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COPS7A

COP9 signalosome complex subunit 7a · UniProt Q9UBW8

Length
275 aa
Mass
30.3 kDa
Annotated
2026-06-09
21 papers in source corpus 9 papers cited in narrative 9 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

COPS7A (CSN7A) is a subunit of the COP9 signalosome that defines the CSN^CSN7A variant complex and functions in the regulation of cullin-RING ubiquitin ligases (CRLs) (PMID:19295130, PMID:33503427). CSN7A-containing CSN participates in deneddylation of CRLs, a function it shares with the paralogous CSN7B, but it is dispensable for DNA double-strand break sensing, which is specific to CSN7B (PMID:33503427). The CSN^CSN7A variant preferentially forms latent complexes with CRL3, and the C-terminal ~60 residues of CSN7A (within residues 201–275) are required for stable CRL3 binding and for downstream function (PMID:37091236, PMID:40857740). During adipogenesis, the small GTPase RAB18 recruits the latent CSN^CSN7A-CRL3 complex to lipid droplet membranes, where CRL3 is activated by neddylation; CRL3^KEAP1 then ubiquitylates the adipogenesis inhibitor CHOP for proteasomal degradation, an essential step that CSN7A loss blocks (PMID:37091236, PMID:40149914, PMID:27833851). The deubiquitylase USP15 associates exclusively with the latent CSN^CSN7A-CRL3 complex, and CSN7A promotes USP15-mediated deubiquitylation of IκBα to suppress NF-κB signaling (PMID:31409899, PMID:37091236). CSN-CRL complexes including CSN^CSN7A-CRL3 are turned over by a selective macroautophagic pathway (PMID:40857740). CSN7A is also phosphorylated by ATM in a UV-dependent manner (PMID:26986008).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 Medium

    Established an early physical partner of CSN7A by showing it binds the proto-oncoprotein Int-6/eIF3e in the context of the whole CSN, anchoring CSN7A within the signalosome interaction network before its CRL-regulatory role was defined.

    Evidence Yeast two-hybrid screen and co-immunoprecipitation of transfected and endogenous proteins in COS7 cells

    PMID:12220626

    Open questions at the time
    • Functional consequence of the CSN7A-Int-6 interaction not defined
    • Does not establish whether CSN7A directly contacts Int-6 or bridges through the complex
  2. 2009 Medium

    Placed CSN7A within the CSN interactome and connected it to cullin-RING E3 ligases, framing the complex's role in CRL regulation.

    Evidence Affinity purification-mass spectrometry using multiple CSN subunit baits including CSN7a

    PMID:19295130

    Open questions at the time
    • Interactome map does not assign CSN7A-specific (vs CSN7B) functions
    • Does not distinguish direct from complex-mediated CRL contacts
  3. 2016 Medium

    Identified a cellular requirement for the CSN7A variant in adipogenesis, showing CSN7A is necessary but not sufficient to drive adipogenic differentiation.

    Evidence Stable overexpression and siRNA knockdown in LiSa-2 preadipocytes and MEFs with adipogenic differentiation assays

    PMID:27833851

    Open questions at the time
    • Molecular substrate/target downstream of CSN7A in adipogenesis not yet identified
    • Mechanism distinguishing CSN7A from CSN7B in this context unresolved
  4. 2016 Medium

    Connected CSN7A to the DNA damage response by identifying ATM-dependent UV-induced phosphorylation, positioning CSN7A as an ATM substrate.

    Evidence Phosphorylation assay after UV irradiation with ATM identified as the kinase

    PMID:26986008

    Open questions at the time
    • Functional consequence of CSN7A phosphorylation not established
    • Phosphosite mapping and downstream effect on CSN/CRL activity unknown
  5. 2019 Medium

    Defined a signaling output for CSN7A by showing it drives USP15-mediated IκBα deubiquitylation to suppress NF-κB, with lncRNA KRT19P3 stabilizing CSN7A in gastric cancer.

    Evidence RNA pull-down, RIP, siRNA knockdown, rescue, NF-κB reporter and ubiquitination assays in gastric cancer cells

    PMID:31409899

    Open questions at the time
    • Direct vs CSN-mediated recruitment of USP15 to IκBα not dissected here
    • Generality beyond gastric cancer cells untested
  6. 2021 High

    Discriminated CSN7A from CSN7B functionally, establishing shared roles in CRL deneddylation but a specific lack of involvement of CSN7A in DSB sensing.

    Evidence CRISPR knockouts, live-cell microscopy, NBS1/γH2AX immunofluorescence, and deneddylation assays

    PMID:33503427

    Open questions at the time
    • Does not explain the structural basis for paralog-specific recruitment
    • CRL subtype preference of CSN7A not yet defined at this stage
  7. 2023 High

    Resolved the CRL specificity and spatial logic of CSN7A, showing the CSN^CSN7A variant forms latent CRL3 complexes that USP15 binds exclusively and that RAB18 recruits to lipid droplets for neddylation-dependent activation during adipogenesis.

