Affinage

COMMD9

COMM domain-containing protein 9 · UniProt Q9P000

Length
198 aa
Mass
21.8 kDa
Annotated
2026-06-09
13 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COMMD9 is an obligate subunit of the CCC (COMMD-CCDC22-CCDC93) Commander complex that drives SNX17-dependent endosomal recycling of multiple cell-surface receptors, returning internalized cargo to the plasma membrane and preventing their lysosomal degradation (PMID:26965651, PMID:40601774). It is structurally central to the system: hepatic loss of COMMD9 collapses the levels of the entire COMMD protein family and destabilizes the CCC core (CCDC22, CCDC93, C16orf62), establishing COMMD9 as a stability determinant for the whole assembly rather than a single-cargo adaptor (PMID:29545368). Through this recycling function it controls the surface presentation of cargo bearing SNX17-recognized ΦxNPxY/F sorting motifs, including LDLR and LRP1, so that COMMD9 deficiency causes receptor mislocalization, impaired LDL uptake, hypercholesterolemia, and accelerated atherosclerosis (PMID:26965651, PMID:29545368, PMID:40601774). The same machinery recycles ATP7B, and hepatic Commd9 loss produces copper accumulation under high-copper conditions (PMID:33262129), and recycles Notch2, whose intracellular accumulation upon COMMD9 disruption reduces Notch signaling and underlies embryonic cardiovascular defects (PMID:26553930); COMMD9 also negatively regulates ENaC surface expression and amiloride-sensitive current through a COMMD1-independent mechanism (PMID:23637203). Pathogenic COMMD9 mutations that impair Commander assembly cause Ritscher-Schinzel syndrome with kidney, bone, and brain involvement (PMID:40601774). Beyond its endosomal role, COMMD9 interacts with TFDP1 via its COMM domain to promote TFDP1/E2F1 transcriptional activity, with its loss attenuating this output and enhancing p53 signaling to arrest the cell cycle at G1/S (PMID:27871936).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2013 Medium

    Established a discrete cellular consequence of COMMD9 action on a membrane channel, showing it limits ENaC surface expression independently of COMMD1 and hinting at a broader role in receptor surface regulation.

    Evidence Co-IP, Ussing chamber current measurement, surface biotinylation, and COMMD1 knockdown in renal collecting duct cells

    PMID:23637203

    Open questions at the time
    • Did not place COMMD9 within the CCC complex or define the recycling step affecting ENaC
    • Mechanism of COMMD1-independent action not resolved
  2. 2015 High

    Defined COMMD9 as a CCC-complex factor required for recycling Notch receptors to the surface, linking its molecular trafficking role to an essential developmental signaling pathway in vivo.

    Evidence siRNA knockdown, co-IP, Notch2 trafficking microscopy, and Commd9 conditional knockout mice with cardiovascular phenotyping

    PMID:26553930

    Open questions at the time
    • Did not identify the cargo-recognition adaptor (SNX17) for Notch
    • Why COMMD9/COMMD5 are specifically required versus other COMMDs unclear
  3. 2016 High

    Extended COMMD9's recycling role to LDLR and to cholesterol homeostasis, showing CCC cooperation with the WASH complex controls receptor fate and plasma lipids.

    Evidence Liver-specific Commd9 knockout mice, cholesterol measurements, LDLR localization, and LDL uptake assays

    PMID:26965651

    Open questions at the time
    • Did not establish whether COMMD9 acts directly on LDLR or through complex integrity
    • Cargo-motif specificity not yet defined
  4. 2016 Medium

    Revealed a transcriptional arm of COMMD9 function distinct from endosomal recycling, mapping a direct COMM-domain interaction with TFDP1 that promotes E2F1 activity and cell-cycle progression.

    Evidence Co-IP with domain-deletion mapping, luciferase reporters, cell cycle and autophagy assays in NSCLC cells

    PMID:27871936

    Open questions at the time
    • Single-lab evidence without in vivo confirmation
    • How COMMD9 partitions between cytoplasmic recycling and nuclear/transcriptional roles is unknown
  5. 2018 High

    Reframed COMMD9 as a structural keystone, showing its loss destabilizes the entire COMMD family and CCC core, explaining the pleiotropic receptor and disease phenotypes.

