{"gene":"COPS5","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2002,"finding":"The JAMM (JAB1/MPN domain metalloenzyme) motif in the CSN5/Jab1 subunit underlies the COP9 signalosome's Nedd8 isopeptidase (deneddylase) activity. Metal chelators and point mutations within JAMM abolished CSN-dependent cleavage of Nedd8 from Cul1, yet had little effect on CSN complex assembly.","method":"In vitro isopeptidase assays, active-site mutagenesis, metal chelation; genetic rescue in yeast and Drosophila","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with mutagenesis, validated in two model organisms (yeast and Drosophila), widely replicated","pmids":["12183637"],"is_preprint":false},{"year":2001,"finding":"Jab1/CSN5 functions as an adaptor between p27(Kip1) and CRM1 to drive CRM1-dependent nuclear export of p27 and its subsequent proteasomal degradation. Jab1/CSN5 contains a leucine-rich NES through which CRM1 binds; mutation of NES leucines abolishes CRM1 interaction, nuclear export, and p27 degradation. A cytoplasmic ~100 kDa sub-complex (CSN4-8, lacking CSN1-3) exists and is the shuttle form.","method":"Leptomycin B inhibition, NES mutagenesis, dominant-negative Jab1 truncation, cell fractionation, glycerol gradient sedimentation, Co-IP","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, LMB inhibition, fractionation, dominant-negative) in single lab; mechanistically replicated in subsequent studies","pmids":["11704659"],"is_preprint":false},{"year":2002,"finding":"Jab1/CSN5 directly interacts with Smad4 and induces its ubiquitination and proteasomal degradation, thereby antagonizing TGF-β signaling; ectopic Jab1 expression decreases endogenous Smad4 and inhibits TGF-β-induced gene transcription.","method":"Co-immunoprecipitation, ectopic overexpression, proteasome inhibitors (lactacystin, MG132), transcriptional reporter assays","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional reporter assay plus proteasome inhibitor validation, single lab","pmids":["11818334"],"is_preprint":false},{"year":2004,"finding":"Jab1/CSN5 constitutively associates with Smad7 and promotes its translocation from nucleus to cytoplasm and proteasomal degradation, thereby releasing Smad7-mediated suppression of TGF-β signaling and enhancing Smad2 phosphorylation. siRNA knockdown of Jab1 stabilizes Smad7.","method":"Co-immunoprecipitation, overexpression, siRNA knockdown, immunofluorescence localization, FRAP, phosphorylation assays","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA, and functional phosphorylation assays; single lab","pmids":["14993265"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of CSN5 in its catalytically inactive monomeric form reveals that the Ins-1 segment obstructs access to the substrate-binding site. A single mutation in Ins-1 is sufficient to restore isopeptidase activity. A dynamic monomer-dimer equilibrium exists both in vitro and in vivo and is functionally relevant for catalytic activation.","method":"X-ray crystallography, molecular dynamics simulation, in vitro isopeptidase assay, Ins-1 mutagenesis, analytical ultracentrifugation","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro enzymatic validation in a single rigorous study","pmids":["23288897"],"is_preprint":false},{"year":2014,"finding":"Association of the CSN5 and CSN6 MPN domains activates CSN5 isopeptidase activity; CSN5 alone is inactive due to an auto-inhibited catalytic domain conformation. The CSN5/CSN6 module is insufficient for efficient CRL deneddylation, indicating further subunits are required. The C-termini of CSN subunits likely form a helical bundle at the core, positioning the MPN catalytic module.","method":"Structural hybrid modeling, cross-linking/mass spectrometry, in vitro isopeptidase assay with CSN5/CSN6 heterodimer reconstitution","journal":"PloS One","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution of heterodimer combined with structural modeling and in vitro enzymatic assay","pmids":["25144743"],"is_preprint":false},{"year":2012,"finding":"A CSN4-5-6-7 subcomplex was biochemically reconstituted; CSN5 associates with the CSN4-6-7 heterotrimer via MPN-MPN interaction between CSN5 and CSN6. PCI-PCI interactions between CSN4 and CSN7, and CSN6 C-terminus interactions with CSN4 and CSN7 further stabilize the subcomplex.","method":"Bacterial co-expression reconstitution, in vitro pulldown, biochemical and biophysical characterization (SEC, ITC)","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with multiple biophysical methods defining pairwise and combinatorial interactions","pmids":["23086934"],"is_preprint":false},{"year":2016,"finding":"CSN5, induced by NF-κB p65 downstream of TNF-α, inhibits ubiquitination and proteasomal degradation of PD-L1, thereby stabilizing PD-L1 on cancer cells and suppressing anti-tumor T-cell immunity.