Affinage

PHF23

PHD finger protein 23 · UniProt Q9BUL5

Length
403 aa
Mass
43.8 kDa
Annotated
2026-06-10
11 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PHF23 is a chromatin-associated regulator that uses its PHD finger to read the H3K4me3 histone mark and translate this binding into control of gene expression, differentiation, and autophagy (PMID:24535671, PMID:32620764). Structural and biochemical analysis defined how the PHF23 PHD finger recognizes H3K4me3, and the small molecule disulfiram directly targets this domain to block the interaction (PMID:32620764). Through its PHD domain, PHF23 represses autophagy gene expression by two routes: recruiting the NuRD nucleosome remodeling and deacetylase complex to autophagy promoters and reducing enhancer chromatin accessibility via downregulation of AP-1 and C/EBPβ; PHF23 is itself degraded upon amino acid starvation or mTOR inhibition, relieving this repression, and its inhibition promotes clearance of Tau and α1-antitrypsin Z aggregates (PMID:41359382). PHF23 also acts post-translationally through its PHD domain to control substrate stability: it promotes ubiquitination and proteasomal degradation of the E3 ligase LRSAM1 to negatively regulate autophagy (PMID:25484098), and conversely inhibits ubiquitination of α-actinin-4 (ACTN4) to stabilize it and activate ERK signaling, driving NSCLC proliferation, migration, and DNA damage repair (PMID:37626047). In neural development, PHF23 is required for embryonic neurogenesis, binding HDAC2 to inhibit its deacetylation of H3K27ac and thereby promote expression of differentiation genes such as Tcf4 and Eya1 (PMID:40447447). When fused to NUP98 in leukemia, the PHF23 PHD finger aberrantly tethers H3K4me3-reading activity to Hoxa, Hoxb, and Meis1 loci to enforce a stem cell-like signature and block differentiation, a leukemogenic activity that disulfiram selectively reverses (PMID:24535671, PMID:20219246).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2010 Medium

    Established that the PHD domain of the NUP98-PHF23 fusion is functionally required for the leukemic differentiation block, linking chromatin-reading capacity to both nuclear positioning and arrested differentiation.

    Evidence PHD deletion mutant expression with TPA differentiation assay and subcellular localization microscopy in K562 cells

    PMID:20219246

    Open questions at the time
    • Did not identify the histone ligand of the PHD domain
    • Single cell line, fusion context only
  2. 2014 High

    Identified H3K4me3 as the PHD ligand and showed the NUP98-PHF23 fusion tethers this reading activity to Hoxa/Hoxb/Meis1 loci to drive a stem-cell signature, establishing the leukemogenic mechanism and a druggable vulnerability.

    Evidence In vivo ChIP, mouse leukemia model, pharmacological inhibition with disulfiram and gene expression analysis

    PMID:24535671

    Open questions at the time
    • Structural basis of recognition not yet defined
    • Selectivity of disulfiram for PHD vs. other targets not resolved
  3. 2014 Medium

    Revealed a non-chromatin, post-translational function: PHF23 negatively regulates autophagy by binding E3 ligase LRSAM1 through its PHD domain and promoting its ubiquitin-proteasomal degradation.

    Evidence Reciprocal Co-IP, knockdown/overexpression with LC3B-II and substrate degradation assays, PHD deletion mutant

    PMID:25484098

    Open questions at the time
    • Single lab
    • Relationship between PHD chromatin-reading and LRSAM1 binding unclear
    • Direct ubiquitination mechanism on LRSAM1 not fully resolved
  4. 2020 High

    Defined the structural basis of PHF23 PHD recognition of H3K4me3 and validated that small molecules including disulfiram directly engage the domain to kill NUP98-PHF23 AML cells via necrotic/apoptotic death.

    Evidence NMR spectroscopy, ChIP-seq, small molecule inhibitor assays and cell death pathway analysis

    PMID:32620764

    Open questions at the time
    • Co-crystal of inhibitor-bound PHD not reported
    • On-target specificity in vivo not fully separated from off-target effects
  5. 2020 Medium

    Extended PHF23's autophagy-suppressive role to chondrocytes and connected it to AMPK/mTOR/S6K signaling, broadening its physiological context beyond leukemia.

