Affinage

COPS6

COP9 signalosome complex subunit 6 · UniProt Q7L5N1

Length
327 aa
Mass
36.2 kDa
Annotated
2026-06-09
37 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COPS6/CSN6 is a non-catalytic MPN-domain subunit of the COP9 signalosome that functions as a broad regulator of the ubiquitin-proteasome system and a driver of oncogenic protein stabilization (PMID:25395170, PMID:25144743). Structurally, its MPN domain lacks the metal-coordination residues needed for metalloprotease activity and instead heterodimerizes with the MPN domain of CSN5 to relieve CSN5 autoinhibition and activate the complex's isopeptidase (deneddylase) activity, while its C-terminal domain is indispensable for assembly and integrity of the CSN complex (PMID:22956996, PMID:25144743, PMID:22575649). Through these activities CSN6 modulates cullin-RING ligase function, enhancing Cullin-1 neddylation (PMID:25395170). Beyond the core complex, CSN6 governs the stability of numerous E3 ubiquitin ligases: it promotes the autoubiquitination/degradation of Fbxw7, CHIP, MEKK1, TRIM21, UBR5, SPOP, and DCAF1, and conversely stabilizes E6AP, thereby controlling the abundance of their downstream substrates including Myc, EGFR, c-Jun, OCT1, CDK9, HMGCS1, and NPM1 (PMID:25395170, PMID:27546621, PMID:26237449, PMID:32225170, PMID:33483464, PMID:38308184, PMID:41114465). It also acts through β-TrCP-dependent routes to stabilize β-catenin and DDX5 (PMID:26267535, PMID:36512632) and is integrated into signaling: ERK2 directly binds CSN6 at Leu163/Val165 and phosphorylates it at Ser148, enabling β-catenin stabilization in colorectal cancer (PMID:26267535). The net consequence of CSN6 overexpression is stabilization of oncoproteins, metabolic reprogramming toward nucleotide biosynthesis, cancer stemness, chemoresistance, and immune evasion via PD-L1 stabilization across multiple tumor types (PMID:32134157, PMID:36512632, PMID:41114465). CSN6 is also a caspase-8 substrate during Nod1-driven apoptosis (PMID:17337451), and in zebrafish cops6 is required for dorsoventral patterning, convergent extension, and embryonic survival (PMID:21425078).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2007 Medium

    Established CSN6 as a target of apoptotic proteolysis, linking it to innate-immune/apoptotic signaling through Nod1.

    Evidence Yeast two-hybrid and Co-IP with Nod1, plus caspase inhibitor and CLARP overexpression in cells

    PMID:17337451

    Open questions at the time
    • Functional consequence of CSN6 cleavage on CSN activity not defined
    • Direct caspase-8 cleavage site not mapped
  2. 2011 Medium

    Showed CSN6 has an essential anti-apoptotic and developmental role in a whole vertebrate, beyond cultured cancer cells.

    Evidence Morpholino knockdown of cops6 in zebrafish embryos with phenotypic analysis

    PMID:21425078

    Open questions at the time
    • Molecular pathway mediating developmental phenotypes not identified
    • Morpholino specificity not genetically confirmed
  3. 2012 High

    Resolved why CSN6 is non-catalytic and what its domains do, establishing the MPN domain as a scaffold and the C-terminus as the assembly determinant.

    Evidence X-ray crystallography of Drosophila CSN6 MPN domain and domain-deletion deneddylation reconstitution in yeast and mammalian CSN

    PMID:22575649 PMID:22956996

    Open questions at the time
    • Full-length CSN6 structure within the holo-complex not resolved in these studies
    • Role of MPN domain in non-CSN functions unaddressed
  4. 2014 High

    Defined how the CSN5/CSN6 MPN heterodimer activates catalysis and connected CSN6 to cullin neddylation and oncoprotein control in vivo.