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, NF-κB reporter, in vivo mouse tumor model","journal":"Cancer Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, NF-κB reporter, and in vivo validation; independently confirmed by multiple subsequent studies","pmids":["27866850"],"is_preprint":false},{"year":2008,"finding":"CSN5 isopeptidase activity is required for breast epithelial transformation; CSN5 potentiates MYC transcriptional activity in a manner dependent on assembly of the full COP9 signalosome. Transgenic inhibition of CSN5 isopeptidase activity blocks MYC/RAS-driven breast cancer progression in vivo.","method":"Isopeptidase-dead mutant expression, oncogene transformation assays in primary human cells, transgenic mouse model","journal":"Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue with catalytic mutant in primary cells and transgenic in vivo model; multiple orthogonal approaches","pmids":["18199546"],"is_preprint":false},{"year":2016,"finding":"COPS5 overexpression, through its isopeptidase activity, leads to ubiquitination and proteasomal degradation of NCoR (nuclear co-repressor for ERα), causing tamoxifen resistance. Genetic inhibition of COPS5 isopeptidase activity re-sensitizes resistant cells to tamoxifen.","method":"Co-immunoprecipitation, ubiquitination assay, isopeptidase-dead COPS5 mutant, genomic amplification analysis, in vitro and in vivo breast cancer models","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — isopeptidase mutant rescue, Co-IP, ubiquitination assay, and in vivo validation in single study","pmids":["27375289"],"is_preprint":false},{"year":2004,"finding":"Jab1-null embryos die shortly after implantation. Jab1-/- embryonic cells lack other CSN components and accumulate p27, p53, and cyclin E, resulting in impaired proliferation and accelerated apoptosis. In Jab1+/- MEFs, the Jab1-containing small subcomplex (not the CSN holocomplex) is selectively reduced, and G0-to-S phase progression is delayed via inefficient p27 down-regulation, while deneddylated Cul1 levels are unchanged.","method":"Jab1 knockout mice (homologous recombination), embryo analysis, MEF proliferation assays, western blotting for p27/p53/cyclin E/neddylated Cul1","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null and heterozygous mouse models with defined molecular readouts; independently confirmed by Tian et al. 2010","pmids":["15299027"],"is_preprint":false},{"year":2010,"finding":"Conditional knockout of CSN5/Jab1 in MEFs ceases proliferation; the JAMM/deneddylase domain is essential for this function. Loss of CSN5 enhances neddylation of cullins 1 and 4, alters cyclin E and p53 levels, blocks cell cycle at multiple points, initiates p53-independent senescence, and increases cell ploidy (endoreduplication).","method":"CRE-lox conditional MEF knockout, cell cycle analysis, neddylation western blot, JAMM-domain rescue experiments","journal":"FEBS Letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic KO with catalytic-domain rescue, multiple orthogonal cell-cycle readouts","pmids":["20974137"],"is_preprint":false},{"year":2010,"finding":"Loss of Jab1 in mice causes early embryonic lethality due to accelerated apoptosis. Loss of Jab1 sensitizes cells to γ-radiation-induced apoptosis, increases spontaneous DNA damage, and causes homologous recombination (HR) defects correlated with reduced Rad51 and elevated p53 levels. Accumulated p53 binds the Rad51 promoter and suppresses its expression, representing the mechanistic link between Jab1 loss and HR deficiency.","method":"Jab1 knockout mice, γ-irradiation assays, comet assay, HR assay, chromatin immunoprecipitation for p53 on Rad51 promoter","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null model combined with ChIP-defined mechanistic pathway linking Jab1→p53→Rad51 promoter","pmids":["20802511"],"is_preprint":false},{"year":2005,"finding":"JAB1/CSN5 dual-regulates MIF-induced ERK signaling: JAB1 overexpression inhibits sustained (CD74-dependent) ERK phosphorylation by MIF, while JAB1 knockdown (siRNA) abolishes transient ERK activation by MIF. Transient