Affinage

COMMD4

COMM domain-containing protein 4 · UniProt Q9H0A8

Length
199 aa
Mass
21.8 kDa
Annotated
2026-06-09
14 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COMMD4 is a multifunctional protein operating in genome maintenance, endosomal protein recycling, and growth signalling (PMID:33875784, PMID:40448120, PMID:41283898). In the DNA damage response, COMMD4 binds histone H2B and shields it from RNF20/RNF40-mediated monoubiquitination; DNA damage-induced phosphorylation of the H2A-H2B heterodimer redirects COMMD4 to H2A, licensing H2B monoubiquitination and the chromatin remodelling required for both non-homologous end-joining and homologous recombination, such that COMMD4-deficient cells show aberrant chromatin elongation and failed repair (PMID:33875784). Disrupting the COMMD4-H2B interface with a competing H2B-derived peptide sensitises NSCLC cells to ionising radiation and triggers mitotic catastrophe (PMID:37914802). Independently, COMMD4 is a structural subunit of the CCC (CCDC22-CCDC93-COMMD) module of the Commander assembly, where its interaction surface with CCDC22 is required for complex assembly and for SNX17-dependent endosomal recycling of integral membrane proteins bearing ΦxNPxY/F sorting motifs to the cell surface; patient mutations disrupting this assembly cause Ritscher-Schinzel syndrome (PMID:40448120, PMID:40601774). COMMD4 also promotes proliferation and epithelial-mesenchymal transition in melanoma by binding the PI3K regulatory subunit p85 to release catalytic p110 and activate PI3K-AKT signalling (PMID:41283898), and regulates neuronal copper-iron balance by suppressing hephaestin/ferroportin-mediated iron efflux, with depletion conferring protection against ferroptosis in ALS models (PMID:40389143).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2021 High

    Established a direct role for COMMD4 in the DNA damage response by showing it gates H2B monoubiquitination through a phosphorylation-controlled histone-binding switch, explaining how chromatin remodelling at break sites is regulated.

    Evidence Co-immunoprecipitation, peptide mapping, mutagenesis, and siRNA knockdown coupled to NHEJ/HR and chromatin remodelling assays

    PMID:33875784

    Open questions at the time
    • Structural basis of the H2A-versus-H2B binding switch not resolved
    • Identity of the kinase driving the H2A-H2B phosphorylation not established
    • Relationship between this nuclear role and the CCC/cytoplasmic functions unaddressed
  2. 2023 High

    Validated the COMMD4-H2B interface as a druggable vulnerability by showing peptide-mediated disruption sensitises cancer cells to radiation, translating the mechanism into a therapeutic concept.

    Evidence Molecular modelling, in vitro binding, mutagenesis, and cell viability/DNA repair/mitotic catastrophe assays in NSCLC cells

    PMID:37914802

    Open questions at the time
    • No structural confirmation of the modelled binding pose
    • Peptide selectivity over other histone interactions not characterized
    • In vivo efficacy not demonstrated
  3. 2025 Medium

    Linked COMMD4 to growth and metastatic signalling, showing it activates PI3K-AKT by binding p85 to liberate p110, driving G2/M transition and EMT in melanoma.

    Evidence COMMD4 knockout with Co-IP, PI3K-AKT reactivation rescue, xenografts, and proliferation/migration/invasion assays

    PMID:41283898

    Open questions at the time
    • Single lab, abstract-level detail
    • Direct versus indirect nature of the p85 interaction not fully resolved
    • How a chromatin-binding protein engages cytoplasmic PI3K not explained
  4. 2025 Medium

    Identified a copper-iron regulatory role, showing COMMD4 suppresses hephaestin/ferroportin-mediated iron efflux and that its depletion is neuroprotective against ferroptosis in ALS models.

    Evidence COMMD4 overexpression/depletion in ALS cell and animal models with copper/iron measurement, ferroptosis and HEPH/FPN pathway analysis

    PMID:40389143

    Open questions at the time
    • Molecular mechanism linking COMMD4 to copper/HEPH suppression unknown (shown independent of HEPH-FPN interaction)
    • Single lab with limited mechanistic detail
    • Connection to CCC complex copper handling not tested
  5. 2025 Medium

    Defined COMMD4 as a structural CCC/Commander subunit required for endosomal recycling, with its CCDC22 interaction surface causally implicated in Ritscher-Schinzel syndrome.

