1/karyopherin beta2 (PMID:11705999). The C-terminal prion-like domain drives phase separation and amyloid fibril formation; alternative splicing of the low-complexity domains controls phase-separation behavior, nuclear complex size and dynamics, shuttling, and amyloidogenicity (PMID:31995753). Cryo-EM of the full-length hnRNPDL-2 isoform shows a Gly/Tyr-rich amyloid core encoded by exon 6 coated by a solenoidal arrangement of RNA-binding domains, with these fibrils being stable, non-toxic, and competent for nucleic acid binding — a functional amyloid architecture, while the exon-6-lacking hnRNPDL-3 isoform stays soluble (PMID:36646699). Disease-causing D378H/D378N mutations in the prion-like domain accelerate aggregation and reduce solubility in muscle, consistent with a loss-of-function mechanism underlying disease (PMID:31995753). As a splicing regulator HNRNPDL controls alternative splicing of genes in transcription and signaling pathways (PMID:30447347), and is turned over via TRIM4-mediated ubiquitination (PMID:39643799).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2001 High

    Established that HNRNPDL is a nucleocytoplasmic shuttling protein and identified its import pathway, framing it as an mRNA-associated factor that traffics between compartments rather than a static nuclear protein.

    Evidence Heterokaryon shuttling assay, GFP localization, deletion mapping, and UV cross-linking to poly(A)+ RNA in cultured cells

    PMID:11705999

    Open questions at the time
    • Did not define sequence-specific RNA targets
    • Cytoplasmic function of shuttling not established
  2. 2002 High

    Defined the molecular basis of RNA recognition, showing that high-affinity sequence-specific binding requires cooperative action of both RBDs plus the glycine-rich domain rather than a single isolated domain.

    Evidence SELEX, filter binding with Kd measurement, and deletion mutant analysis with recombinant protein

    PMID:12406575

    Open questions at the time
    • Physiological RNA targets bearing the ACUAGC motif not identified
    • Functional consequence of binding not tested
  3. 2014 Medium

    Linked HNRNPDL to human disease and to an in vivo requirement, showing loss-of-function mutations cause LGMD1G and that the gene is needed for muscle development.

    Evidence Whole genome sequencing of patients, zebrafish morpholino knockdown, and yeast HRP1 orthologue proteomics

    PMID:24647604

    Open questions at the time
    • Molecular mechanism connecting mutation to muscle pathology not resolved
    • Morpholino knockdown specificity not orthogonally confirmed
  4. 2015 Medium

    Demonstrated that the prion-like domain confers intrinsic amyloid-forming capacity, raising the question of whether aggregation is pathological or functional.

    Evidence Bacterial inclusion body characterization by amyloid dye binding, FTIR, TEM, and neurotoxicity assay

    PMID:26160665

    Open questions at the time
    • Toxicity assessed in bacterial inclusion body context, not native cells
    • Relationship to physiological assembly unclear
  5. 2020 High

    Unified splicing, phase separation, and disease by showing alternative splicing of low-complexity domains tunes condensate behavior and amyloidogenicity, and that codon-378 mutations reduce solubility in muscle.

    Evidence In vitro phase separation, FRAP, heterokaryon shuttling, ThT aggregation, and Drosophila muscle solubility assays with disease mutants

    PMID:31995753

    Open questions at the time
    • Direct cause of muscle dysfunction from reduced solubility not mechanistically traced
    • Endogenous isoform ratios in human muscle not quantified
  6. 2023 High

    Provided atomic-level structure showing the amyloid core is encoded by exon 6 and coated by RNA-binding domains, explaining how alternative splicing controls assembly and supporting a functional, non-toxic amyloid.

    Evidence Cryo-EM structure of full-length hnRNPDL-2 fibrils with nucleic acid binding and toxicity assays and isoform comparison

    PMID:36646699

    Open questions at the time
    • Cellular function of the fibrillar state not directly demonstrated in tissue
    • How disease mutations alter this architecture not structurally resolved
  7. 2018 Low

    Profiled HNRNPDL as a global splicing regulator affecting hundreds of transcripts in transcription and signaling pathways.

    Evidence RNA-seq of shRNA knockdown cells

    PMID:30447347

    Open questions at the time
    • No direct binding evidence for individual target transcripts
    • Splicing changes not separated from indirect effects
  8. 2024 Medium

    Identified post-translational control and a specific splicing target, with TRIM4 driving ubiquitin-mediated degradation and hnRNPDL suppressing CDKN2C isoform 2.

    Evidence Reciprocal Co-IP, GST pull-down, and RIP assays plus in vivo tumor model

    PMID:39643799

    Open questions at the time
    • Ubiquitination site and degradation kinetics not mapped
    • Generality of CDKN2C regulation beyond the tumor model untested
  9. 2024 Low

    Placed HNRNPDL in an ALKBH5-associated signaling axis promoting MAPK nuclear translocation in renal cancer.

