Affinage

HNRNPF

Heterogeneous nuclear ribonucleoprotein F · UniProt P52597

Length
415 aa
Mass
45.7 kDa
Annotated
2026-06-10
16 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/6 claims corpus-supported (67%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HNRNPF is an RNA-binding protein that recognizes G-rich sequences and RNA G-quadruplex structures to control alternative splicing, mRNA stability, and translation across diverse cellular programs (PMID:29269483, PMID:41495911). In splicing, HNRNPF binds G-quadruplex-forming RNA elements to promote exon inclusion, governing an EMT-associated CD44 isoform switch in a manner that depends specifically on G-quadruplex formation rather than on G-tract sequence alone (PMID:29269483). Beyond splicing, HNRNPF binds target 3' UTRs to modulate transcript stability — stabilizing Snail1 mRNA to drive EMT (PMID:31221586) and, through cytoplasmic lncRNA interactions, governing CTGF and p21/CDKN1A mRNA stability (PMID:41232621, PMID:41492473). In embryonic stem cells, ERK2 directly phosphorylates HNRNPF on Ser346 and Tyr356, which increases its binding to Cdk1, Ccnb1, and Eed mRNAs and enhances their translation; this phospho-regulated activity sustains proliferation and suppresses differentiation, and Hnrnpf loss reduces CDK1/CCNB1 and EED to impair proliferation (PMID:41495911). HNRNPF activity is constrained at multiple levels: FOXP3 binds its second quasi-RNA recognition motif (qRRM2) to block pre-mRNA binding (PMID:29773655), FOXO1 downstream of PI3K/AKT transcriptionally represses HNRNPF (PMID:33391425), and cytoplasmic noncoding RNAs (circCacna1c) sequester it to prevent nuclear translocation (PMID:39533214, PMID:41232621). HNRNPF also acts in viral pre-mRNA processing, where it is recruited by the foamy virus Tas protein to a G-cluster cis-element to redirect splicing (PMID:41935299).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2017 High

    Established that HNRNPF reads RNA structure, not merely sequence — it binds G-quadruplex-forming elements to promote exon inclusion, explaining how it controls a functionally important CD44 isoform switch in EMT.

    Evidence CLIP-seq, mutational disruption of G-quadruplex while preserving G-tracts, and splicing reporter assays with knockdown

    PMID:29269483

    Open questions at the time
    • Does not define the full repertoire of G-quadruplex targets genome-wide
    • Structural basis of qRRM-G-quadruplex recognition not resolved
  2. 2018 Medium

    Revealed a protein-based brake on HNRNPF splicing activity: FOXP3 docks on the qRRM2 domain to block pre-mRNA binding, linking HNRNPF to regulatory T cell function.

    Evidence Co-IP with reciprocal domain mapping (FOXP3 exon 2, hnRNPF qRRM2 mutants) and Treg splicing/suppression assays

    PMID:29773655

    Open questions at the time
    • Which endogenous splicing targets are affected in Tregs not enumerated
    • Single lab; interaction not validated by orthogonal structural methods
  3. 2019 Medium

    Extended HNRNPF function beyond splicing to mRNA stabilization, showing direct 3' UTR binding to Snail1 transcript stabilizes it and promotes EMT in bladder cancer.

    Evidence RIP, actinomycin D stability assay, and Snail1 truncation/mutant constructs

    PMID:31221586

    Open questions at the time
    • Precise binding motif within the Snail1 3' UTR not defined
    • Whether stabilization requires G-quadruplex unknown
  4. 2019 Medium

    Connected HNRNPF to cell cycle control via a protein partner, TPX2, whose levels depend on HNRNPF and whose restoration rescues the proliferation defect of HNRNPF loss.

    Evidence Mass spectrometry, Co-IP, western blot, and TPX2 overexpression rescue with flow cytometry

    PMID:31814907

    Open questions at the time
    • Whether HNRNPF regulates TPX2 at the RNA level vs. protein level not resolved
    • Direct RNA target underlying cyclin D1/p21 changes not identified
  5. 2021 Medium

    Placed HNRNPF in a signaling hierarchy, showing FOXO1 downstream of PI3K/AKT directly represses HNRNPF transcription, establishing it as an output rather than a regulator of this pathway.

