{"gene":"COPS7A","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2009,"finding":"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.","method":"Mass spectrometry-based interactome mapping (affinity purification-MS of CSN subunits including Csn7a)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal MS-based interactome, single lab, multiple subunit baits providing cross-validation","pmids":["19295130"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Two-hybrid screen, co-immunoprecipitation (transient expression in COS7 cells and endogenous proteins)","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, two orthogonal methods (yeast two-hybrid + Co-IP), confirmed with endogenous proteins","pmids":["12220626"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Stable overexpression and siRNA knockdown in LiSa-2 preadipocytes and mouse embryonic fibroblasts, adipogenic differentiation assay","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, single lab, two cell models","pmids":["27833851"],"is_preprint":false},{"year":2016,"finding":"ATM kinase phosphorylates CSN7a in a UV-dependent manner, placing CSN7a downstream of ATM in the DNA damage response pathway.","method":"Phosphorylation assay following UV irradiation; ATM identified as the kinase; time-course analysis post-UV","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, direct biochemical detection of phosphorylation with identified writer (ATM), but limited mechanistic follow-up for CSN7a specifically","pmids":["26986008"],"is_preprint":false},{"year":2019,"finding":"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.","method":"RNA pull-down, RNA immunoprecipitation (RIP), siRNA knockdown, overexpression rescue experiments, NF-κB reporter assays, ubiquitination assays in gastric cancer cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal methods (RNA pull-down, RIP, functional rescue, pathway reporter) establishing COPS7A-USP15-IκBα axis","pmids":["31409899"],"is_preprint":false},{"year":2021,"finding":"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.","method":"CRISPR knockout cell construction, live-cell microscopy, NBS1S343p and γH2AX immunofluorescence, deneddylation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout cells with multiple orthogonal phenotypic readouts, live-cell imaging, specific negative finding for CSN7A in DSB sensing confirmed by direct comparison with CSN7B","pmids":["33503427"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, knockout/knockdown cell lines, live-cell imaging, neddylation assays, adipogenesis assays with C-terminal truncation mutants of CSN7A in LiSa-2 cells","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KO/KD, domain truncation, neddylation assay, live-cell imaging), single lab but convergent mechanistic findings","pmids":["37091236"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Domain deletion mutagenesis, CSN5i-3 inhibitor treatment, detection of ubiquitylated CSN-CRL particles, autophagy assays","journal":"Essays in biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic domain mapping and autophagy pathway placement, single lab, review-style article summarizing experimental findings","pmids":["40857740"],"is_preprint":false},{"year":2025,"finding":"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.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitination assays, adipogenesis model (LiSa-2 cells)","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway placement with loss-of-function and biochemical assays, single lab, consistent with prior iScience findings","pmids":["40149914"],"is_preprint":false}],"current_model":"COPS7A (CSN7A) is a subunit of the COP9 signalosome (CSN) that defines the CSNCSN7A variant complex, which preferentially forms latent complexes with CRL3 ubiquitin ligases; these latent CSNCSN7A-CRL3 complexes are recruited by the small GTPase RAB18 to lipid droplet membranes during adipogenesis, where CRL3 is activated by neddylation and ubiquitylates the adipogenesis inhibitor CHOP for proteasomal degradation; CSN7A also mediates IκBα deubiquitylation via the associated deubiquitylase USP15, thereby suppressing NF-κB signaling; CSN7A participates in deneddylation of CRLs but is dispensable for DNA double-strand break sensing (a function specific to the CSN7B variant); ATM phosphorylates CSN7A in a UV-dependent manner; and the C-terminal ~60 amino acids of CSN7A are required for CRL3 binding and function."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2002,"claim":"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","pmids":["12220626"],"confidence":"Medium","gaps":["Functional consequence of the CSN7A-Int-6 interaction not defined","Does not establish whether CSN7A directly contacts Int-6 or bridges through the complex"]},{"year":2009,"claim":"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","pmids":["19295130"],"confidence":"Medium","gaps":["Interactome map does not assign CSN7A-specific (vs CSN7B) functions","Does not distinguish direct from complex-mediated CRL contacts"]},{"year":2016,"claim":"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","pmids":["27833851"],"confidence":"Medium","gaps":["Molecular substrate/target downstream of CSN7A in adipogenesis not yet identified","Mechanism distinguishing CSN7A from CSN7B in this context unresolved"]},{"year":2016,"claim":"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","pmids":["26986008"],"confidence":"Medium","gaps":["Functional consequence of CSN7A phosphorylation not established","Phosphosite mapping and downstream effect on CSN/CRL activity unknown"]},{"year":2019,"claim":"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","pmids":["31409899"],"confidence":"Medium","gaps":["Direct vs CSN-mediated recruitment of USP15 to IκBα not