Affinage

CCDC8

Coiled-coil domain-containing protein 8 · UniProt Q9H0W5

Length
538 aa
Mass
59.4 kDa
Annotated
2026-06-09
10 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCDC8 is a membrane-associated scaffold protein that operates within a CUL7–OBSL1 E3 ubiquitin ligase axis controlling mammalian growth and proteostasis (PMID:21737058, PMID:25752541). It binds OBSL1 through its N-terminal region and associates with the CUL7 ligase scaffold, where it facilitates proteasome-dependent degradation of p53 and thereby represses the p53 effectors P21 and BAX; this activity is neddylation-dependent and reversible by MLN4924 (PMID:25752541, PMID:41644704). A C-terminal PxLPxL motif in CCDC8 is specifically recognized by the ankyrin repeats of ANKRA2, defining a distinct motif-mediated interaction (PMID:25752541). Loss of CCDC8 selectively impairs growth hormone–driven STAT5b and MAPK signaling while sparing IGF1-stimulated AKT activation, placing it downstream in GH signaling (PMID:23018678). CCDC8 expression is epigenetically constrained, being repressed by G9a-mediated H3K9me3 at its promoter and regulated through interaction with the demethylase JMJD2A, contexts in which CCDC8 acts as a pro-apoptotic effector influencing cancer cell drug and radiation resistance (PMID:31677131, PMID:34140780). CCDC8 also promotes apoptosis via the TNF signaling pathway in cardiomyocytes (PMID:39424266) and restricts HIV-1 by redirecting plasma-membrane Gag particles to lysosomal degradation through its membrane-binding N-terminal domain (PMID:32651437).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2011 Medium

    Established that CCDC8 is not an isolated factor but a member of a growth-regulatory module by showing it physically partners with OBSL1.

    Evidence Co-immunoprecipitation linking CCDC8, OBSL1, and CUL7 in a growth pathway

    PMID:21737058

    Open questions at the time
    • Direct CCDC8-CUL7 interaction not detected in this study
    • Molecular function within the complex undefined
  2. 2012 Medium

    Resolved which signaling arm CCDC8 supports by showing its loss specifically blunts GH-driven STAT5b/MAPK activation but leaves IGF1-AKT intact.

    Evidence GH and IGF1 stimulation assays in CCDC8-deficient patient fibroblasts with phospho-Western readouts

    PMID:23018678

    Open questions at the time
    • Molecular step at which CCDC8 acts in GH signaling unknown
    • Single lab
  3. 2015 High

    Defined the structural basis of CCDC8 interactions, mapping a C-terminal PxLPxL motif recognized by ANKRA2 ankyrin repeats and an N-terminal OBSL1/CUL7 interface.

    Evidence Structural analysis combined with binding assays and cellular Co-IP

    PMID:25752541

    Open questions at the time
    • Functional consequence of ANKRA2 binding not established
    • Whether ANKRA2 and OBSL1 binding are mutually exclusive unknown
  4. 2019 Medium

    Connected CCDC8 to chromatin-modifier control by showing JMJD2A interacts with and regulates CCDC8, which acts as a pro-apoptotic, drug-sensitizing target.

    Evidence Immunoprecipitation, expression array after JMJD2A knockdown, and siRNA rescue in gastric cancer cells

    PMID:31677131

    Open questions at the time
    • Mechanism by which CCDC8 promotes apoptosis not defined
    • Single Co-IP without reciprocal validation
  5. 2020 Medium

    Identified an antiviral function, showing CCDC8 is membrane-associated and redirects HIV-1 Gag to lysosomal degradation via its N-terminal domain.

    Evidence Live-cell imaging, deletion mutants, subcellular fractionation, and PTM site mutagenesis in overexpression systems

    PMID:32651437

    Open questions at the time
    • Relies on overexpression rather than endogenous levels
    • Mapped PTMs (T87, S261, K491) have no demonstrated functional role in antiviral activity
  6. 2021 Medium

    Showed CCDC8 is epigenetically repressed by G9a-deposited H3K9me3 at its promoter, linking its silencing to radioresistance.

    Evidence ChIP for H3K9me3 at the CCDC8 promoter plus siRNA and apoptosis assays in lung cancer cells

    PMID:34140780

    Open questions at the time
    • Downstream effectors of CCDC8 in radioresistance not defined
    • Single lab
  7. 2024 Medium

    Demonstrated a pro-apoptotic role through TNF signaling, where CCDC8 silencing suppresses TNF-α-induced apoptosis and ROS in cardiomyocytes.

    Evidence AAV9 overexpression and siRNA knockdown in vivo/in vitro, mRNA-seq with KEGG analysis, and flow cytometry under hypoxia-reoxygenation

    PMID:39424266

    Open questions at the time
    • Direct molecular link between CCDC8 and TNF pathway components not established
    • Single lab
  8. 2026 Medium

    Mechanistically united CCDC8 with the CUL7 ligase by showing it drives neddylation-dependent proteasomal degradation of p53, suppressing P21 and BAX.