    Evidence Liver-specific Commd9 knockout mice with quantitative targeted proteomics, surface receptor quantification, and atherosclerosis assessment

    PMID:29545368

    Open questions at the time
    • Did not resolve the assembly hierarchy or stoichiometry that makes COMMD9 essential for stability
    • Which phenotypes are direct versus secondary to complex collapse unclear
  6. 2021 Medium

    Tied COMMD9-dependent recycling to copper metabolism via ATP7B, while showing tissue-specific limits (enterocyte ATP7A regulation unaffected).

    Evidence Hepatocyte- and enterocyte-specific Commd9 knockout mice with tissue copper measurements, CCC component Western blotting, and ATP7B localization

    PMID:33262129

    Open questions at the time
    • Basis for tissue-specific cargo dependence not defined
    • Direct ATP7B trafficking step not visualized at high resolution
  7. 2022 Low

    Implicated COMMD9 in transcriptional repression by ETV6 in leukemia cells, broadening its transcription-regulatory associations.

    Evidence Genome-wide shRNA screen in pre-B ALL cells with validation of ETV6 target gene expression after COMMD9 knockdown

    PMID:35198911

    Open questions at the time
    • No biochemical binding or direct mechanism linking COMMD9 to ETV6
    • Effect may be indirect via complex-wide functions
  8. 2025 High

    Unified COMMD9's role under SNX17-dependent recycling and connected it to human disease, showing patient mutations disrupt Commander assembly and selectively reduce surface presentation of ΦxNPxY/F-motif cargo, causing Ritscher-Schinzel syndrome.

    Evidence Patient genetics, interactome co-IP, cell surface proteomics, and RSS mouse models with renal, skeletal, and neurological phenotypes