dissected here","Generality beyond gastric cancer cells untested"]},{"year":2021,"claim":"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","pmids":["33503427"],"confidence":"High","gaps":["Does not explain the structural basis for paralog-specific recruitment","CRL subtype preference of CSN7A not yet defined at this stage"]},{"year":2023,"claim":"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","pmids":["37091236"],"confidence":"High","gaps":["Substrate of the lipid-droplet CRL3 not identified in this study","Structural detail of the RAB18-CSN-CRL3 recruitment interface unknown"]},{"year":2025,"claim":"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","pmids":["40857740"],"confidence":"Medium","gaps":["Autophagy receptor mediating CSN-CRL capture not identified","Review-style summary; some claims aggregate prior work"]},{"year":2025,"claim":"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","pmids":["40149914"],"confidence":"Medium","gaps":["Direct interaction between KEAP1 and CHOP at lipid droplets not structurally resolved","Whether other CRL3 adaptors act in parallel is untested"]},{"year":null,"claim":"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.","evidence":"No timeline discovery resolves the determinants of paralog selection or the functional output of CSN7A phosphorylation","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,6,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[6,8]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]}],"complexes":["COP9 signalosome (CSN^CSN7A variant)","latent CSN^CSN7A-CRL3 complex"],"partners":["CUL3","USP15","RAB18","KEAP1","EIF3E","ATM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBW8","full_name":"COP9 signalosome complex subunit 7a","aliases":["Dermal papilla-derived protein 10","JAB1-containing signalosome subunit 7a"],"length_aa":275,"mass_kda":30.3,"function":"Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, JUN, I-kappa-B-alpha/NFKBIA, ITPK1 and IRF8/ICSBP, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UBW8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/COPS7A","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDB1","stoichiometry":4.0},{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COPS7A","total_profiled":1310},"omim":[{"mim_id":"616009","title":"COP9 SIGNALOSOME, SUBUNIT 7A; COPS7A","url":"https://www.omim.org/entry/616009"},{"mim_id":"148041","title":"KERATIN 6A, TYPE II; KRT6A","url":"https://www.omim.org/entry/148041"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COPS7A"},"hgnc":{"alias_symbol":["CSN7A"],"prev_symbol":[]},"alphafold":{"accession":"Q9UBW8","domains":[{"cath_id":"-","chopping":"8-72","consensus_level":"medium","plddt":91.3109,"start":8,"end":72},{"cath_id":"1.10.10.10","chopping":"88-161","consensus_level":"medium","plddt":95.8666,"start":88,"end":161},{"cath_id":"1.20.5","chopping":"164-220","consensus_level":"high","plddt":96.3572,"start":164,"end":220}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBW8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBW8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBW8-F1-predicted_aligned_error_v6.png","plddt_mean":84.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COPS7A","jax_strain_url":"https://www.jax.org/strain/search?query=COPS7A"},"sequence":{"accession":"Q9UBW8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBW8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBW8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBW8"}},"corpus_meta":[{"pmid":"19389958","id":"PMC_19389958","title":"Identification of internal control genes for quantitative polymerase chain reaction in mammary tissue of lactating cows receiving lipid supplements.","date":"2009","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/19389958","citation_count":74,"is_preprint":false},{"pmid":"19295130","id":"PMC_19295130","title":"An interaction network of the mammalian COP9 signalosome identifies Dda1 as a core subunit of multiple Cul4-based E3 ligases.","date":"2009","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19295130","citation_count":71,"is_preprint":false},{"pmid":"31409899","id":"PMC_31409899","title":"Long non-coding RNA KRT19P3 suppresses proliferation and metastasis through COPS7A-mediated NF-κB pathway in gastric cancer.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31409899","citation_count":58,"is_preprint":false},{"pmid":"12220626","id":"PMC_12220626","title":"Association of the mammalian proto-oncoprotein Int-6 with the three protein complexes eIF3, COP9 signalosome and 26S proteasome.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12220626","citation_count":53,"is_preprint":false},{"pmid":"26826601","id":"PMC_26826601","title":"Nuclear introns outperform mitochondrial DNA in inter-specific phylogenetic reconstruction: Lessons from horseshoe bats (Rhinolophidae: Chiroptera).","date":"2016","source":"Molecular phylogenetics and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/26826601","citation_count":42,"is_preprint":false},{"pmid":"27219343","id":"PMC_27219343","title":"Transcriptome analysis of cortical tissue reveals shared sets of downregulated genes in autism and schizophrenia.","date":"2016","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/27219343","citation_count":33,"is_preprint":false},{"pmid":"27833851","id":"PMC_27833851","title":"Overexpression of COP9 signalosome subunits, CSN7A and CSN7B, exerts different effects on adipogenic 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syndrome reveal partial dosage compensation of tetrasomy 12p and hypomethylation of gene-poor regions on 12p.","date":"2016","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26890086","citation_count":6,"is_preprint":false},{"pmid":"34584547","id":"PMC_34584547","title":"lncRNA LOC339524 inhibits the proliferation of bladder cancer cells by targeting the miR-875-5p/COPS7A signaling axis.","date":"2021","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34584547","citation_count":5,"is_preprint":false},{"pmid":"33503427","id":"PMC_33503427","title":"CSN7B defines a variant COP9 signalosome complex with distinct function in DNA damage response.