    Evidence ChIP and luciferase promoter assays, plus LY294002 inhibition and knockdown epistasis

    PMID:33391425

    Open questions at the time
    • FOXO1 binding site on the HNRNPF promoter not mapped to a specific element
    • Single lab
  6. 2024 Medium

    Defined a cytoplasmic sequestration mechanism: noncoding RNAs control HNRNPF by blocking its nuclear entry, with circCacna1c suppressing nuclear HNRNPF and its target RIPK1 to inhibit cardiomyocyte necroptosis, itself tuned by FTO-mediated m6A demethylation.

    Evidence RNA pull-down, nuclear/cytoplasmic fractionation, MeRIP-qPCR, and an in vivo MI model

    PMID:39533214

    Open questions at the time
    • How HNRNPF activates RIPK1 expression mechanistically not detailed
    • Generality of circRNA sequestration across cell types untested
  7. 2024 Medium

    Generalized the cytoplasmic sequestration paradigm, showing LINC03047 binds HNRNPF and retains it in the cytoplasm where it stabilizes CTGF mRNA to drive smooth muscle mitophagy and proliferation in pulmonary hypertension.

    Evidence RNA pull-down, fractionation, mRNA stability assays, knockdown, and in vivo hypoxia PH model

    PMID:41232621

    Open questions at the time
    • Whether cytoplasmic HNRNPF stabilizes CTGF directly via 3' UTR binding not fully mapped
    • Single lab
  8. 2025 Low

    Added further noncoding-RNA control points — USP30-AS1 disrupting HNRNPF binding to the p21 3' UTR to destabilize it, and LINC01189 promoting HNRNPF ubiquitination/degradation — linking HNRNPF turnover and target binding to cancer proliferation and invasion.

    Evidence RIP, mRNA stability and ubiquitination assays, knockdown/overexpression functional assays

    PMID:37865686 PMID:41492473

    Open questions at the time
    • Limited methodological detail for HNRNPF-specific binding/ubiquitination in abstracts
    • E3 ligase mediating LINC01189-dependent degradation not identified
  9. 2026 High

    Established post-translational control of HNRNPF activity, showing ERK2 phosphorylates Ser346/Tyr356 to enhance binding and translation of Cdk1, Ccnb1, and Eed mRNAs, coupling HNRNPF to ESC proliferation and self-renewal.

    Evidence In vitro kinase assay, phospho-mimetic/unphospho-mimetic mutagenesis, RIP, translation/ribosome assays, and Hnrnpf knockout ESC rescue

    PMID:41495911

    Open questions at the time
    • Whether phosphorylation alters G-quadruplex recognition specifically not addressed
    • Upstream signals activating ERK2 toward HNRNPF in ESCs not defined
  10. 2026 Medium

    Demonstrated HNRNPF participates in viral RNA processing, being recruited by foamy virus Tas to a G-cluster cis-element to promote tas/bet splicing and restrict replication.

    Evidence Yeast two-hybrid, Co-IP, splicing assays with cis-element mutation, and viral replication assays

    PMID:41935299

    Open questions at the time
    • Whether the GC-II element forms a G-quadruplex recognized by HNRNPF not tested
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HNRNPF integrates its dual nuclear (splicing) and cytoplasmic (stability/translation) roles, and what determines target selection across these compartments, remains unresolved.
  • No unified model of how phosphorylation and noncoding-RNA sequestration jointly partition HNRNPF between splicing and cytoplasmic functions
  • No structural model of qRRM-G-quadruplex engagement
  • Genome-wide direct target catalog across cell types incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0140098 catalytic activity, acting on RNA 2 GO:0045182 translation regulator activity 1
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-74160 Gene expression (Transcription) 1
Partners
ERK2FOXO1FOXP3TPX2ZFP36