MIF-ERK signaling requires a Src-type kinase upstream and minimum JAB1 levels.","method":"siRNA knockdown of JAB1, Src-deficient cells with Src re-expression, Src inhibitor PP2, genistein inhibition, ERK/Raf/MEK phosphorylation assays","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (Src-KO rescue) and pharmacological inhibition plus siRNA; single lab","pmids":["16122907"],"is_preprint":false},{"year":2005,"finding":"The MPN domain of JAB1 (without requiring the JAMM catalytic motif) mediates direct binding to MIF. The MIF sequence MIF(50-65) and the MPN domain are sufficient for the MIF-JAB1 interaction, confirmed by endogenous Co-IP showing that MPN (via CSN6 as a proxy) mediates the interaction in mammalian cells.","method":"Yeast two-hybrid with domain deletions, in vitro CoIP, GST pulldown, MALDI-TOF mass spectrometry with nanobead affinity matrix","journal":"FEBS Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping by Y2H and pulldown plus in vivo Co-IP; single lab, multiple methods","pmids":["15757663"],"is_preprint":false},{"year":2006,"finding":"Jab1 acts as a specificity factor for E2F1-induced apoptosis: Jab1 binds E2F1 specifically (not other E2Fs) via the E2F1 marked box region, and co-expression of Jab1+E2F1 synergistically induces apoptosis coincident with p53 accumulation. Jab1 depletion impairs both E2F1-induced apoptosis and p53 induction.","method":"Yeast two-hybrid screen, Co-IP, shRNA depletion, apoptosis and cell cycle assays, p53 western blot","journal":"Genes & Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H confirmed by Co-IP, functional rescue/depletion experiments; single lab","pmids":["16481464"],"is_preprint":false},{"year":2008,"finding":"CSN5 is a critical regulator of both p53 and MDM2: CSN5 interacts with p53, promotes MDM2-mediated p53 ubiquitination, facilitates p53 nuclear export, and stabilizes MDM2 by reducing its self-ubiquitination. CSN5 also antagonizes p53 transcriptional activity.","method":"Co-immunoprecipitation, ubiquitination assay, nuclear export assay, transcriptional reporter, curcumin (CSN-kinase inhibitor) treatment","journal":"Journal of Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional ubiquitination/export/reporter assays; single lab","pmids":["17879958"],"is_preprint":false},{"year":2004,"finding":"Thioredoxin (Trx) directly interacts with and negatively regulates Jab1, competing with p27(Kip1) for Jab1 binding; Trx inhibits both AP-1 transcriptional activation and p27 degradation through this interaction. The negative effect on AP-1 is Jab1-dependent.","method":"FRET, Co-immunoprecipitation, antisense knockdown of Jab1, competition binding assay, AP-1 reporter assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET plus Co-IP plus competition assay plus Jab1-dependent reporter; single lab","pmids":["15480426"],"is_preprint":false},{"year":2009,"finding":"CSN5-associated deubiquitinase activity (via its JAMM domain) regulates sorting of proteins into exosomes: CSN5 knockdown increases ubiquitinated and non-ubiquitinated exosomal proteins. JAMM-domain-deleted CSN5 increases ubiquitinated (but not non-ubiquitinated) exosomal Hsp70, and promotes HIV Gag sorting and HIV-1 release.","method":"siRNA knockdown, JAMM-deletion mutant expression, western blot of exosomal fractions, HIV-1 release assay","journal":"American Journal of Pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion mutant combined with siRNA and biochemical fractionation; single lab","pmids":["19246649"],"is_preprint":false},{"year":2004,"finding":"JAB1 interacts with IRE1α in the absence of ER stress, and this interaction is decreased upon ER stress induction. A JAB1 mutant that binds IRE1α constitutively down-regulates UPR signaling, suggesting JAB1 modulates the choice between UPR and apoptosis via its association/dissociation with IRE1α.","method":"Yeast two-hybrid, Co-immunoprecipitation, UPR reporter assay, mutant JAB1 expression","journal":"Neurochemistry International","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus Y2H and reporter assay; single lab, limited mechanistic depth","pmids":["15234121"],"is_preprint":false},{"year":2005,"finding":"CSN5/Jab1 co-immunoprecipitates with ERα and overexpression of CSN5/Jab1 increases ligand-induced ERα proteasomal degradation. This requires CSN-associated kinase activity (blocked by curcumin) and nuclear export (blocked by leptomycin B) for estradiol-induced degradation.","method":"Co-immunoprecipitation, LMB/curcumin