| 1998 |
HNRNPR was molecularly defined as an 82 kDa protein with a modular domain structure comprising an acidic N-terminal region (~150 aa), three central RNA recognition motifs (RRMs), a nuclear localization signal, an octapeptide (PPPRMPPP) with similarity to snRNP core protein B epitope, and a C-terminal glycine- and arginine-rich (RGG box) region containing three copies of a tyrosine-rich decapeptide. The protein was identified as a component of hnRNP complexes by immunoprecipitation and co-migration in 2D gel electrophoresis with autoimmune patient serum. |
Autoimmune serum screening of cDNA expression library, SDS-PAGE, 2D gel electrophoresis, immunoprecipitation of hnRNP complexes, sequence analysis |
Nucleic acids research |
High |
9421497
|
| 2002 |
HNRNPR interacts specifically with the SMN (survival motor neuron) protein via yeast two-hybrid and co-immunoprecipitation. This interaction requires wild-type SMN; truncated or SMA-associated mutant SMN forms do not interact. HNRNPR is predominantly localized in axons of motor neurons where it co-localizes with SMN, suggesting a motor neuron-specific function in RNA processing. |
Yeast two-hybrid, co-immunoprecipitation, immunofluorescence localization in motor neuron axons |
Human molecular genetics |
High |
11773003
|
| 2008 |
HNRNPR regulates c-fos mRNA expression in retinal cells by binding to the AU-rich element (ARE) in the c-fos 3' UTR. HNRNPR accelerates both the rise and decline phases of c-fos mRNA and protein, producing an augmented pulse response. An ARE-GFP reporter assay showed HNRNPR significantly reduced GFP expression when an ARE was inserted, and immunoprecipitation-RT-PCR confirmed direct association of HNRNPR with c-fos mRNA in R28 cells and rat retinal tissue. |
ARE-GFP reporter assay, immunoprecipitation-RT-PCR, overexpression/knockdown in retinal cells |
Cellular & molecular biology letters |
Medium |
18197392
|
| 2014 |
SMN and hnRNP R are present in presynaptic compartments at neuromuscular endplates of embryonic and postnatal mice, co-localizing in close proximity in axons and axon terminals both in vitro and in vivo. A direct interaction between SMN and hnRNP R was confirmed in vitro and in vivo, particularly in the cytosol of motoneurons, pointing to functions beyond snRNP assembly including RNA particle recruitment and transport into axons. |
Immunofluorescence at neuromuscular junctions in vivo, co-immunoprecipitation from motoneuron cytosol, in vitro pull-down |
PloS one |
High |
25338097
|
| 2016 |
HNRNPR acts as a positive regulator of both classical (HLA-A, B, C) and nonclassical (HLA-G) MHC class I molecule expression. HNRNPR binds to the 3' UTRs of MHC class I mRNAs, enhancing their stability and expression. Knockdown of HNRNPR reduced MHC class I surface expression and consequently modulated NK cell cytotoxic activity. |
RNA immunoprecipitation (RIP), mRNA stability assays, siRNA knockdown, NK cell cytotoxicity assay, flow cytometry |
Journal of immunology |
High |
27194785
|
| 2018 |
Using iCLIP in motoneurons, hnRNP R was found to have ~3,500 RNA targets predominantly with functions in synaptic transmission and axon guidance. The noncoding RNA 7SK was identified as the top interactor of hnRNP R. 7SK localizes in axons in close proximity to hnRNP R, and hnRNP R depletion reduces axonal 7SK. The function of 7SK in axon elongation depends on its interaction with hnRNP R but not on P-TEFb complex binding, establishing a non-transcriptional role for 7SK in axons mediated through hnRNP R. |
iCLIP (individual nucleotide-resolution crosslinking and immunoprecipitation), hnRNP R knockdown, 7SK deletion mutant series, axon growth assays, RNA FISH |
Proceedings of the National Academy of Sciences of the United States of America |
High |
29507242
|
| 2019 |
HNRNPR promotes gastric cancer cell proliferation and invasion by stabilizing CCNB1 (cyclin B1) and CENPF mRNAs. Knockdown of HNRNPR reduced tumor aggressiveness in mouse models, and knockdown of CCNB1 or CENPF individually abolished hnRNPR-induced cell growth or invasion, respectively, placing HNRNPR upstream of these oncogenic transcripts. |
siRNA knockdown, mRNA stability assays, mouse tumor models (two types), rescue experiments with CCNB1/CENPF knockdown |
Aging |
Medium |
31527303
|
| 2021 |