    Evidence Lentiviral knockdown/overexpression, TEM of autophagosomes, western blot for autophagy and signaling markers in IL-1β-treated chondrocytes

    PMID:32380078

    Open questions at the time
    • Whether AMPK/mTOR changes are direct or downstream is unclear
    • Single lab and cell type
  6. 2023 Medium

    Demonstrated an opposite substrate-stabilizing activity in cancer: PHF23 binds ACTN4 via its PHD domain and inhibits its ubiquitination, activating ERK and promoting NSCLC malignancy.

    Evidence Co-IP, ubiquitination assay, knockdown/overexpression, ERK western blot, colony formation, Transwell, xenograft

    PMID:37626047

    Open questions at the time
    • How PHF23 both promotes (LRSAM1) and inhibits (ACTN4) ubiquitination mechanistically is unresolved
    • Single lab
  7. 2025 High

    Resolved the transcriptional mechanism of autophagy repression—NuRD recruitment to promoters plus AP-1/C/EBPβ-dependent enhancer closing—and showed PHF23 is degraded under starvation/mTOR inhibition, with its inhibition clearing disease-relevant protein aggregates.

    Evidence CRISPR interference screen, NuRD interaction assays, ATAC-seq, TF binding analysis, PHD mutagenesis and aggregate clearance assays

    PMID:41359382

    Open questions at the time
    • Direct PHF23-NuRD contact subunit not defined
    • How H3K4me3 reading couples to repression at these loci unresolved
  8. 2025 High

    Established a developmental requirement: PHF23 is needed for embryonic neurogenesis, acting by binding and inhibiting HDAC2 to preserve H3K27ac and activate differentiation genes such as Tcf4 and Eya1.

    Evidence Phf23 knockout mouse, PHF23-HDAC2 Co-IP, H3K27ac chromatin assays and Tcf4 rescue of differentiation defects

    PMID:40447447

    Open questions at the time
    • Reconciliation of HDAC2 inhibition (activating) with NuRD recruitment (repressive) not addressed
    • Whether H3K4me3 reading directs HDAC2 inhibition unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single PHD-finger reader unifies its opposing activities—activating versus repressive chromatin roles and promoting versus inhibiting substrate ubiquitination—into one coherent regulatory logic remains unresolved.
  • No model reconciling context-dependent activation vs. repression
  • Determinants of substrate-specific ubiquitination outcomes unknown
  • Physiological full-length PHF23 genomic binding map across tissues incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0140110 transcription regulator activity 2
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-9612973 Autophagy 3 R-HSA-1643685 Disease 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1266738 Developmental Biology 1
Partners
ACTN4HDAC2LRSAM1NUP98
Complex memberships
NuRD