    Evidence Interactome analysis, cell-surface proteomics, patient missense mutation characterisation, in vitro assembly assays, and RSS mouse models

    PMID:40448120 PMID:40601774

    Open questions at the time
    • Stoichiometry and architecture of COMMD4 within the full Commander assembly not resolved
    • Specific cargo set dependent on COMMD4 incompletely mapped
    • Single-lab convergence pending broader replication
  6. 2025 Low

    Flagged COMMD4 as a cuproptosis sensor via spatio-temporal proteomics, providing a reporter tool for inhibitor screening.

    Evidence Spatio-temporal mass spectrometry, genetic functional screen, and GFP-tagged reporter cell model for high-content drug screening (preprint)

    PMID:bio_10.1101_2025.07.01.662679

    Open questions at the time
    • Preprint, not peer-reviewed
    • No mechanistic follow-up on how COMMD4 senses copper stress
    • Relationship to the CCC copper-handling role untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How COMMD4's distinct nuclear (histone-binding), cytoplasmic (CCC/Commander), signalling (PI3K), and metal-homeostasis activities are coordinated within one protein remains unresolved.
  • No unifying structural or regulatory model connecting the chromatin and CCC roles
  • Tissue- and context-specific partitioning of functions unknown
  • Whether copper sensing integrates the CCC and ferroptosis roles untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-73894 DNA Repair 1
Partners
CCDC22H2AH2BPIK3R1RNF20RNF40SNX17
Complex memberships
CCC complexCommander complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 COMMD4 binds to histone H2B and protects it from monoubiquitination by RNF20/RNF40 at DNA double-strand break sites. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer, causing COMMD4 to preferentially bind H2A instead, which allows RNF20/40 to monoubiquitinate H2B and enable chromatin remodelling at break sites. COMMD4-deficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous end-joining and homologous recombination. Co-immunoprecipitation, peptide mapping, mutagenesis, siRNA knockdown with DNA repair assays (NHEJ and HR), chromatin remodelling assays Communications biology High 33875784
2023 COMMD4 binds directly to histone H2B; a short H2B-derived peptide that occupies the COMMD4 H2B-binding site disrupts the COMMD4-H2B interaction both in vitro and in vivo, leading to increased sensitivity to ionising radiation, increased DNA double-strand breaks, and induction of mitotic catastrophe in NSCLC cells. Molecular modelling, in vitro binding assays, site-directed mutagenesis, cell viability assays, DNA repair assays, mitotic catastrophe assays British journal of cancer High 37914802
2025 COMMD4 activates PI3K-AKT signalling by binding PI3K-p85 (the regulatory subunit), thereby releasing PI3K-p110 (the catalytic subunit) to drive G2/M transition and epithelial-mesenchymal transition in skin cutaneous melanoma cells. COMMD4 knockout induced G2/M arrest via disruption of the p21-CDK1-cyclinB1 axis and impeded EMT by reversing the E/N-cadherin switch; reactivation of PI3K-AKT in knockout cells rescued these phenotypes. COMMD4 gene knockout, co-immunoprecipitation (COMMD4 with PI3K-p85), rescue experiments with PI3K-AKT reactivation, xenograft tumour models, cell proliferation/migration/invasion assays Annals of the New York Academy of Sciences Medium 41283898
2025 COMMD4 inhibits ferroportin (FPN)-mediated neuronal iron efflux by suppressing intracellular copper and hephaestin (HEPH), thereby disrupting Cu-Fe balance and inducing neuronal ferroptosis in ALS models. COMMD4 depletion increased intracellular copper, activated the HEPH/FPN pathway, and exerted neuroprotective effects; the mechanism was shown to be independent of effects on the HEPH-FPN protein interaction itself. COMMD4 overexpression/depletion in ALS cell and animal models, measurement of intracellular copper and iron, ferroptosis assays, HEPH and FPN pathway analysis Brain research Medium 40389143
2025 COMMD4 is a component of the CCC (CCDC22-CCDC93-COMMD) complex within the Commander multiprotein assembly; mutations in CCDC22 that disrupt a conserved CCDC22-COMMD4 interaction surface impair CCC complex assembly and reduce cell-surface recycling of integral membrane proteins, causing Ritscher-Schinzel syndrome phenotypes. Interactome analysis, cell surface proteomics, characterisation of patient missense mutations, in vitro complex assembly assays BMC medical genomics Medium 40448120
2025 Genetic and clinical analysis identified causative mutations in COMMD4 as part of the Commander complex in Ritscher-Schinzel syndrome patients; these mutations disrupted Commander complex assembly and reduced cell-surface presentation of integral membrane proteins bearing ΦxNPxY/F or ΦxNxxY/F sorting motifs recognised by SNX17 for Commander-dependent endosomal recycling. Interactome analysis of patient mutations, cell surface proteomics, mouse models of RSS replicating clinical phenotypes (proteinuria, skeletal malformation, neurological impairment) Science translational medicine Medium 40601774
2011 COMMD4 was identified as a putative interactor of myomegalin (MMGL) isoform 4, an A-kinase anchoring protein, in a yeast two-hybrid screen of a cardiac cDNA library; the interaction was confirmed by fluorescent 3D co-localisation in differentiated H9C2 cells and co-immunoprecipitation in vivo. Yeast two-hybrid screen, fluorescent 3D co-localisation, co-immunoprecipitation BMC cell biology Low 21569246
2025 COMMD4 was identified as a cuproptosis sensor using spatio-temporal mass spectrometry profiling of subcellular proteome changes during copper stress; a GFP-tagged COMMD4 cell model was established and used for high-content drug screening to identify cuproptosis inhibitors. Spatio-temporal mass spectrometry (STMS), genetic functional screen, GFP-tagged COMMD4 reporter cell model, high-content drug screening bioRxivpreprint Low bio_10.1101_2025.07.01.662679