    Evidence Co-IP, KO/KD lines, live-cell imaging, neddylation and adipogenesis assays with CSN7A C-terminal truncation (201–275) mutants in LiSa-2 cells

    PMID:37091236

    Open questions at the time
    • Substrate of the lipid-droplet CRL3 not identified in this study
    • Structural detail of the RAB18-CSN-CRL3 recruitment interface unknown
  8. 2025 Medium

    Mapped the CRL3-binding determinant to the C-terminal ~60 residues of CSN7A and placed CSN-CRL complex turnover within a selective macroautophagy pathway downstream of deneddylation.

    Evidence Domain deletion mutagenesis, CSN5i-3 deneddylation inhibition, detection of ubiquitylated CSN-CRL particles, autophagy assays

    PMID:40857740

    Open questions at the time
    • Autophagy receptor mediating CSN-CRL capture not identified
    • Review-style summary; some claims aggregate prior work
  9. 2025 Medium

    Completed the adipogenic axis by identifying CHOP as the CRL3^KEAP1 substrate ubiquitylated at lipid droplets, explaining how CSN7A relieves a brake on adipogenesis.

    Evidence siRNA knockdown, co-IP, ubiquitination assays in the LiSa-2 adipogenesis model

    PMID:40149914

    Open questions at the time
    • Direct interaction between KEAP1 and CHOP at lipid droplets not structurally resolved
    • Whether other CRL3 adaptors act in parallel is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CSN7A versus CSN7B incorporation is selected to build variant CSN complexes, and whether the ATM-dependent phosphorylation regulates CSN7A's CRL or NF-κB functions, remains open.
  • No mechanism for paralog-specific CSN assembly
  • Functional role of ATM-mediated CSN7A phosphorylation unknown
  • Structural model of CSN^CSN7A-CRL3 not available

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005811 lipid droplet 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-162582 Signal Transduction 1 R-HSA-9612973 Autophagy 1
Partners
ATMCUL3EIF3EKEAP1RAB18USP15
Complex memberships
COP9 signalosome (CSN^CSN7A variant)latent CSN^CSN7A-CRL3 complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 CSN7A (COPS7A) is a subunit of the mammalian COP9 signalosome (CSN) complex; mass spectrometric interrogation using CSN7a as bait identified a protein interaction network including cullin-RING E3 ligases (CRLs) and CRL4-associated proteins, establishing CSN7a as part of the CSN interactome with CRLs. Mass spectrometry-based interactome mapping (affinity purification-MS of CSN subunits including Csn7a) Journal of cell science Medium 19295130
2002 CSN7a (COPS7A) physically interacts with the proto-oncoprotein Int-6 (eIF3e); co-immunoprecipitation in COS7 cells confirmed the interaction, and immunoprecipitation of endogenous proteins showed Int-6 associates with the entire CSN complex. Two-hybrid screen, co-immunoprecipitation (transient expression in COS7 cells and endogenous proteins) FEBS letters Medium 12220626
2016 Overexpression of CSN7A (but not CSN7B) does not accelerate adipogenic differentiation in LiSa-2 cells, whereas silencing of CSN7A reduces adipogenic differentiation, demonstrating that the CSNCSN7A variant is required for but not sufficient to drive adipogenesis. Stable overexpression and siRNA knockdown in LiSa-2 preadipocytes and mouse embryonic fibroblasts, adipogenic differentiation assay FEBS open bio Medium 27833851
2016 ATM kinase phosphorylates CSN7a in a UV-dependent manner, placing CSN7a downstream of ATM in the DNA damage response pathway. Phosphorylation assay following UV irradiation; ATM identified as the kinase; time-course analysis post-UV Oncology reports Medium 26986008
2019 COPS7A promotes deubiquitylation of IκBα via the CSN-associated deubiquitylase USP15, thereby inactivating the NF-κB signaling pathway; lncRNA KRT19P3 directly binds COPS7A (confirmed by RNA pull-down and RIP) and enhances COPS7A protein stability to suppress GC cell proliferation and metastasis. RNA pull-down, RNA immunoprecipitation (RIP), siRNA knockdown, overexpression rescue experiments, NF-κB reporter assays, ubiquitination assays in gastric cancer cells Oncogene Medium 31409899
2021 CSN7A and CSN7B have overlapping functions in the deneddylation of cullin-RING ubiquitin ligases (CRLs); however, CSN7A does not participate in DNA double-strand break (DSB) sensing—live-cell microscopy showed no recruitment of CSN7A to DSBs, and CSN7A knockout cells do not show the DSB-sensing defects seen in CSN7B knockout cells. CRISPR knockout cell construction, live-cell microscopy, NBS1S343p and γH2AX immunofluorescence, deneddylation assays Cell reports High 33503427
2023 CSNCSN7A variant preferentially forms latent complexes with CRL3 (not CRL4A/B); ubiquitin-specific protease 15 (USP15) exclusively binds to latent CSNCSN7A-CRL3 complexes; the small GTPase RAB18 recruits the latent CSNCSN7A-CRL3 complex to lipid droplet membranes where CRL3 is activated by neddylation, an essential step for lipid droplet formation during adipogenesis; truncation of CSN7A C-terminal residues 201–275 blocks latent complex stability and abolishes adipogenesis. Co-immunoprecipitation, knockout/knockdown cell lines, live-cell imaging, neddylation assays, adipogenesis assays with C-terminal truncation mutants of CSN7A in LiSa-2 cells iScience High 37091236
2025 The C-terminal ~60 amino acids of CSN7A are essential for specific binding to CRL3; without this C-terminus, CSNCSN7A1-200 loses CRL3 interaction and associated function; CSN-CRL complexes including CSNCSN7A-CRL3 are degraded by a selective macroautophagic pathway, and inhibition of deneddylation by CSN5i-3 causes accumulation of ubiquitylated CSN-CRL complexes prior to autophagosome formation. Domain deletion mutagenesis, CSN5i-3 inhibitor treatment, detection of ubiquitylated CSN-CRL particles, autophagy assays Essays in biochemistry Medium 40857740
2025 During adipogenesis, CSNCSN7A-CRL3 is recruited by RAB18 to lipid droplet membranes and neddylated there; CRL3KEAP1 ubiquitylates CHOP (C/EBP homologous protein, an inhibitor of adipogenesis) for proteasomal degradation; knockdown of CSN7A blocks this adipogenic step. siRNA knockdown, co-immunoprecipitation, ubiquitination assays, adipogenesis model (LiSa-2 cells) Biomolecules Medium 40149914