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 RNA G-quadruplex secondary structures promote exon inclusion by serving as binding sites for hnRNPF; destroying G-quadruplex-forming capacity while keeping G tracts intact abrogates exon inclusion. hnRNPF binds G-quadruplex-forming RNA elements and regulates an EMT-associated CD44 isoform switch in a G-quadruplex-dependent manner. RNA-binding protein footprint analysis (CLIP-seq), mutational analysis of G-quadruplex-forming sequences, alternative splicing reporter assays, knockdown experiments Genes & development High 29269483
2019 hnRNP-F directly binds the 3' UTR of Snail1 mRNA (validated by RNA immunoprecipitation and Snail1 mRNA truncation/mutation constructs) and stabilizes Snail1 mRNA, thereby promoting EMT in bladder cancer. RNA immunoprecipitation (RIP), actinomycin D mRNA stability assay, Snail1 mRNA truncation and mutant constructs EBioMedicine Medium 31221586
2018 FOXP3 physically associates with hnRNPF through the exon 2-encoded region of FOXP3 and the second quasi-RNA recognition motif (qRRM2) of hnRNPF, and represses hnRNPF's ability to bind target pre-mRNAs, thereby modulating alternative splicing and suppressive function of regulatory T cells. Co-immunoprecipitation, domain-mapping experiments (FOXP3 exon 2 and hnRNPF qRRM2 mutants), alternative splicing assays, Treg suppression functional assays The Journal of biological chemistry Medium 29773655
2019 hnRNP-F physically interacts with TPX2 protein (identified by mass spectrometry and co-immunoprecipitation); hnRNP-F knockdown reduces TPX2 protein levels, which decreases cyclin D1 and increases p21, leading to cell cycle arrest. Overexpression of TPX2 rescues the proliferation defect caused by hnRNP-F knockdown. Mass spectrometry, co-immunoprecipitation, western blotting, rescue experiments with TPX2 overexpression, flow cytometry American journal of translational research Medium 31814907
2021 hnRNP-F expression is regulated downstream of the PI3K/AKT signaling pathway; FOXO1, a downstream target of PI3K/AKT, binds to the hnRNPF promoter and transcriptionally represses hnRNPF expression (shown by ChIP and luciferase reporter assays). PI3K/AKT inhibition (LY294002) decreases hnRNP-F levels, while hnRNP-F knockdown does not affect PI3K or AKT expression. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, western blotting with PI3K/AKT inhibitor LY294002, siRNA knockdown Journal of Cancer Medium 33391425
2024 circCacna1c directly interacts with Hnrnpf in the cytoplasm, preventing its nuclear translocation; this reduces nuclear Hnrnpf levels and suppresses Hnrnpf-dependent RIPK1 expression, thereby inhibiting necroptosis in cardiomyocytes. FTO-mediated m6A demethylation of circCacna1c promotes its degradation and releases this inhibition. RNA pull-down assay, western blotting (nuclear/cytoplasmic fractionation), MeRIP-qPCR, overexpression in H9c2 cells and MI mouse model Cellular & molecular biology letters Medium 39533214
2024 LINC03047 physically binds hnRNPF and inhibits its nuclear translocation; this cytoplasmic sequestration of hnRNPF enhances CTGF mRNA stability, promoting mitophagy and proliferation of pulmonary artery smooth muscle cells under hypoxia. Targeted inhibition of hnRNPF mitigates hypoxia-induced pulmonary hypertension in vivo. RNA pull-down, nuclear/cytoplasmic fractionation, mRNA stability assays, siRNA knockdown of hnRNPF, in vivo hypoxia-induced PH model Free radical biology & medicine Medium 41232621
2025 In the cytoplasm, the lncRNA USP30-AS1 interacts with HnRNPF and disrupts its binding to the p21 (CDKN1A) 3' UTR, destabilizing p21 mRNA and reducing p21 expression to promote breast cancer cell proliferation. RNA immunoprecipitation, mRNA stability assay, knockdown/overexpression experiments Genes & diseases Low 41492473
2025 hnRNPF binds to the lncRNA LINC01189, which promotes hnRNPF degradation through ubiquitination, thereby modulating gastric cancer cell invasion and migration. Co-immunoprecipitation/pull-down, ubiquitination assay, knockdown/overexpression functional assays Cell death discovery Low 37865686
2025 hnRNP-F overexpression suppresses the TNFα/NFκB signaling pathway in renal tubular epithelial cells under high-glucose conditions; integrative CLIP-seq/RNA-seq analysis suggests hnRNPF binds lncRNA SNHG1 to negatively regulate inflammatory gene transcription, and also regulates alternative splicing by interacting with ZFP36 to form a complex. RNA-seq, CLIP-seq (downloaded GEO dataset), western blotting, overexpression in HK-2 and MPC5 cells Frontiers in physiology Low 40995516
2026 ERK2 directly phosphorylates HNRNPF on Ser346 and Tyr356; phospho-mimetic HNRNPF more potently rescues ESC proliferation and suppresses differentiation than unphospho-mimetic mutant. HNRNPF binds Cdk1, Ccnb1, and Eed mRNAs and enhances their translation; phosphorylation of HNRNPF increases its binding to these mRNAs and promotes their translation. Hnrnpf knockout reduces ESC proliferation by downregulating CDK1 and CCNB1 and promotes differentiation by reducing EED. In vitro kinase assay (ERK2 phosphorylation), phospho-mimetic and unphospho-mimetic mutagenesis, RNA immunoprecipitation, ribosome/translation assays, Hnrnpf knockout ESCs Nucleic acids research High 41495911
2026 hnRNPF is recruited by the PFV Tas protein to nascent viral RNA; hnRNPF specifically recognizes a G-cluster II cis-acting element (GC-II) in the tas/bet pre-mRNA and promotes its splicing into bet mRNA (reducing unspliced tas transcript), thereby shifting viral expression from Tas to Bet and inhibiting PFV replication. Yeast two-hybrid screen, co-immunoprecipitation, splicing assays, cis-element mutation analysis, viral replication assays Cell & bioscience Medium 41935299