    Evidence Co-IP, gain/loss-of-function in vitro and in vivo, and MLN4924 neddylation-inhibitor rescue with p53/P21/BAX Westerns

    PMID:41644704

    Open questions at the time
    • Whether CCDC8 directly recruits p53 as substrate versus acting indirectly unresolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how CCDC8's distinct activities — GH signaling, p53 degradation, antiviral defense, and TNF-driven apoptosis — are mechanistically integrated within a single protein.
  • No structural model of CCDC8 within an assembled CUL7-OBSL1 complex
  • No defined enzymatic activity intrinsic to CCDC8
  • Determinants selecting between its growth, antiviral, and apoptotic roles unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-5357801 Programmed Cell Death 3 R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 1
Partners
ANKRA2CUL7JMJD2AOBSL1
Complex memberships
CUL7-OBSL1-CCDC8 E3 ubiquitin ligase complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 CCDC8 physically interacts with OBSL1 but not CUL7, placing CCDC8 in a pathway with CUL7 and OBSL1 to control mammalian growth; identified via coimmunoprecipitation. Coimmunoprecipitation (Co-IP) American journal of human genetics Medium 21737058
2012 In CCDC8-deficient (CCDC8−/−) fibroblasts, GH-stimulated STAT5b and MAPK activation is reduced compared to controls, while IGF1-stimulated AKT activation is normal, indicating CCDC8 loss specifically impairs GH signaling downstream. Signaling assays in patient-derived fibroblast cell lines (CCDC8−/−) with GH and IGF1 stimulation; Western blot readouts for STAT5b, MAPK, AKT phosphorylation Journal of molecular endocrinology Medium 23018678
2015 The ankyrin repeats of ANKRA2 recognize a PxLPxL motif at the C-terminal region of CCDC8, establishing CCDC8 as a major binding partner of ANKRA2 (but not the paralog RFXANK) in cells; the N-terminal region of CCDC8 interacts with OBSL1 to form a CUL7 ligase complex. Binding assays, structural analysis (crystal/structural data), coimmunoprecipitation in cells Structure High 25752541
2019 JMJD2A (a histone lysine demethylase) directly interacts with CCDC8 and regulates its expression; CCDC8 is a downstream pro-apoptotic target of JMJD2A, and CCDC8 inhibition restores drug resistance in gastric cancer cells. Immunoprecipitation, whole-gene expression array after JMJD2A knockdown, siRNA knockdown of CCDC8 with cell viability assays Gastric cancer Medium 31677131
2020 Overexpressed CCDC8 inhibits HIV-1 production by causing newly assembled HIV-1 Gag particles on the plasma membrane to be endocytosed and degraded in lysosomes rather than budding out; CCDC8 is a membrane-associated protein and its N-terminal domain is critical for membrane binding and inhibition of Gag assembly. CCDC8 is phosphorylated at T87 and S261 and mono-methylated at K491, but alanine mutations at these sites do not affect anti-HIV activity. Live-cell imaging, overexpression studies, deletion mutant analysis, subcellular fractionation/co-localization with organelle markers, site-directed mutagenesis Scientific reports Medium 32651437
2021 G9a-mediated H3K9me3 binds to the CCDC8 promoter and suppresses CCDC8 expression, linking G9a epigenetic activity to CCDC8 regulation; CCDC8 dysregulation mediates G9a-driven radioresistance in lung cancer cells. Chromatin immunoprecipitation (ChIP) assay, Western blotting, siRNA knockdown, cell proliferation and apoptosis assays OncoTargets and therapy Medium 34140780
2024 CCDC8 promotes cardiomyocyte apoptosis via the TNF signaling pathway; silencing CCDC8 suppresses TNF-α-induced apoptosis and ROS production in cardiomyocytes under hypoxia-reoxygenation conditions. AAV9 overexpression and siRNA knockdown in vivo and in vitro, mRNA sequencing, KEGG pathway analysis, flow cytometry for apoptosis, TNF-α stimulation assays Life sciences Medium 39424266
2026 CCDC8 interacts with the E3 ubiquitin ligase scaffold CUL7 and facilitates proteasome-dependent degradation of p53, thereby suppressing p53 downstream effectors P21 and BAX; pharmacological inhibition of neddylation (MLN4924) restores p53 levels and reverses CCDC8-driven oncogenic effects. Co-immunoprecipitation, functional overexpression and knockdown studies in vitro and in vivo, neddylation inhibitor (MLN4924) rescue experiments, Western blotting for p53/P21/BAX Oncogene Medium 41644704

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth. American journal of human genetics 95 21737058
2015 The GALNT9, BNC1 and CCDC8 genes are frequently epigenetically dysregulated in breast tumours that metastasise to the brain. Clinical epigenetics 78 26052355
2012 Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling. Journal of molecular endocrinology 50 23018678
2019 JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 24 31677131
2015 Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M syndrome protein CCDC8. Structure (London, England : 1993) 16 25752541
2021 G9a Regulates Cell Sensitivity to Radiotherapy via Histone H3 Lysine 9 Trimethylation and CCDC8 in Lung Cancer. OncoTargets and therapy 11 34140780
2017 Two Siblings with a Mutation in CCDC8 Presenting with Mild Short Stature: A Case of 3-M Syndrome. Hormone research in paediatrics 7 28675896
2020 Overexpressed coiled-coil domain containing protein 8 (CCDC8) mediates newly synthesized HIV-1 Gag lysosomal degradation. Scientific reports 5 32651437
2026 Interstitial cystitis-related gene CCDC8 accelerates tumorigenesis by participating in CUL7-mediated degradation of P53 in bladder cancer. Oncogene 2 41644704
2024 Ablation of CCDC8 provides cardioprotection against cardiomyocyte apoptosis via TNF signaling pathway in myocardial ischemia reperfusion injury. Life sciences 2 39424266

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