inhibition, proteasome inhibitor, ERα degradation assays","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus multiple pharmacological inhibitors dissecting pathway; single lab","pmids":["15899841"],"is_preprint":false},{"year":2000,"finding":"JAB1 interacts with both the progesterone receptor (PR) and steroid receptor coactivator 1 (SRC-1), stabilizing PR-SRC-1 complexes and potentiating the transcriptional activity of multiple SRC-1-associated transcription factors without altering PR or SRC-1 protein levels.","method":"Yeast two-hybrid, mammalian two-hybrid, GST pulldown, transcriptional reporter assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H confirmed by pulldown and functional reporter; single lab","pmids":["10722692"],"is_preprint":false},{"year":2002,"finding":"Drosophila CSN5/JAB1, expressed in photoreceptor R cells, is required for lamina glial cell migration into the optic lobe target region. Missense mutations in CSN5 specifically disrupt R1-R6 axon targeting; protein-null alleles additionally impair R cell differentiation at an earlier stage.","method":"Drosophila genetic analysis, CSN5 missense and null alleles, immunostaining of optic lobe development","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic allelic series (missense vs null) establishing distinct developmental functions; complementary to Cope et al. 2002","pmids":["11779478"],"is_preprint":false},{"year":2002,"finding":"In Drosophila oogenesis, CSN5/JAB1 is required for meiotic progression and axis specification. CSN5 mutations reduce Gurken protein accumulation and cause Vasa modification, phenocopying spindle-class DNA-repair genes. The phenotype is suppressed by mutations in the DNA-damage checkpoint kinase mei-41 or by abolishing double-strand breaks (mei-W68), linking CSN5 to meiotic DNA repair checkpoint control of Gurken translation.","method":"Drosophila genetic epistasis (mei-41 and mei-W68 suppressors), immunostaining for Gurken and Vasa, oocyte axis analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple suppressors firmly places CSN5 in a defined checkpoint pathway","pmids":["12397113"],"is_preprint":false},{"year":2013,"finding":"CSN5, but not the CSN holocomplex, directly binds CDK2 in vivo and in vitro. CSN5 depletion enhances Akt-mediated CDK2 phosphorylation, causing cytoplasmic accumulation of CDK2/cyclin E and impaired Rb phosphorylation. Additional knockdown of CDK2 (reducing cyclin E) suppresses senescence in CSN5-depleted cells, and enforced cytoplasmic cyclin E alone induces premature senescence.","method":"Co-IP (in vivo and in vitro), siRNA double knockdown, cytoplasmic cyclin E overexpression, SA-β-gal senescence assay, Rb phosphorylation assay","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro Co-IP plus genetic epistasis (double KD); single lab","pmids":["23316279"],"is_preprint":false},{"year":2013,"finding":"Jab1/CSN5 induces nuclear export and proteasomal degradation of RUNX3. The nuclear export is controlled by CSN-associated kinases, and cytoplasmic RUNX3 is rapidly degraded via the proteasome pathway.","method":"Co-immunoprecipitation, nuclear export assay (LMB inhibition), proteasome inhibitor, overexpression/knockdown","journal":"Journal of Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus LMB and proteasome inhibitor validation; single lab","pmids":["19350572"],"is_preprint":false},{"year":2013,"finding":"COPS5 interacts with RanBP9 (confirmed by Co-IP in neuronal and non-neuronal cells and mouse brain) and increases RanBP9 protein stability (half-life). Overexpression of COPS5 increases amyloid-β generation via increased sAPP-β, and siRNA knockdown of COPS5 reduces Aβ generation.","method":"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, APP processing assays (ELISA for Aβ, western blot for sAPP-α/β), protein half-life assay","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H confirmed by Co-IP in multiple cell types and mouse brain, plus functional Aβ assays; single lab","pmids":["23926111"],"is_preprint":false},{"year":2013,"finding":"JAB1 interacts with unphosphorylated STAT3 in the nucleus (demonstrated by Co-IP from nuclear extract) and positively regulates its DNA-binding activity. JAB1 knockdown decreases unphosphorylated STAT3 DNA-binding and reduces expression of MDR1, NANOG, and VEGF (STAT3 target genes).","method":"Nuclear fractionation, Co-immunoprecipitation from nuclear extract, siRNA knockdown, STAT3 DNA-binding ELISA, qPCR