The full-length isoform of hnRNP R (containing its N-terminal acidic domain) is required for maintaining genomic integrity in motoneurons. Motoneurons from Hnrnprtm1a/tm1a mice (expressing only the truncated isoform lacking the N-terminal acidic domain) showed enhanced double-strand break accumulation and impaired DNA damage response. Proteomic analysis identified YB1 (Yb1) as a top interactor of full-length hnRNP R. Upon DNA damage, full-length hnRNP R is required for Yb1 recruitment to chromatin where Yb1 interacts with γ-H2AX. |
Hnrnpr knockout/knock-in mouse model, γ-H2AX assays, mass spectrometry interactome, Yb1 chromatin fractionation, co-immunoprecipitation with γ-H2AX |
Nucleic acids research |
High |
34850154
|
| 2021 |
HNRNPR acts as a post-transcriptional repressor of HMGCR expression in neurons. HNRNPR binds to the 3' UTR of HMGCR mRNA via its RNA recognition motif (RRM), reducing HMGCR mRNA stability and translation. Knockdown of HNRNPR increases HMGCR expression and cellular cholesterol levels, while overexpression decreases them. RNA immunoprecipitation and luciferase reporter assays confirmed direct binding of HNRNPR to HMGCR 3' UTR. |
RNA immunoprecipitation, luciferase reporter assay, siRNA knockdown, HNRNPR overexpression, cholesterol measurement in N2a and MN1 cells |
Journal of integrative neuroscience |
Medium |
34258925
|
| 2022 |
hnRNP R negatively regulates transcription elongation by modulating P-TEFb complex activity and stability. Loss of hnRNP R promotes release of P-TEFb from 7SK (accompanied by enhanced hnRNP A1 binding to 7SK), increases BRD4 binding to CDK9, and stabilizes CDK9 with enhanced association with Cyclin K. This results in increased RNA Pol II phosphorylation and transcription. hnRNP R was shown to interact directly with BRD4. |
hnRNP R knockdown, RNA Pol II phosphorylation assay, co-immunoprecipitation (hnRNP R-BRD4, P-TEFb/7SK complex), CDK9 stability assay, transcription elongation readouts |
EMBO reports |
High |
35856391
|
| 2023 |
hnRNPR strongly represses SMN2 exon 7 inclusion by binding to an AU-rich element (ARE) located toward the 3' end of exon 7. Both hnRNPR and Sam68 bind this element competitively, with hnRNPR exerting stronger inhibitory effects. Among four hnRNPR splicing isoforms, the exon 5-skipped isoform has minimal inhibitory effect. Antisense oligonucleotides inducing hnRNPR exon 5 skipping promote SMN2 exon 7 inclusion. |
SMN2 minigene system, deletion analysis, RNA-affinity chromatography, co-overexpression analysis, tethering assay, antisense oligonucleotide screen |
Journal of medical genetics |
High |
37225410
|
| 2023 |
Cytosolic Ptbp2 regulates axon growth in motoneurons by controlling the axonal localization and local translation of Hnrnpr mRNA. Ptbp2 binds the 3' UTR of Hnrnpr mRNA, and its depletion strongly reduces axonal Hnrnpr mRNA localization and hnRNP R protein synthesis in axons. Ptbp2 mediates ribosome association of Hnrnpr mRNA in an eIF5A2-dependent manner. This establishes hnRNP R as a locally translated axonal protein whose synthesis is regulated upstream by Ptbp2. |
RNA immunoprecipitation, ribosome association assays, axonal localization by FISH, siRNA/shRNA knockdown of Ptbp2, eIF5A2 inhibition, axon growth measurements |
Nature communications |
High |
37438340
|
| 2024 |
HNRNPR promotes hepatocellular carcinoma metastasis by binding to UPF3B pre-mRNA via its RRM2 domain to generate an exon 8-exclusion truncated splice variant UPF3B-S. UPF3B-S in turn targets the 3' UTR of CDH1 mRNA to enhance its degradation (reducing E-cadherin and activating EMT) and enhances dephosphorylation of LATS1 to promote nuclear YAP1 accumulation and activate Hippo signaling. |
RNA immunoprecipitation, domain-specific deletion analysis (RRM2 identified), in vitro and in vivo invasion/migration assays, Basescope assay, UPF3B-S knockdown/overexpression, CDH1 mRNA stability assay, LATS1/YAP1 signaling readouts |
Journal of advanced research |
High |
38402949
|
| 2024 |
HNRNPR and HNRNPA2B1 stabilize ASCL1 mRNA in an m6A-dependent manner in neuroblastoma. HNRNPR binds the 3' UTR of ASCL1 mRNA, while HNRNPA2B1 binds the 5' UTR. METTL14-mediated m6A modification of ASCL1 mRNA is required for efficient HNRNPR binding; mutations at m6A sites in the UTRs reduced HNRNPR-ASCL1 mRNA association. HNRNPR interacts with IGF2BP1, and knockdown of either impairs ASCL1 mRNA binding. |