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 The PHF23 PHD finger domain binds H3K4me3 histone marks. The NUP98-PHF23 fusion protein binds chromatin at H3K4me3 sites including Hoxa, Hoxb, and Meis1 loci, driving a stem cell-like expression signature. Disulfiram inhibits PHD-H3K4me3 binding and selectively kills NUP98-PHF23-expressing myeloblasts, preceded by decreased Hoxa, Hoxb, and Meis1 expression. Chromatin immunoprecipitation (ChIP), mouse leukemia model, pharmacological inhibition with disulfiram, gene expression analysis Cancer discovery High 24535671
2014 PHF23 negatively regulates autophagy by interacting with E3 ligase LRSAM1 via its PHD finger domain and promoting LRSAM1 ubiquitination and proteasomal degradation; loss of PHF23 increases autophagic flux (LC3B-II levels, substrate degradation), while overexpression impairs it. Co-immunoprecipitation, overexpression/knockdown with LC3B-II western blot, autophagic substrate degradation assays, PHD finger deletion mutant analysis Autophagy Medium 25484098
2020 NMR structural analysis and biochemical assays defined the molecular basis by which the PHF23 PHD finger recognizes H3K4me3. Small molecule compounds including disulfiram directly target PHF23PHD to block this interaction, leading to cell death via necrotic and late apoptosis pathways in NUP98-PHF23 AML cells. NMR spectroscopy, ChIP-seq, small molecule inhibitor assays, cell death pathway analysis (necrosis/apoptosis) Nature communications High 32620764
2010 The PHD domain of NUP98-PHF23 is required to impair TPA-induced differentiation of K562 cells; deletion of the PHD domain causes the fusion protein to relocalize from the nucleus to the nucleolus, linking chromatin-binding PHD function to nuclear architecture and differentiation block. PHD domain deletion mutant expression, TPA differentiation assay, subcellular localization by fluorescence/microscopy Leukemia research Medium 20219246
2020 PHF23 negatively regulates autophagy and mitophagy in chondrocytes and alters phosphorylation of AMPK, mTOR, and S6K; knockdown of PHF23 enhanced IL-1β-induced autophagy and protected chondrocytes from OA-associated protein changes. Lentiviral knockdown/overexpression, transmission electron microscopy of autophagosomes, western blot for LC3B, P62, MMP13, ADAMTS5, AMPK/mTOR/S6K phosphorylation Life sciences Medium 32380078
2023 PHF23 interacts with alpha-actinin-4 (ACTN4) via its PHD domain and stabilizes ACTN4 by inhibiting its ubiquitination, leading to activation of the ERK pathway and promoting NSCLC cell proliferation, migration, and DNA damage repair. Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, ERK pathway western blot, colony formation, Transwell migration, xenograft model Cell death & disease Medium 37626047
2025 PHF23 represses autophagy gene expression through two distinct mechanisms: (1) recruiting the NuRD (nucleosome remodeling and deacetylase) complex to autophagy gene promoters, and (2) reducing chromatin accessibility at enhancers by downregulating AP-1 and C/EBPβ transcription factors. Both mechanisms require an intact PHD domain. PHF23 is degraded under amino acid starvation or mTOR inhibition to relieve this repression. Genetic or pharmacological inhibition of PHF23 induces autophagy and promotes clearance of Tau and α1-antitrypsin Z aggregates. CRISPR interference screen, NuRD complex interaction assays, ATAC-seq/chromatin accessibility, transcription factor binding analysis, PHD domain mutagenesis, protein aggregate clearance assays Nucleic acids research High 41359382
2025 PHF23 is required for embryonic neurogenesis; Phf23 knockout in mice causes cortical developmental defects due to differentiation blockade of radial glial cells (RGCs). Mechanistically, PHF23 binds HDAC2 and inhibits its deacetylation activity on H3K27ac, thereby promoting expression of neuronal differentiation genes including Tcf4 and Eya1. Overexpression of Tcf4 rescues differentiation defects in PHF23-KO neural stem cells. Phf23 knockout mouse model, Co-immunoprecipitation of PHF23-HDAC2, H3K27ac chromatin assays, rescue experiment with Tcf4 overexpression, cortical development histology The Journal of neuroscience High 40447447

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 NUP98-PHF23 is a chromatin-modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function. Cancer discovery 73 24535671
2014 PHF23 (plant homeodomain finger protein 23) negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1. Autophagy 25 25484098
2020 Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion. Nature communications 24 32620764
2020 PHF23 negatively regulates the autophagy of chondrocytes in osteoarthritis. Life sciences 17 32380078
2015 Identification of the NUP98-PHF23 fusion gene in pediatric cytogenetically normal acute myeloid leukemia by whole-transcriptome sequencing. Journal of hematology & oncology 17 26066811
2023 PHF23 promotes NSCLC proliferation, metastasis, and chemoresistance via stabilization of ACTN4 and activation of the ERK pathway. Cell death & disease 12 37626047
2010 Regulation of differentiation by a PHD domain in the NUP98-PHF23 fusion protein. Leukemia research 8 20219246
2016 A cryptic translocation leading to NUP98-PHF23 fusion in AML. Best practice & research. Clinical haematology 6 27890253
2025 The Epigenetic Reader PHF23 Is Required for Embryonic Neurogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 2 40447447
2025 Structure, function, and pathology of PHF23. Frontiers in cell and developmental biology 0 41268576
2025 Dual mechanism of autophagy gene repression by PHF23 and therapeutic potential of its inhibition in protein aggregation disorders. Nucleic acids research 0 41359382

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