    Evidence Co-IP, GST pull-down, immunofluorescence, and tumor assays

    PMID:39657539

    Open questions at the time
    • Mechanism by which binding drives MEK/ERK/p38 translocation not dissected
    • Single lab without independent confirmation
  10. 2025 Low

    Reported a cytoplasmic mRNA-stabilizing role whereby a lncRNA relocalizes HNRNPDL to stabilize ZEB1 mRNA, linking it to ferroptosis control.

    Evidence RNA pull-down/RIP, subcellular fractionation, mRNA stability and promoter binding assays, and tumor models

    PMID:41249383

    Open questions at the time
    • Multi-step mechanistic chain not independently validated
    • Direct vs indirect mRNA stabilization not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how the functional amyloid/condensate state of HNRNPDL relates mechanistically to its RNA-processing function in muscle and how disease mutations convert this into pathology.
  • Endogenous physiological RNA targets in muscle unidentified
  • Causal link from reduced solubility to muscle degeneration unresolved
  • Structural impact of D378 mutations on the fibril not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0140110 transcription regulator activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 2 R-HSA-74160 Gene expression (Transcription) 1
Partners
ALKBH5TNPO1TRIM4

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 JKTBP1 (HNRNPDL isoform 1) shuttles between the nucleus and cytoplasm; the 25-residue C-terminal tail was identified as the nucleocytoplasmic shuttling sequence (analogous to M9 of hnRNP A1), and nuclear import is mediated by transportin 1/karyopherin beta2. UV cross-linking showed JKTBP1 directly interacts with poly(A)+ RNA in the cytoplasm following transcription inhibition. Immunofluorescence microscopy, immunoblotting of subcellular fractions, GFP-tagged overexpression, heterokaryon shuttling assay, deletion mutant analysis, UV cross-linking The Journal of biological chemistry High 11705999
2002 JKTBP (HNRNPDL) binds poly(A)+ RNA but not poly(A)- RNA. SELEX identified a consensus high-affinity RNA binding site (ACUAGC) with Kd ~6–12 nM. Both RNA-binding domains (RBDs) together plus the N-terminal 15 amino acids of the C-terminal glycine-rich domain are required for sequence-specific, high-affinity RNA binding; individual RBDs alone are insufficient. UV cross-linking in HL-60 cells, Northwestern blotting with recombinant protein, SELEX (8 rounds), filter binding assays, deletion mutant analysis Gene High 12406575
2014 Loss-of-function mutations in HNRPDL (HNRNPDL) cause limb-girdle muscular dystrophy 1G (LGMD1G). Knockdown of hnrpdl in zebrafish caused a myopathic phenotype, establishing that hnrpdl is required for muscle development in vivo. Loss of the yeast orthologue HRP1 dramatically altered protein levels and cell localizations of RNA-processing pathway proteins. Whole genome sequencing (mutation identification), zebrafish morpholino knockdown (in vivo loss-of-function), yeast proteomics of hrp1 deletion strain Human molecular genetics Medium 24647604
2015 The prion-like domain-containing HNRPDL forms inclusion bodies in bacteria that display amyloid hallmarks: binding to amyloid dyes (Congo red, Thioflavin S) in vitro and in cells, enrichment in intermolecular β-sheet conformation by FTIR, and inner fibrillar ultrastructure by TEM. These inclusion bodies are highly neurotoxic despite their ordered amyloid-like structure. Bacterial expression of inclusion bodies, amyloid dye binding (Congo red, ThT/ThS), FTIR spectroscopy, transmission electron microscopy, neurotoxicity assay Microbial cell factories Medium 26160665
2020 Alternative splicing (AS) of HNRNPDL controls its phase separation properties, the size and dynamics of its nuclear complexes, its nucleus-cytoplasm shuttling, and its amyloidogenicity. The three AS isoforms differ in which disordered low-complexity domains they contain. Disease-causing mutations D378H and D378N in the C-terminal prion-like domain accelerate hnRNPDL aggregation and dramatically reduce protein solubility in Drosophila muscle, consistent with a loss-of-function mechanism. In vitro phase separation assays, fluorescence recovery after photobleaching (FRAP) of nuclear complexes, heterokaryon shuttling, amyloid aggregation assays (ThT fluorescence), Drosophila muscle solubility assay with disease mutants Cell reports High 31995753
2023 Cryo-EM structure of full-length hnRNPDL-2 amyloid fibrils shows a single Gly/Tyr-rich hydrophilic filament with internal water channels as the amyloid core (corresponding to exon 6 sequence), with RNA-binding domains arranged as a solenoidal coat around the core. These fibrils are stable, non-toxic, and retain nucleic acid binding activity, suggesting functional amyloid. Exon 6 is absent in soluble hnRNPDL-3 isoform, providing structural evidence that alternative splicing controls assembly by including/excluding an amyloid-forming exon. Cryo-electron microscopy (cryo-EM) structure determination, nucleic acid binding assay, toxicity assay, isoform comparison Nature communications High 36646699
2018 HNRNPDL regulates alternative splicing of hundreds of genes enriched in transcription regulation and signaling pathways (including NOD-like receptor, Notch, and TNF signaling), and its knockdown increases expression of genes involved in cell apoptosis, proliferation, and migration. RNA-seq transcriptome analysis of shRNA-mediated HNRNPDL knockdown cells Gene Low 30447347
2024 TRIM4 E3 ubiquitin ligase binds to hnRNPDL via its RING and B-box domains and promotes its ubiquitin-mediated degradation. hnRNPDL binds to CDKN2C isoform 2 mRNA and suppresses its expression through alternative splicing. Co-immunoprecipitation, GST pull-down, RIP (RNA immunoprecipitation) assay, in vivo tumor model Frontiers of medicine Medium 39643799
2024 ALKBH5 physically binds to HNRNPDL (confirmed by Co-IP and GST pull-down), and this interaction facilitates the nuclear translocation of MEK, ERK, and p38, activating downstream targets c-Myc and PCNA to promote ccRCC malignant progression. Co-immunoprecipitation, GST pull-down, immunofluorescence, in vitro and in vivo tumor assays International immunopharmacology Low 39657539
2025 RBMS3-AS3 lncRNA directly binds HNRNPDL and recruits it from the nucleus to the cytoplasm, where HNRNPDL stabilizes ZEB1 mRNA. ZEB1 then suppresses GPX4 transcription via E-box binding, promoting ferroptosis in lung adenocarcinoma. RNA pull-down/RIP for lncRNA-HNRNPDL interaction, subcellular fractionation, mRNA stability assay, promoter binding assay (E-box), in vitro and in vivo tumor models NPJ precision oncology Low 41249383