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33503427","citation_count":5,"is_preprint":false},{"pmid":"30350918","id":"PMC_30350918","title":"Blood-based dynamic genomic signature for obsessive-compulsive disorder.","date":"2018","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30350918","citation_count":4,"is_preprint":false},{"pmid":"37869444","id":"PMC_37869444","title":"Exploring the endangerment mechanisms of Hipposideros pomona based on molecular phylogeographic methods.","date":"2023","source":"Ecology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/37869444","citation_count":3,"is_preprint":false},{"pmid":"40857740","id":"PMC_40857740","title":"The COP9 signalosome variants CSNCSN7A and CSNCSN7B form complexes with specific CRLs which are targets of autophagy.","date":"2025","source":"Essays in biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40857740","citation_count":2,"is_preprint":false},{"pmid":"32021672","id":"PMC_32021672","title":"Light at Night Exposure Effects on Differentiation and Cell Cycle in the Rat Liver With Autonomic Nervous System Denervation.","date":"2019","source":"Journal of lasers in medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32021672","citation_count":2,"is_preprint":false},{"pmid":"41616282","id":"PMC_41616282","title":"Multiomics analysis of red blood cells reveals thalassemia severity beyond globin gene mutations.","date":"2026","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/41616282","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13257,"output_tokens":2499,"usd":0.038628,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9641,"output_tokens":3373,"usd":0.066265,"stage2_stop_reason":"end_turn"},"total_usd":0.104893,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry-based interactome mapping (affinity purification-MS of CSN subunits including Csn7a)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal MS-based interactome, single lab, multiple subunit baits providing cross-validation\",\n      \"pmids\": [\"19295130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Two-hybrid screen, co-immunoprecipitation (transient expression in COS7 cells and endogenous proteins)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, two orthogonal methods (yeast two-hybrid + Co-IP), confirmed with endogenous proteins\",\n      \"pmids\": [\"12220626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Stable overexpression and siRNA knockdown in LiSa-2 preadipocytes and mouse embryonic fibroblasts, adipogenic differentiation assay\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype, single lab, two cell models\",\n      \"pmids\": [\"27833851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ATM kinase phosphorylates CSN7a in a UV-dependent manner, placing CSN7a downstream of ATM in the DNA damage response pathway.\",\n      \"method\": \"Phosphorylation assay following UV irradiation; ATM identified as the kinase; time-course analysis post-UV\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, direct biochemical detection of phosphorylation with identified writer (ATM), but limited mechanistic follow-up for CSN7a specifically\",\n      \"pmids\": [\"26986008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation (RIP), siRNA knockdown, overexpression rescue experiments, NF-κB reporter assays, ubiquitination assays in gastric cancer cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal methods (RNA pull-down, RIP, functional rescue, pathway reporter) establishing COPS7A-USP15-IκBα axis\",\n      \"pmids\": [\"31409899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR knockout cell construction, live-cell microscopy, NBS1S343p and γH2AX immunofluorescence, deneddylation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout cells with multiple orthogonal phenotypic readouts, live-cell imaging, specific negative finding for CSN7A in DSB sensing confirmed by direct comparison with CSN7B\",\n      \"pmids\": [\"33503427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, knockout/knockdown cell lines, live-cell imaging, neddylation assays, adipogenesis assays with C-terminal truncation mutants of CSN7A in LiSa-2 cells\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KO/KD, domain truncation, neddylation assay, live-cell imaging), single lab but convergent mechanistic findings\",\n      \"pmids\": [\"37091236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Domain deletion mutagenesis, CSN5i-3 inhibitor treatment, detection of ubiquitylated CSN-CRL particles, autophagy assays\",\n      \"journal\": \"Essays in biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic domain mapping and autophagy pathway placement, single lab, review-style article summarizing experimental findings\",\n      \"pmids\": [\"40857740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitination assays, adipogenesis model (LiSa-2 cells)\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway placement with loss-of-function and biochemical assays, single lab, consistent with prior iScience findings\",\n      \"pmids\": [\"40149914\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COPS7A (CSN7A) is a subunit of the COP9 signalosome (CSN) that defines the CSNCSN7A variant complex, which preferentially forms latent complexes with CRL3 ubiquitin ligases; these latent CSNCSN7A-CRL3 complexes are recruited by the small GTPase RAB18 to lipid droplet membranes during adipogenesis, where CRL3 is activated by neddylation and ubiquitylates the adipogenesis inhibitor CHOP for proteasomal degradation; CSN7A also mediates IκBα deubiquitylation via the associated deubiquitylase USP15, thereby suppressing NF-κB signaling; CSN7A participates in deneddylation of CRLs but is dispensable for DNA double-strand break sensing (a function specific to the CSN7B variant); ATM phosphorylates CSN7A in a UV-dependent manner; and the C-terminal ~60 amino acids of CSN7A are required for CRL3 binding and function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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) [#0, #5]. 