of target genes","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear Co-IP plus functional DNA-binding and target gene assays; single lab","pmids":["23911788"],"is_preprint":false},{"year":2006,"finding":"Jab1 directly interacts with the West Nile virus capsid protein (WNVCp) and promotes its CRM1-dependent nuclear export to the cytoplasm and subsequent proteasomal degradation, preventing WNVCp-induced G2 cell cycle arrest. The first 15 aa of WNVCp (including P5/P8) are required for interaction.","method":"Yeast two-hybrid, Co-IP, GST pulldown, immunofluorescence, LMB inhibition, deletion/point mutant analysis, flow cytometry","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (Y2H, pulldown, CoIP) plus LMB and functional cell-cycle assay; single lab","pmids":["16882664"],"is_preprint":false},{"year":2006,"finding":"Jab1 directly interacts with and acts as a pro-apoptotic co-activator for BclGs (a BH3-only protein). Jab1 competes with Bcl-XL/Bcl-2 for BclGs binding, promotes Bax translocation to mitochondria, cytochrome c release, and caspase-3 activation. JAB1 knockdown reduces BclGs-induced apoptosis.","method":"Yeast two-hybrid, Co-IP, GST pulldown, competition binding assay, RNAi knockdown, apoptosis assays (caspase, cytochrome c)","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H confirmed by Co-IP/pulldown plus competition assay and RNAi rescue; single lab","pmids":["18006276"],"is_preprint":false},{"year":2013,"finding":"CUL4B E3 ubiquitin ligase (as part of DDB1-CUL4B-ROC1 complex) targets Jab1/CSN5 for polyubiquitination and proteasomal degradation. RNAi depletion of CUL4B impairs Jab1 degradation; in vitro and in vivo ubiquitination assays confirm CUL4B promotes Jab1 polyubiquitination. This degradation is independent of CUL4A. In Cul4b-deficient mouse fibroblasts, Jab1 accumulates and BMP signaling is aberrantly activated.","method":"siRNA knockdown of CUL4B, in vitro ubiquitination assay, in vivo ubiquitination assay, CUL4B-null MEFs, BMP signaling reporter","journal":"Biochimica et Biophysica Acta","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro and in vivo ubiquitination assays combined with genetic null model and specific functional pathway readout","pmids":["23357576"],"is_preprint":false},{"year":2013,"finding":"Jab1/CSN5 is required for normal Schwann cell proliferation and axonal sorting. Loss of Jab1 in Schwann cells increases p27 levels causing cell cycle defects and aberrant differentiation; genetic reduction of p27 in Jab1-null Schwann cells rescues cell number, differentiation, axonal sorting, and dysmyelinating neuropathy.","method":"Schwann-cell-specific Jab1 conditional knockout mice, genetic epistasis with p27 knockout, nerve morphology, cell cycle analysis","journal":"Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with genetic rescue (p27 KO epistasis) demonstrating causal pathway in vivo","pmids":["24344238"],"is_preprint":false},{"year":2022,"finding":"Oligodendrocyte-specific deletion of JAB1/CSN5 causes DNA damage and defective DNA repair, leading to a p21CIP1-dependent senescence-like phenotype that triggers chronic neuroinflammation and oxidative stress. Deletion of p21CIP1 (but not p16INK4a) ameliorates the disease, linking CSN5 to senescence pathway selection in myelinating glia.","method":"Oligodendrocyte-specific Jab1 conditional KO mice, DNA damage markers, SA-β-gal, microglia inhibition, p21/p16 genetic epistasis","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with genetic epistasis (p21 vs p16) defining pathway; rigorous in vivo model","pmids":["34874913"],"is_preprint":false},{"year":2008,"finding":"JAB1 overexpression in hematopoietic cells promotes myeloproliferative disease in vivo; stable JAB1 transgenic mice have larger stem cell populations with higher transplantable proliferative potential. JAB1 interacts with the histone methyltransferase SMYD3, and together they suppress p16(INK4a) transcription.","method":"Jab1 transgenic mice, bone marrow transplantation, Co-IP (JAB1-SMYD3), p16 promoter reporter assay","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic in vivo model plus Co-IP and promoter assay; single lab","pmids":["18667426"],"is_preprint":false},{"year":2006,"finding":"CSN5/Jab1 inhibits cardiac L-type Ca2+ channel (α1C subunit) activity through direct protein-protein interaction with the II-III linker of α1C. Silencing CSN5 with siRNA in COS7 cells activates L-type Ca2+ channel current. CSN5 and α1C