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Human molecular genetics 92 24647604
2001 Identification of the nucleocytoplasmic shuttling sequence of heterogeneous nuclear ribonucleoprotein D-like protein JKTBP and its interaction with mRNA. The Journal of biological chemistry 60 11705999
2020 hnRNPDL Phase Separation Is Regulated by Alternative Splicing and Disease-Causing Mutations Accelerate Its Aggregation. Cell reports 52 31995753
2004 A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21. European journal of human genetics : EJHG 44 15367920
2018 hnRNPDL extensively regulates transcription and alternative splicing. Gene 41 30447347
2023 Cryo-EM structure of hnRNPDL-2 fibrils, a functional amyloid associated with limb-girdle muscular dystrophy D3. Nature communications 29 36646699
2019 HNRNPDL-related muscular dystrophy: expanding the clinical, morphological and MRI phenotypes. Journal of neurology 24 31267206
1999 Two forms of expression and genomic structure of the human heterogeneous nuclear ribonucleoprotein D-like JKTBP gene (HNRPDL). Gene 23 10072754
2019 Limb girdle muscular dystrophy D3 HNRNPDL related in a Chinese family with distal muscle weakness caused by a mutation in the prion-like domain. Journal of neurology 20 30604053
2000 Molecular characterization of a mouse heterogeneous nuclear ribonucleoprotein D-like protein JKTBP and its tissue-specific expression. Gene 20 10717477
2002 Interactions of heterogeneous nuclear ribonucleoprotein D-like protein JKTBP and its domains with high-affinity binding sites. Gene 15 12406575
2021 The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual "window of treatment success" in RA patients. Arthritis research & therapy 9 34521462
2015 The prion-like RNA-processing protein HNRPDL forms inherently toxic amyloid-like inclusion bodies in bacteria. Microbial cell factories 9 26160665
2020 Respiratory muscle involvement in HNRNPDL LGMD D3 muscular dystrophy: an extensive clinical description of the first Italian patient. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology 3 32904822
2024 ALKBH5 promotes malignant proliferation of renal clear cell carcinoma by activating the MAPK pathway through binding to HNRNPDL. International immunopharmacology 2 39657539
2025 M6A-ALKBH5-dependent RBMS3-AS3 down-regulation suppresses ferroptosis to promote lung adenocarcinoma progression through HNRNPDL/ZEB1/GPX4 axis. NPJ precision oncology 1 41249383
2024 TRIM4 modulates the ubiquitin-mediated degradation of hnRNPDL and weakens sensitivity to CDK4/6 inhibitor in ovarian cancer. Frontiers of medicine 1 39643799
2026 HNRNPDL facilitates the advancement of non-small cell lung carcinoma via modulating the alternative splicing of the BTC gene. Immunobiology 0 41861445

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