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 [#5]. 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 [#6, #7]. 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 [#6, #8, #2]. 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 [#4, #6]. CSN-CRL complexes including CSN^CSN7A-CRL3 are turned over by a selective macroautophagic pathway [#7]. CSN7A is also phosphorylated by ATM in a UV-dependent manner [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid screen and co-immunoprecipitation of transfected and endogenous proteins in COS7 cells\",\n      \"pmids\": [\"12220626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the CSN7A-Int-6 interaction not defined\", \"Does not establish whether CSN7A directly contacts Int-6 or bridges through the complex\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed CSN7A within the CSN interactome and connected it to cullin-RING E3 ligases, framing the complex's role in CRL regulation.\",\n      \"evidence\": \"Affinity purification-mass spectrometry using multiple CSN subunit baits including CSN7a\",\n      \"pmids\": [\"19295130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interactome map does not assign CSN7A-specific (vs CSN7B) functions\", \"Does not distinguish direct from complex-mediated CRL contacts\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a cellular requirement for the CSN7A variant in adipogenesis, showing CSN7A is necessary but not sufficient to drive adipogenic differentiation.\",\n      \"evidence\": \"Stable overexpression and siRNA knockdown in LiSa-2 preadipocytes and MEFs with adipogenic differentiation assays\",\n      \"pmids\": [\"27833851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrate/target downstream of CSN7A in adipogenesis not yet identified\", \"Mechanism distinguishing CSN7A from CSN7B in this context unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CSN7A to the DNA damage response by identifying ATM-dependent UV-induced phosphorylation, positioning CSN7A as an ATM substrate.\",\n      \"evidence\": \"Phosphorylation assay after UV irradiation with ATM identified as the kinase\",\n      \"pmids\": [\"26986008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of CSN7A phosphorylation not established\", \"Phosphosite mapping and downstream effect on CSN/CRL activity unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNA pull-down, RIP, siRNA knockdown, rescue, NF-κB reporter and ubiquitination assays in gastric cancer cells\",\n      \"pmids\": [\"31409899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs CSN-mediated recruitment of USP15 to IκBα not dissected here\", \"Generality beyond gastric cancer cells untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discriminated CSN7A from CSN7B functionally, establishing shared roles in CRL deneddylation but a specific lack of involvement of CSN7A in DSB sensing.\",\n      \"evidence\": \"CRISPR knockouts, live-cell microscopy, NBS1/γH2AX immunofluorescence, and deneddylation assays\",\n      \"pmids\": [\"33503427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain the structural basis for paralog-specific recruitment\", \"CRL subtype preference of CSN7A not yet defined at this stage\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"37091236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate of the lipid-droplet CRL3 not identified in this study\", \"Structural detail of the RAB18-CSN-CRL3 recruitment interface unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Domain deletion mutagenesis, CSN5i-3 deneddylation inhibition, detection of ubiquitylated CSN-CRL particles, autophagy assays\",\n      \"pmids\": [\"40857740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Autophagy receptor mediating CSN-CRL capture not identified\", \"Review-style summary; some claims aggregate prior work\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Completed the adipogenic axis by identifying CHOP as the CRL3^KEAP1 substrate ubiquitylated at lipid droplets, explaining how CSN7A relieves a brake on adipogenesis.\",\n      \"evidence\": \"siRNA knockdown, co-IP, ubiquitination assays in the LiSa-2 adipogenesis model\",\n      \"pmids\": [\"40149914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction between KEAP1 and CHOP at lipid droplets not structurally resolved\", \"Whether other CRL3 adaptors act in parallel is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"No timeline discovery resolves the determinants of paralog selection or the functional output of CSN7A phosphorylation\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanism for paralog-specific CSN assembly\", \"Functional role of ATM-mediated CSN7A phosphorylation unknown\", \"Structural model of CSN^CSN7A-CRL3 not available\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 6, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"COP9 signalosome (CSN^CSN7A variant)\",\n      \"latent CSN^CSN7A-CRL3 complex\"\n    ],\n    \"partners\": [\n      \"CUL3\",\n      \"USP15\",\n      \"RAB18\",\n      \"KEAP1\",\n      \"EIF3E\",\n      \"ATM\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}