    Evidence Crystal structure of CSN5/CSN6 MPN dimer with isopeptidase assays; Eµ-Myc mouse with Csn6 haploinsufficiency, Co-IP, ubiquitination and neddylation assays

    PMID:25144743 PMID:25395170

    Open questions at the time
    • CSN5/CSN6 module alone is inefficient on CRLs, requiring other subunits not fully defined
    • Direct vs. indirect basis of CSN6 enhancing Cullin-1 neddylation not separated
  5. 2015 High

    Embedded CSN6 in growth-factor signaling and broadened its E3-ligase regulatory repertoire, revealing a recurring 'degrade-the-ligase' or 'stabilize-the-ligase' logic that controls substrate abundance.

    Evidence ERK2-CSN6 direct binding and Ser148 phosphorylation mutagenesis; Co-IP and ubiquitination assays for CHIP/EGFR, COP1/p27, MEKK1/c-Jun, E6AP/p53 axes

    PMID:25945542 PMID:25957415 PMID:26237449 PMID:26267535 PMID:26318036 PMID:27546621

    Open questions at the time
    • Whether these effects require the holo-CSN complex or free CSN6 is unclear
    • Most ligase axes shown in single labs without reciprocal cross-validation
  6. 2023 High

    Connected CSN6 to metabolic reprogramming and chemoresistance through genetic in vivo models, moving beyond correlative cancer-cell observations.

    Evidence Intestinal conditional Csn6 KO mouse with isotope metabolite tracing, Co-IP and ubiquitination assays (β-TrCP/DDX5/PHGDH axis)

    PMID:36512632

    Open questions at the time
    • Mechanism by which CSN6 selects β-TrCP substrates not defined
    • Generalizability of nucleotide-biosynthesis axis to other tumors untested here
  7. 2025 High

    Demonstrated CSN6-driven ribosome biogenesis and gemcitabine resistance via DCAF1/NPM1, with a spontaneous-tumor genetic requirement.

    Evidence Co-IP, proteomics, ubiquitination assays, and conditional CSN6 KO in a KPP spontaneous PDAC mouse model

    PMID:41114465

    Open questions at the time
    • Structural basis of CSN6-DCAF1 interaction not defined
    • Whether NPM1 stabilization depends on CSN deneddylase activity unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved which CSN6 functions require the intact COP9 signalosome versus free or sub-complexed CSN6, and how CSN6 achieves selectivity among its many E3-ligase partners and substrates.
  • No structural model of CSN6 bound to any of its E3-ligase partners
  • Determinants of substrate/ligase selectivity unknown
  • Relationship between deneddylase activity and ligase-stability control not mechanistically linked

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2 R-HSA-1266738 Developmental Biology 1
Partners
CHIPCOP1COPS5DCAF1ERK2SPOPTRIM21UBR5
Complex memberships
COP9 signalosome