    PMID:40601774

    Open questions at the time
    • Genotype-phenotype and tissue-specificity determinants of mutant cargo loss not fully resolved
    • Structural detail of how mutations impair assembly not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How COMMD9 reconciles its cytoplasmic endosomal-recycling function with its nuclear transcriptional interactions (TFDP1/E2F1, ETV6) within a single regulatory framework remains unresolved.
  • No structural model of the COMMD9 COMM domain within the assembled Commander complex
  • Mechanism partitioning COMMD9 between recycling and transcription unknown
  • Determinants of cargo and tissue selectivity undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005768 endosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9609507 Protein localization 2 R-HSA-382551 Transport of small molecules 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
C16ORF62CCDC22CCDC93COMMD5SNX17TFDP1
Complex memberships
CCC (Commander) complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 COMMD9, together with its binding partner COMMD5, is specifically required within the CCC (COMMD-CCDC22-CCDC93) complex for endosomal recycling of Notch receptors to the cell surface; disruption of COMMD9 causes intracellular accumulation of Notch2 and reduced Notch signaling, while Commd9 deletion in mice causes embryonic lethality with cardiovascular defects bearing hallmarks of Notch deficiency. siRNA knockdown, co-immunoprecipitation, fluorescence microscopy of Notch2 trafficking, Commd9 conditional knockout mouse with phenotypic analysis The Journal of cell biology High 26553930
2016 The CCC complex (containing COMMD9) and the WASH complex cooperate to mediate endosomal sorting of LDLR back to the cell surface; hepatic COMMD9 deficiency in mice leads to LDLR mislocalization, increased lysosomal degradation of LDLR, impaired LDL uptake, and elevated plasma LDL cholesterol levels. Liver-specific Commd9 knockout mice, plasma cholesterol measurements, LDLR localization by microscopy, LDL uptake assays Nature communications High 26965651
2016 COMMD9 interacts with TFDP1 (DP1) through its COMM domain; the DNA-binding domain of TFDP1 is required for this interaction; COMMD9 promotes TFDP1/E2F1 transcriptional activity, and COMMD9 knockdown attenuates TFDP1/E2F1 activation and enhances p53 signaling in NSCLC cells, arresting the cell cycle at G1/S. Co-immunoprecipitation, domain-deletion mapping, siRNA knockdown with luciferase reporter assays, cell cycle analysis, and autophagy assays Cellular signalling Medium 27871936
2018 COMMD9 (like COMMD1 and COMMD6) is required for the stability of the entire COMMD protein family and the core CCC complex (CCDC22, CCDC93, C16orf62); hepatic Commd9 knockout causes massive reduction in all 10 COMMD protein levels, destabilization of the CCC core, reduced cell-surface levels of LDLR and LRP1, hypercholesterolemia, and accelerated atherosclerosis. Liver-specific Commd9 knockout mice, quantitative targeted proteomics, Western blotting, cell surface receptor quantification, plasma lipid measurements, atherosclerosis assessment in ApoE3*Leiden mice Circulation research High 29545368
2013 COMMD9 interacts with the epithelial sodium channel (ENaC) and reduces amiloride-sensitive current by decreasing ENaC cell surface expression; this effect is retained when COMMD1 is knocked down, indicating a COMMD1-independent mechanism. Co-immunoprecipitation, electrophysiological current measurement (Ussing chamber), cell surface biotinylation, COMMD1 siRNA knockdown, immunofluorescence colocalization in renal collecting duct cells American journal of physiology. Renal physiology Medium 23637203
2021 Hepatic Commd9 deficiency (like Commd1 and Commd6 deficiency) causes destabilization of the entire CCC complex and leads to hepatic copper accumulation under high-copper diets, consistent with impaired ATP7B endosomal recycling; by contrast, enterocyte-specific Commd9 deficiency does not significantly alter ATP7A regulation or intestinal copper absorption. Hepatocyte-specific and enterocyte-specific Commd9 knockout mice, tissue copper level measurements, Western blotting for CCC complex components, ATP7B localization Disease models & mechanisms Medium 33262129
2025 Pathogenic mutations in COMMD9 (identified in Ritscher-Schinzel syndrome patients) disrupt Commander complex assembly; interactome analysis showed reduced binding of mutant COMMD9 to Commander subunits, and cell surface proteomics showed tissue-specific reduction in presentation of integral membrane proteins containing ΦxNPxY/F or ΦxNxxY/F sorting motifs recognized by SNX17, establishing COMMD9 as essential for SNX17-dependent endosomal recycling of multiple cargo proteins critical for kidney, bone, and brain development. Patient genetic analysis, interactome/co-immunoprecipitation assays, cell surface proteomics, mouse models of RSS with proteinuria, skeletal malformation, and neurological phenotypes Science translational medicine High 40601774
2022 Silencing of COMMD9 abrogates ETV6 repressive transcriptional activity in pre-B acute lymphoblastic leukemia cells, identifying COMMD9 as a modulator of ETV6 function. Genome-wide shRNA screen in pre-B ALL cells followed by validation of ETV6 target gene expression upon COMMD9 knockdown iScience Low 35198911

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nature communications 165 26965651
2018 The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking. Circulation research 107 29545368
2015 Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling. The Journal of cell biology 54 26553930
2016 COMMD9 promotes TFDP1/E2F1 transcriptional activity via interaction with TFDP1 in non-small cell lung cancer. Cellular signalling 51 27871936
2021 Regulation of murine copper homeostasis by members of the COMMD protein family. Disease models & mechanisms 33 33262129
2013 Functional interaction of COMMD3 and COMMD9 with the epithelial sodium channel. American journal of physiology. Renal physiology 27 23637203
2023 Identification of biomarkers related to sepsis diagnosis based on bioinformatics and machine learning and experimental verification. Frontiers in immunology 12 37449204
2010 Screening and identification of differentially expressed genes from chickens infected with Newcastle disease virus by suppression subtractive hybridization. Avian pathology : journal of the W.V.P.A 10 20544419
2023 Whole-Exome Sequencing Indicated New Candidate Genes Associated with Unilateral Cryptorchidism in Pigs. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 6 36758533
2022 Identification of new ETV6 modulators through a high-throughput functional screening. iScience 6 35198911
2025 Ritscher-Schinzel syndrome can be characterized as an endosomal recyclinopathy. Science translational medicine 2 40601774
2025 Whole-exome sequencing and burden analysis identify six novel candidate risk genes and expand the genetic landscape of Parkinson's disease. NPJ Parkinson's disease 2 41339365
2025 Study on the molecular mechanism of dietary FCE supplementation in regulating chicken meat quality. Gene 0 41173221

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