co-immunoprecipitate from rat heart and co-localize in sarcolemmal membranes and transverse tubules.","method":"Yeast two-hybrid, co-immunoprecipitation from cardiac tissue, siRNA knockdown, electrophysiology (patch clamp), immunofluorescence co-localization","journal":"Journal of Molecular and Cellular Cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H confirmed by tissue Co-IP plus electrophysiology functional assay; single lab","pmids":["16483597"],"is_preprint":false},{"year":2017,"finding":"CSN5 directly binds ZEB1 and decreases its ubiquitination, enhancing ZEB1 protein stability. This promotes RCC cell EMT, migration, and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro migration/invasion, in vivo xenograft","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay and functional rescue; single lab","pmids":["28479251"],"is_preprint":false},{"year":2016,"finding":"Jab1/Csn5 mediates proteasome-dependent degradation of the CDK inhibitor p57(KIP2) through direct physical interaction in HCC cells, independently of Skp2 and Akt pathways.","method":"Co-immunoprecipitation, 26S proteasome inhibitor treatment, siRNA knockdown, in vitro interaction assay, in vivo xenograft","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus proteasome inhibitor plus pathway-specificity controls (Skp2/Akt); single lab","pmids":["26606000"],"is_preprint":false},{"year":2019,"finding":"Asrij/OCIAD1 sequesters CSN5 via its conserved OCIA domain, preventing CSN5-mediated p53 ubiquitination and degradation. Loss of Asrij in mouse HSCs leads to increased CSN5-mediated p53 ubiquitination, reduced p53 levels, and HSC over-proliferation; Nutlin-3 treatment restores p53 and normalizes HSC frequencies.","method":"Asrij knockout mice, Co-IP of Asrij-CSN5 interaction, polyubiquitination assays, Nutlin-3 rescue, transplantation studies","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with biochemical Co-IP and pharmacological rescue (Nutlin-3) confirming mechanism in vivo","pmids":["30952670"],"is_preprint":false},{"year":2013,"finding":"CSN5 knockdown in HCC cells causes accumulation of neddylated Cullin 1, alters SKP2, p53, p27, and NF-κB protein levels, induces apoptosis, and inhibits cell cycle progression. Systemic delivery of CSN5 siRNA via lipid nanoparticles suppresses orthotopic HCC xenograft growth in vivo.","method":"siRNA knockdown, neddylation western blot, transcriptomic analysis, in vivo xenograft with siRNA nanoparticle delivery","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple molecular readouts and in vivo validation; single lab","pmids":["21499307"],"is_preprint":false},{"year":2011,"finding":"Stat3 and C/EBP-β transcriptionally regulate Jab1/CSN5 expression in breast cancer cells. Stat3 and C/EBP-β directly bind overlapping sites in the Jab1 promoter; Src/Stat3/IL-6 axis activates Jab1 transcription. Re-activation of Stat3 in normal mammary epithelial cells is sufficient to reactivate Jab1 expression.","method":"5'-deletion reporter assays, mutational analysis of promoter binding sites, EMSA, ChIP, Stat3 and Src siRNA knockdown, IL-6 stimulation","journal":"Breast Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus EMSA plus mutational reporter analysis; single lab","pmids":["21689417"],"is_preprint":false},{"year":2017,"finding":"COPS5 and LASP1 synergistically interact (SH3 domain of LASP1 binds the MPN domain of COPS5, confirmed by GST pulldown) to promote ubiquitination and degradation of 14-3-3σ and activate PI3K/Akt signaling, driving CRC cell proliferation, migration, and invasion.","method":"Yeast two-hybrid, GST pulldown (domain mapping), Co-IP, siRNA knockdown, in vitro and in vivo functional assays","journal":"International Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapped pulldown plus Co-IP plus functional assays in vitro/in vivo; single lab","pmids":["29226323"],"is_preprint":false},{"year":2020,"finding":"CSN5 directly binds HK2 (hexokinase 2) and inhibits its ubiquitin-proteasome-mediated degradation, thereby stabilizing HK2 and promoting glycolysis. Silencing CSN5 decreases HK2 protein, glucose uptake, and glycolytic flux; HK2 re-expression rescues glycolysis in CSN5 knockdown cells.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, HK2 rescue overexpression, glycolysis assays, in vivo xenograft","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus epistatic rescue; single lab","pmids":["31991125"],"is_preprint":false},{"year":2018,"finding":"CSN5 directly binds survivin and decreases its ubiquitination, enhancing survivin protein stability in NSCLC cells; the tumor-promoting effects of CSN5 are at least partially mediated through this survivin stabilization.