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 CSN6 enhances neddylation of Cullin-1 and facilitates autoubiquitination/degradation of Fbxw7 (a CRL component involved in Myc ubiquitination), thereby stabilizing Myc. Csn6 haplo-insufficiency decreased Cullin-1 neddylation, increased Fbxw7 stability, and compromised Myc stability in an Eμ-Myc mouse model, decelerating lymphomagenesis. Genetic epistasis (Eμ-Myc mouse model with Csn6 haplo-insufficiency), Co-IP, ubiquitination assays, neddylation assays Nature communications High 25395170
2015 ERK2 directly binds CSN6 at Leu163/Val165 and phosphorylates CSN6 at Ser148. Phosphorylated CSN6 then inhibits β-Trcp-mediated ubiquitination of β-catenin, stabilizing β-catenin and promoting colorectal cancer development. Direct binding assay (ERK2-CSN6 interaction), phosphorylation site mutagenesis, ubiquitination assays, Co-IP Cancer cell High 26267535
2016 CSN6 associates with the E3 ligase CHIP and facilitates CHIP self-ubiquitination and degradation, thereby reducing CHIP-mediated ubiquitination of EGFR and stabilizing EGFR protein levels in glioblastoma cells. Co-IP, ubiquitination assays, EGFR stability assays (cycloheximide chase), knockdown/overexpression Oncogene Medium 27546621
2015 CSN6 interacts with COP1 (E3 ubiquitin ligase) and facilitates ubiquitin-mediated degradation of p27(Kip1). CSN6-mediated p27 degradation depends on nuclear export of p27, which is regulated through COP1's nuclear export signal. COP1 overexpression leads to cytoplasmic distribution of p27, accelerating its degradation. Co-IP, ubiquitination assay, subcellular fractionation/localization, knockdown/overexpression Cell cycle (Georgetown, Tex.) Medium 25945542
2015 CSN6 associates with MEKK1 and reduces MEKK1 expression by facilitating ubiquitin-mediated degradation of MEKK1. This reduces MEKK1-mediated c-Jun ubiquitination, stabilizing c-Jun and mitigating osmotic stress-mediated c-Jun downregulation. Co-IP, ubiquitination assay, overexpression/knockdown, osmotic stress treatment Cell cycle (Georgetown, Tex.) Medium 26237449
2015 During DNA damage response, COP1 (regulated by CSN6) is downregulated, compromising COP1's E3 ligase activity toward p27(Kip1) and reducing ubiquitin-mediated degradation of p27. COP1 overexpression downregulates p27 and promotes Aurora A expression, linking the CSN6-COP1-p27-Aurora A axis to genome integrity. Ubiquitination assay, knockdown/overexpression, western blotting in DNA damage response contexts Oncotarget Medium 25957415
2015 CSN6 regulates E6AP (UBE3A) stability in cervical cancer: CSN6 associates with E6AP and stabilizes E6AP by reducing its poly-ubiquitination, thereby regulating p53 activity. The CSN6-E6AP axis is regulated by EGF/Akt signaling. Co-IP, ubiquitination assay, knockdown/overexpression, in vivo xenograft Oncotarget Medium 26318036
2012 The MPN(-) domain of CSN6 is not required for CSN deneddylase activity, but the C-terminal domain of CSN6 is indispensable for maintaining the integrity of the CSN complex. A CSN assembled with only the C-terminal fragment of Csn6 (lacking the MPN domain) is fully active in cullin deneddylation. Comparative structural/domain analysis, functional deneddylation assays with domain mutants of mouse Csn6 in yeast and mammalian CSN systems PloS one High 22956996
2014 The MPN domains of CSN5 and CSN6 form a heterodimer; this CSN5/CSN6 association activates the isopeptidase (deneddylase) activity of CSN5, which is otherwise auto-inhibited. However, the CSN5/CSN6 module alone is inefficient in CRL deneddylation, indicating a requirement for other CSN subunits. A hybrid structural model shows that C-termini of CSN subunits likely form a helical bundle scaffolding the complex. Crystal structure (CSN5/CSN6 MPN domains), isopeptidase activity assay, cross-linking mass spectrometry, cryo-EM docking PloS one High 25144743