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Identification of internal control genes for quantitative polymerase chain reaction in mammary tissue of lactating cows receiving lipid supplements. Journal of dairy science 74 19389958
2009 An interaction network of the mammalian COP9 signalosome identifies Dda1 as a core subunit of multiple Cul4-based E3 ligases. Journal of cell science 71 19295130
2019 Long non-coding RNA KRT19P3 suppresses proliferation and metastasis through COPS7A-mediated NF-κB pathway in gastric cancer. Oncogene 58 31409899
2002 Association of the mammalian proto-oncoprotein Int-6 with the three protein complexes eIF3, COP9 signalosome and 26S proteasome. FEBS letters 53 12220626
2016 Nuclear introns outperform mitochondrial DNA in inter-specific phylogenetic reconstruction: Lessons from horseshoe bats (Rhinolophidae: Chiroptera). Molecular phylogenetics and evolution 42 26826601
2016 Transcriptome analysis of cortical tissue reveals shared sets of downregulated genes in autism and schizophrenia. Translational psychiatry 33 27219343
2016 Overexpression of COP9 signalosome subunits, CSN7A and CSN7B, exerts different effects on adipogenic differentiation. FEBS open bio 14 27833851
2020 Proteomic Analysis of Atrial Appendages Revealed the Pathophysiological Changes of Atrial Fibrillation. Frontiers in physiology 13 33041871
2015 Proteomic analysis reveals that COP9 signalosome complex subunit 7A (CSN7A) is essential for the phase transition of migratory locust. Scientific reports 11 26212173
2022 Panels of mRNAs and miRNAs for decoding molecular mechanisms of Renal Cell Carcinoma (RCC) subtypes utilizing Artificial Intelligence approaches. Scientific reports 10 36180558
2023 Latent CSN-CRL complexes are crucial for curcumin-induced apoptosis and recruited during adipogenesis to lipid droplets via small GTPase RAB18. iScience 9 37091236
2016 UV-dependent phosphorylation of COP9/signalosome in UV-induced apoptosis. Oncology reports 9 26986008
2025 CSN-CRL Complexes: New Regulators of Adipogenesis. Biomolecules 7 40149914
2016 Methylation and expression analyses of Pallister-Killian syndrome reveal partial dosage compensation of tetrasomy 12p and hypomethylation of gene-poor regions on 12p. Epigenetics 6 26890086
2021 CSN7B defines a variant COP9 signalosome complex with distinct function in DNA damage response. Cell reports 5 33503427
2021 lncRNA LOC339524 inhibits the proliferation of bladder cancer cells by targeting the miR-875-5p/COPS7A signaling axis. Experimental and therapeutic medicine 5 34584547
2018 Blood-based dynamic genomic signature for obsessive-compulsive disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 4 30350918
2023 Exploring the endangerment mechanisms of Hipposideros pomona based on molecular phylogeographic methods. Ecology and evolution 3 37869444
2025 The COP9 signalosome variants CSNCSN7A and CSNCSN7B form complexes with specific CRLs which are targets of autophagy. Essays in biochemistry 2 40857740
2019 Light at Night Exposure Effects on Differentiation and Cell Cycle in the Rat Liver With Autonomic Nervous System Denervation. Journal of lasers in medical sciences 2 32021672
2026 Multiomics analysis of red blood cells reveals thalassemia severity beyond globin gene mutations. Blood advances 0 41616282

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