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, cell growth/apoptosis assays","journal":"Biochemical and Biophysical Research Communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus ubiquitination assay; single lab, limited validation","pmids":["29596838"],"is_preprint":false},{"year":2018,"finding":"CSN5 directly binds FOXM1 and decreases its ubiquitination, enhancing FOXM1 protein stability and thereby promoting MMP2 expression to drive pancreatic cancer invasion and metastasis.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro/in vivo invasion assays","journal":"Experimental Cell Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus ubiquitination assay; single lab","pmids":["30352219"],"is_preprint":false},{"year":2004,"finding":"JAB1 directly binds the HLH domain of HAND2 and augments HAND2 transcriptional activity by enhancing HAND2 DNA binding rather than by recruiting a transcriptional activation domain.","method":"Yeast two-hybrid, Co-IP, domain-deletion mapping, transcriptional reporter assay, DNA-binding assay","journal":"Journal of Neuroscience Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H confirmed by Co-IP, functional reporter and DNA-binding assay with domain mapping; single lab","pmids":["15139020"],"is_preprint":false},{"year":2005,"finding":"p8 directly interacts with Jab1 (confirmed by His6-pulldown and Co-IP) and is required for Jab1-mediated nuclear-to-cytoplasmic translocation of p27 and its subsequent degradation. p8 knockdown strongly inhibits Jab1-induced p27 degradation.","method":"Yeast two-hybrid, His6-pulldown, Co-immunoprecipitation, siRNA knockdown of p8, p27 localization/degradation assay","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H confirmed by two biochemical methods plus siRNA functional assay; single lab","pmids":["16300740"],"is_preprint":false},{"year":2006,"finding":"NRBP (nuclear receptor binding protein) interacts with Jab1 in vivo and inhibits Jab1-induced c-Jun phosphorylation and AP-1 activation, acting as a negative regulator of Jab1-mediated transcription.","method":"Co-immunoprecipitation, AP-1 reporter assay, overexpression in mammalian cells","journal":"FEBS Letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus reporter assay; single lab, limited mechanistic depth","pmids":["17052710"],"is_preprint":false},{"year":2013,"finding":"Jab1/CSN5 positively regulates Rad51 through a p53-dependent pathway, and elevated Rad51 confers cellular resistance to cisplatin and radiation in NPC cells. Jab1 knockdown reduces Rad51 and sensitizes cells to DNA-damaging agents.","method":"siRNA knockdown, Rad51 overexpression rescue, cisplatin/radiation survival assays, p53 pathway analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (Rad51 rescue of Jab1 KD), confirmed in three NPC cell lines; single lab","pmids":["22797071"],"is_preprint":false},{"year":2014,"finding":"CSN5 affects β-catenin signaling in CRC cells via regulation of the SIAH-1 E3 ubiquitin ligase: CSN5 promotes SIAH-1 degradation in a deNEDDylase-dependent manner, and β-catenin and SIAH-1 both form protein complexes with CSN5.","method":"Co-immunoprecipitation, siRNA knockdown, deNEDDylase inhibitor (MLN-4924), qPCR and western blot for SIAH-1 and β-catenin","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus pharmacological deNEDDylase inhibition confirming mechanism; single lab","pmids":["24882689"],"is_preprint":false},{"year":2010,"finding":"5-HT6 receptor (5-HT6R) physically interacts with Jab1 (confirmed by GST pulldown, FRET, Co-IP). Jab1 siRNA decreases 5-HT6R cell membrane expression and 5-HT6R-mediated signaling. 