2012 Crystal structure of the MPN domain from Drosophila CSN6 was solved at 2.5 Å. Structural comparison with other MPN domains shows that CSN6's MPN domain lacks the metal coordination residues required for metalloprotease activity and instead functions as a scaffold. X-ray crystallography (2.5 Å resolution), structural comparison with other MPN domains, bioinformatics analysis FEBS letters High 22575649
2007 Nod1 interacts with CSN6 (and other COP9 signalosome components) through its CARD domain. Activation of the Nod1 apoptotic pathway leads to specific cleavage of CSN6, generating a short N-terminal ~3 kDa peptide. This cleavage is blocked by the broad-spectrum caspase inhibitor Z-VAD and by overexpression of CLARP (a caspase-8 inhibitor), implicating caspase-8 in CSN6 processing. Yeast two-hybrid screening, Co-IP, western blotting with pharmacological caspase inhibitors, overexpression of CLARP The Journal of biological chemistry Medium 17337451
2020 CSN6 facilitates ubiquitin-mediated degradation of TRIM21 E3 ligase, which decreases TRIM21-mediated OCT1 ubiquitination and stabilizes OCT1. OCT1 stabilization drives ALDH1A1 expression and promotes cancer stemness in colorectal cancer. Co-IP, ubiquitination assay, organoid formation, limited dilution analysis, in vivo experiments, tissue microarray British journal of cancer Medium 32225170
2021 CSN6 stabilizes CDK9 by reducing its ubiquitination levels, thereby activating CDK9-mediated signaling in melanoma. CSN6 associates with and negatively regulates the E3 ligase UBR5, which mediates CDK9 ubiquitination and degradation. UBR5 knockdown abrogated effects caused by CSN6 silencing. Co-IP, ubiquitination assay, knockdown/rescue experiments, in vivo xenograft Cell death & disease Medium 33483464
2019 CSN6 interacts with p16INK4a and the proteasome activator REGγ (PA28γ), facilitating ubiquitin-independent proteasomal degradation of p16 in gastric cancer cells. This promotes gastric cancer cell growth and proliferation. Co-immunoprecipitation, immunofluorescence localization, ubiquitination assay (demonstrating ubiquitin-independence), xenograft model Cancer biology & medicine Medium 31565481
2020 The EGFR-ERK pathway upregulates CSN6, which in turn inhibits PD-L1 degradation via the proteasome, stabilizing PD-L1 in glioblastoma cells. CSN6 knockdown decreased PD-L1 expression and increased CHIP expression. ERK blocker PD98059 inhibited CSN6 and PD-L1 upregulation. siRNA knockdown, EGF stimulation, cycloheximide chase, MG132 proteasome inhibition, western blotting Molecular carcinogenesis Medium 32134157
2019 CSN6 inhibits autophagic degradation of Cathepsin L (CTSL) in cervical cancer cells, thereby promoting migration and invasion. CSN6 inhibits autophagy through the mTOR pathway; blocking mTOR reversed CSN6-mediated autophagy inhibition. Knockdown/overexpression, autophagy flux assays, mTOR inhibition (rapamycin), migration/invasion assays International journal of biological sciences Medium 31223289
2023 CSN6 inhibits β-Trcp-mediated polyubiquitination and degradation of DDX5, stabilizing DDX5, which in turn promotes DDX5-mediated PHGDH mRNA stabilization. This increases PHGDH expression and upregulates de novo nucleotide biosynthesis (purine and pyrimidine synthesis) in colorectal cancer, contributing to chemoresistance. Co-IP, ubiquitination assay, isotope metabolite tracing, transcriptomic analysis, Csn6 intestinal conditional knockout mouse model, in vitro/in vivo chemosensitivity assays Cancer research High 36512632