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 COMMD9 promotes TFDP1/E2F1 transcriptional activity via interaction with TFDP1 in non-small cell lung cancer. Cellular signalling 51 27871936
2011 Myomegalin is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C. BMC cell biology 47 21569246
2019 Cardiac and Skeletal Muscle Transcriptome Response to Heat Stress in Kenyan Chicken Ecotypes Adapted to Low and High Altitudes Reveal Differences in Thermal Tolerance and Stress Response. Frontiers in genetics 38 31681427
2017 Altered expression of genes involved in programmed cell death in primary cultured rat cerebellar granule cells acutely challenged with tetrabromobisphenol A. Neurotoxicology 16 28970181
2021 COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks. Communications biology 14 33875784
2015 Profiling of differentially expressed genes in sheep T lymphocytes response to an artificial primary Haemonchus contortus infection. Parasites & vectors 13 25903558
2012 Cloning and characterization of a COMMD4 gene from amphioxus (Branchiostoma belcheri): an insight into the function and evolution of COMMD4. Immunology letters 6 23085603
2023 Targeting the COMMD4-H2B protein complex in lung cancer. British journal of cancer 5 37914802
2025 Ritscher-Schinzel syndrome can be characterized as an endosomal recyclinopathy. Science translational medicine 2 40601774
2024 Identification, diversity, and evolution analysis of Commd gene family in Haliotis discus hannai and immune response to biotic and abiotic stresses. Fish & shellfish immunology 2 38575039
2025 CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome. BMC medical genomics 1 40448120
2025 Non-Lethal heat shock induces COMMD gene activation and enhances pathogen defense in Procambarus clarkii. BMC genomics 1 41233790
2025 COMM domain containing 4 inhibits hephaestin and ferroportin to enhance neuronal ferroptosis by disturbing the Cu-Fe balance in amyotrophic lateral sclerosis. Brain research 0 40389143
2025 COMMD4 Drives Skin Cutaneous Melanoma Progression by Targeting PI3K-p85 to Activate PI3K-AKT. Annals of the New York Academy of Sciences 0 41283898

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