RNA immunoprecipitation, m6A site mutagenesis, METTL14 knockdown, co-immunoprecipitation (HNRNPR-IGF2BP1), mRNA stability assays, neuroblastoma cell growth/invasion assays with rescue |
Biochimica et biophysica acta. Molecular basis of disease |
High |
38331110
|
| 2024 |
hnRNP R is a component of translation initiation complexes in motoneuron axons and promotes O-GlcNAcylation of eIF4G through interaction with O-GlcNAc transferase (OGT). In Hnrnpr knockout motoneurons, axon growth is reduced along with lowered synthesis of cytoskeletal and synaptic components. Restoring axonal O-GlcNAc levels rescues local protein synthesis and axon growth defects. Mutant mice display denervated neuromuscular junctions and impaired motor behavior. |
Hnrnpr knockout mouse, ribosome/translation initiation complex co-immunoprecipitation, OGT interaction assay, O-GlcNAc modification measurement of eIF4G, puromycin incorporation (local translation assay), NMJ morphology, motor behavior tests |
Nature communications |
High |
39198412
|
| 2024 |
hnRNP R regulates axonal mitochondrial transport and function in motoneurons. hnRNP R-deficient motoneurons show decreased anterograde and increased retrograde transport of axonal mitochondria. Loss of hnRNP R causes mitochondrial hyperpolarization due to decreased complex I activity and reversed complex V activity in the respiratory chain. |
Hnrnpr knockout motoneurons, live-cell mitochondrial motility imaging, mitochondrial membrane potential measurement (JC-1), respiratory chain complex activity assays |
Neurobiology of disease |
Medium |
38408684
|
| 2025 |
The first RNA recognition motif of human HNRNPR adopts an extended RRM (eRRM1) structure featuring a canonical RRM with a structured N-terminal extension (Next) motif that docks against the RRM and extends the β-sheet surface. A tryptophan cage motif in the adjoining loop positions the Next motif for docking. Mutagenesis of the Next-RRM interface and loop residues disrupts protein solubility, conformational ordering, and thermal stability. This tryptophan cage is evolutionarily conserved across the hnRNPR-like protein family. |
1.90 Å X-ray crystal structure, solution NMR spectroscopy, site-directed mutagenesis, thermal denaturation assays |
Protein science |
High |
40247750
|
| 2025 |
HNRNPR protects XB130 mRNA from degradation mediated by the exonucleases XRN1 and DIS3L2 by binding to specific regions within the XB130 3' UTR. This stabilization elevates XB130 protein levels, promoting NSCLC cell proliferation and EMT via Akt signaling. Dual-luciferase reporter assays, RNA pulldown, and RNA immunoprecipitation confirmed direct HNRNPR binding to XB130 3' UTR. |
RNA pulldown, RNA immunoprecipitation, dual-luciferase reporter assay, XRN1/DIS3L2 knockdown epistasis, NSCLC proliferation/EMT assays, Western blotting, qRT-PCR |
Cellular signalling |
Medium |
40268079
|
| 2025 |
RRM3 of HNRNPR, together with a downstream C-terminal charged region, is required for RNA binding. RRM1 and RRM2 do not contribute equally to binding; RRM3 plus the C-terminal charged region are necessary and sufficient for RNA recognition. HNRNPR also binds RNA G-quadruplexes (rG4s) through RRM3 with its C-terminal charged region and through RG-rich regions within the low-complexity domain (LCD). Binding to rG4s depends on RNA folding and specific rG4 structural features. |
High-throughput biochemical RNA binding assays, domain deletion analysis, rG4-focused RNA pool binding assays, mutagenesis |
bioRxivpreprint |
Medium |
40654891
|
| 2026 |
HNRNPR mutations cause sperm-borne oocyte activation failure and male infertility by reducing expression and causing mislocalization of phospholipase C zeta (PLCζ) in spermatozoa. ICSI with sperm from Hnrnpr-mutated mice failed to induce normal calcium oscillations in oocytes. Mechanistically, hnRNPR regulates Plcz1 splicing in an m6A-dependent manner. Artificial oocyte activation (AOA) or NusA-PLCζ supplementation restored fertilization. |
Whole-exome sequencing in patients, Hnrnpr knock-in mouse model, ICSI with calcium oscillation measurement, PLCζ localization by immunofluorescence, m6A-dependent splicing analysis, rescue with AOA and recombinant PLCζ |
EMBO molecular medicine |
High |
41618099
|