2024 CSN6 antagonizes SPOP ubiquitin ligase to stabilize HMGCS1, which activates YAP1 to promote hepatocellular carcinoma tumor growth. Targeting CSN6 and HMGCS1 hinders tumor growth in orthotopic liver cancer models including high-fat diet conditions. Co-IP, ubiquitination assay, orthotopic liver cancer model, patient-derived xenograft, knockdown/overexpression Advanced science Medium 38308184
2020 CSN6 blocks ubiquitin-proteasome-mediated degradation of Nkx2.2 by interacting with it and inhibiting its ubiquitination, thereby stabilizing Nkx2.2. Nkx2.2 acts as a transcriptional repressor of SIRT2, reducing SIRT2 expression and aggravating cardiac hypertrophy. Co-IP, ubiquitination assay, overexpression/knockdown in cardiomyocytes, Ang II-induced hypertrophy model Experimental cell research Medium 32882218
2020 CSN6 stabilizes c-Fos by binding to it and decreasing its ubiquitination in pancreatic adenocarcinoma cells. Stabilized c-Fos promotes FOXA1 expression, which drives invasion and metastasis. Co-IP, ubiquitination assay, knockdown/rescue experiments Experimental cell research Low 32289284
2020 CSN6 associates with Snail1 and enhances Snail1 protein stability by inhibiting ubiquitin-mediated degradation of Snail1, thereby promoting breast cancer cell migration. Co-IP, ubiquitination assay, migration assay, xenograft experiment International journal of medical sciences Low 33162808
2018 CSN6 positively regulates β-catenin expression in a β-Trcp-dependent manner in papillary thyroid cancer cells, stabilizing β-catenin and facilitating EMT. CSN6 silencing sensitized PTC cells to FH535 via Wnt/β-catenin pathway downregulation. Western blotting, knockdown, in vitro/in vivo proliferation and migration assays Cancer medicine Low 29341469
2018 CSN6 regulates androgen receptor (AR) transport in mouse testicular Sertoli cells through phosphorylation signaling. CSN6 was identified by mass spectrometry as an AR-interacting protein, verified by Co-IP, and its knockdown disrupted testosterone-induced cytoplasmic AR translocation to the plasma membrane. Mass spectrometry, Co-IP, western blot, shRNA knockdown Cellular physiology and biochemistry Low 29991022
2025 CSN6 antagonizes DCAF1-mediated ubiquitination of NPM1 by interacting with DCAF1, thereby stabilizing NPM1 and promoting NPM1-orchestrated ribosome biogenesis and translation of gemcitabine resistance genes (CDA, RRM1/2) in pancreatic ductal adenocarcinoma. Conditional KO of CSN6 hinders tumor formation in a KPP spontaneous PDAC mouse model. Co-IP, proteomic analysis, conditional knockout mouse model (KPP spontaneous PDAC), ubiquitination assay, xenograft Advanced science High 41114465
2011 In zebrafish, cops6 knockdown disrupts dorsoventral patterning, convergent extension movement, brain formation, and promotes apoptosis during segmentation, establishing cops6 as playing anti-apoptotic and developmental roles during early embryogenesis. Morpholino knockdown in zebrafish embryos, phenotypic analysis of developmental processes The International journal of developmental biology Medium 21425078
2023 ALDOA (aldolase A) binds COPS6 (identified by immunoprecipitation and mass spectrometry), and COPS6 depletion inhibited the promoting effects of ALDOA on CRC cell proliferation and metastasis, placing COPS6 downstream of ALDOA in the MAPK/EMT-activating pathway. Immunoprecipitation, mass spectrometry, epistasis via COPS6 knockdown in ALDOA-overexpressing cells Disease markers Low 37457886
2023 p53 negatively regulates COPS6 promoter activity in osteosarcoma (U2OS) and lung cancer (H1299) cells, placing COPS6 downstream of p53 transcriptional regulation. Promoter activity (luciferase) assay, p53 overexpression/knockdown Acta pharmacologica Sinica Low 37095198