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 RNA G-quadruplex secondary structure promotes alternative splicing via the RNA-binding protein hnRNPF. Genes & development 151 29269483
2019 HnRNP-F regulates EMT in bladder cancer by mediating the stabilization of Snail1 mRNA by binding to its 3' UTR. EBioMedicine 51 31221586
2023 The HNRNPF/H RNA binding proteins and disease. Wiley interdisciplinary reviews. RNA 32 37042074
2021 HnRNP-F promotes the proliferation of bladder cancer cells mediated by PI3K/AKT/FOXO1. Journal of Cancer 24 33391425
2018 FOXP3 interacts with hnRNPF to modulate pre-mRNA alternative splicing. The Journal of biological chemistry 20 29773655
2019 HnRNP-F promotes cell proliferation by regulating TPX2 in bladder cancer. American journal of translational research 19 31814907
2023 The VAX2-LINC01189-hnRNPF signaling axis regulates cell invasion and migration in gastric cancer. Cell death discovery 10 37865686
2024 m6A-modified circCacna1c regulates necroptosis and ischemic myocardial injury by inhibiting Hnrnpf entry into the nucleus. Cellular & molecular biology letters 8 39533214
2024 The role of HnrnpF/H as a driver of oligoteratozoospermia. iScience 2 39092172
2025 Circ_0057582 inhibits breast cancer progression via hnRNPF/YAP/SOX9 axis and M2 polarization in TAMs by autophagic degradation of ISG15. Biochemical pharmacology 1 41241017
2025 Nuclear and cytoplasmic USP30-AS1 coordinately regulate breast cancer progression through HnRNPF/p21 and EZH2/c-Myc/p21 axes. Genes & diseases 1 41492473
2026 ERK phosphorylates HNRNPF to promote the proliferation and suppress the differentiation of embryonic stem cells. Nucleic acids research 0 41495911
2026 PFV Tas protein recruits hnRNPF to promote the splicing of tas/bet pre-mRNA. Cell & bioscience 0 41935299
2025 Integrative RNA-seq and CLIP-seq analysis reveals hnRNP-F regulation of TNFα/NFκB signaling in high-glucose conditions. Frontiers in physiology 0 40995516
2025 Super-enhancer-associated long noncoding RNA lnc-SPI1U mediates SPI1 feedback regulation by interacting with HNRNPH1 and HNRNPF. Oncogene 0 41136556
2025 LINC03047 promotes mitophagy by recruiting hnRNPF to enhance CTGF mRNA stability in hypoxic pulmonary hypertension. Free radical biology & medicine 0 41232621

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