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR. Oncogene 84 27546621
2016 Quercetin-induced apoptosis of HT-29 colon cancer cells via inhibition of the Akt-CSN6-Myc signaling axis. Molecular medicine reports 69 27748879
2015 ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development. Cancer cell 68 26267535
2014 CSN6 drives carcinogenesis by positively regulating Myc stability. Nature communications 68 25395170
2020 EGFR-ERK pathway regulates CSN6 to contribute to PD-L1 expression in glioblastoma. Molecular carcinogenesis 36 32134157
2024 CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 33 38308184
2015 Regulating the stability and localization of CDK inhibitor p27(Kip1) via CSN6-COP1 axis. Cell cycle (Georgetown, Tex.) 32 25945542
2020 CSN6-TRIM21 axis instigates cancer stemness during tumorigenesis. British journal of cancer 31 32225170
2023 CSN6 Mediates Nucleotide Metabolism to Promote Tumor Development and Chemoresistance in Colorectal Cancer. Cancer research 30 36512632
2012 The minimal deneddylase core of the COP9 signalosome excludes the Csn6 MPN- domain. PloS one 29 22956996
2014 Structural and biochemical characterization of the Cop9 signalosome CSN5/CSN6 heterodimer. PloS one 27 25144743
2007 The subunit CSN6 of the COP9 signalosome is cleaved during apoptosis. The Journal of biological chemistry 26 17337451
2021 CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9. Cell death & disease 25 33483464
2018 Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/β-catenin signaling and sensitizes cancer cells to FH535 therapy. Cancer medicine 24 29341469
2019 CSN6 Promotes the Migration and Invasion of Cervical Cancer Cells by Inhibiting Autophagic Degradation of Cathepsin L. International journal of biological sciences 21 31223289
2015 COP9 signalosome subunit 6 (CSN6) regulates E6AP/UBE3A in cervical cancer. Oncotarget 19 26318036
2012 The crystal structure of the MPN domain from the COP9 signalosome subunit CSN6. FEBS letters 19 22575649
2013 The COP9 signalosome subunit 6 (CSN6): a potential oncogene. Cell division 18 24286178
2015 CSN6 deregulation impairs genome integrity in a COP1-dependent pathway. Oncotarget 17 25957415
2020 CSN6 aggravates Ang II-induced cardiomyocyte hypertrophy via inhibiting SIRT2. Experimental cell research 16 32882218
2019 CSN6 promotes tumorigenesis of gastric cancer by ubiquitin-independent proteasomal degradation of p16INK4a. Cancer biology & medicine 15 31565481
2023 COPS6 promotes tumor progression and reduces CD8+ T cell infiltration by repressing IL-6 production to facilitate tumor immune evasion in breast cancer. Acta pharmacologica Sinica 13 37095198
2015 CSN6 positively regulates c-Jun in a MEKK1-dependent manner. Cell cycle (Georgetown, Tex.) 10 26237449
2011 The deubiquitylating enzyme Cops6 regulates different developmental processes during early zebrafish embryogenesis. The International journal of developmental biology 8 21425078
2020 CSN6 inhibition suppresses pancreatic adenocarcinoma metastasis via destabilizing the c-Fos protein. Experimental cell research 7 32289284
2020 CUL4A regulates endometrial cancer cell proliferation, invasion and migration by interacting with CSN6. Molecular medicine reports 6 33179082
2018 CSN6 and Rab34 Are Involved in Androgen Receptor Trafficking in Mouse Testicular Sertoli Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 6 29991022
2023 Aldolase A Promotes Colorectal Cancer Progression through Targeting COPS6 and Regulating MAPK Signaling Pathway. Disease markers 5 37457886
2020 CSN6: a promising target for cancer prevention and therapy. Histology and histopathology 5 32016946
2020 CSN6 promotes malignant progression of oral squamous cell carcinoma by down-regulating TIMP-2. European review for medical and pharmacological sciences 5 32495877
2020 CSN6 promotes the cell migration of breast cancer cells by positively regulating Snail1 stability. International journal of medical sciences 4 33162808
2019 The Emerging Role of CSN6 in Biological Behavior and Cancer Progress. Anti-cancer agents in medicinal chemistry 3 30961513
2025 CSN6 Promotes Pancreatic Cancer Progression and Gemcitabine Resistance via Antagonizing DCAF1-Mediated Ubiquitination of NPM1. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2 41114465
2023 Computational exploration of the significance of COPS6 in cancer: Functional and clinical relevance across tumor types. World journal of clinical oncology 1 38059183
2026 ZNF460 Promotes the m6A Modification of COPS6 to Facilitate Immune Escape in Colorectal Cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41806184
2025 CSN6 aggravates inflammation and Myocardial injury in macrophage of sepsis model by MIF. Scientific reports 0 40595050
2024 Mechanisms and potential applications of COPS6 in pan-cancer therapy. World journal of clinical oncology 0 38576589

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