5-HT6R activation induces Jab1 nuclear translocation and increased c-Jun phosphorylation.","method":"Yeast two-hybrid, GST pulldown, FRET, Co-immunoprecipitation, siRNA knockdown, immunocytochemistry","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding confirmation methods (FRET, GST pulldown, Co-IP) plus functional siRNA; single lab","pmids":["20093369"],"is_preprint":false},{"year":2020,"finding":"Cops5 is essential for genomic stability in mouse ESCs: it suppresses autophagic degradation of Mtch2 to direct cellular metabolism toward glycolysis, minimizing ROS and endogenous DNA damage. Independently, Cops5 is required for DNA damage repair (DDR) activities. Loss of Cops5 causes elevated ROS, DNA damage accumulation, p53-dependent G2/M arrest, and apoptosis.","method":"Inducible CRISPR/Cas9 Cops5 KO ESCs, metabolic assays, ROS measurement, comet assay, DDR marker analysis, autophagy/Mtch2 western blot","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible genetic KO with multiple orthogonal mechanistic readouts (metabolism, autophagy, ROS, DDR); single lab but comprehensive study","pmids":["31964807"],"is_preprint":false},{"year":2017,"finding":"Jab1 interacts with and stabilizes Thioredoxin (Trx) protein; ectopic Jab1 expression increases Trx expression, while Jab1 silencing reduces it. Jab1 also transcriptionally regulates Trx.","method":"Co-immunoprecipitation, western blot, siRNA knockdown, ectopic overexpression, qRT-PCR for Trx mRNA","journal":"Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus bidirectional expression manipulation; single lab","pmids":["28270496"],"is_preprint":false},{"year":2013,"finding":"In endothelial cells, CSN5 forms a super-complex with IKK that dissociates upon TNF-α stimulation. CSN5 silencing enhances TNF-α-induced IκBα degradation and NF-κB activity, increases chemokine/adhesion molecule expression, and promotes monocyte arrest. CSN5 overexpression has reverse effects, indicating CSN5 is a negative regulator of NF-κB in endothelial cells.","method":"Co-immunoprecipitation (CSN-IKK super-complex), siRNA knockdown, luciferase NF-κB reporter, flow cytometry, monocyte adhesion assay","journal":"Thrombosis and Haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of CSN-IKK complex plus bidirectional manipulation and functional adhesion assay; single lab","pmids":["23636414"],"is_preprint":false},{"year":2019,"finding":"CSN5i-3 (pharmacological CSN5 inhibitor) causes endothelial barrier disruption by activating NF-κB pathway, inducing RhoB (and to lesser extent RhoA) expression and activation, and consequent Rho/ROCK-dependent MLC activation and endothelial contraction. This establishes that sustained CRL neddylation (via CSN5 inhibition) drives NF-κB→RhoB axis in endothelial cells.","method":"CSN5i-3 pharmacological inhibition, RhoGTPase activity assays, NF-κB reporter, ROCK inhibitor, endothelial permeability assay in vitro and in vivo","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with pathway inhibitor rescue and in vivo validation; single lab","pmids":["31148579"],"is_preprint":false}],"current_model":"COPS5/CSN5/JAB1 is the catalytic subunit of the COP9 signalosome (CSN), carrying a JAMM-motif metalloprotease that deneddylates cullin-RING E3 ubiquitin ligases (CRLs); its isopeptidase activity is autoinhibited in the free monomer by the Ins-1 loop and is activated upon assembly into the CSN holocomplex (especially via MPN-MPN interaction with CSN6), enabling it to regulate CRL activity and the stability of diverse substrates including p27, p53, Smad4, Smad7, RUNX3, NCoR, PD-L1, HK2, ZEB1, and RanBP9 through deubiquitination or nuclear export/proteasomal degradation; independently of the CSN, CSN5 also functions as a nuclear-export adaptor (via its CRM1-binding NES), a transcriptional co-activator (for AP-1/c-Jun, HAND2, unphosphorylated STAT3), and a regulator of DNA repair (via Rad51/p53 axis), senescence (via CDK2/cyclin E and p21), and cellular metabolism (via suppression of Mtch2 autophagic degradation to promote glycolysis and minimize ROS in embryonic stem cells)."},"narrative":{"mechanistic_narrative":"COPS5 (CSN5/JAB1) is the catalytic subunit of the COP9 signalosome (CSN) and the cell's principal deneddylase for cullin-RING E3 ubiquitin ligases, thereby acting as a master regulator of protein stability across proliferation, DNA repair, and metabolism [PMID:12183637, PMID:20974137]. Its enzymatic activity is encoded by a JAMM-motif metalloprotease that cleaves Nedd8 from Cul1; metal chelation or active-site mutation abolishes this activity without disrupting complex assembly [PMID:12183637]. In the free monomer this isopeptidase is autoinhibited by the Ins-1 segment occluding the substrate site, and a single Ins-1 mutation restores activity [PMID:23288897]; productive catalysis is unlocked upon assembly into the CSN, where an MPN-MPN interaction between CSN5 and CSN6 within a CSN4-5-6-7 module activates the enzyme, though that module alone is insufficient for efficient CRL deneddylation [PMID:25144743, PMID:23086934]. Genetic loss of CSN5 disrupts the entire CSN, leaving cullins hyper-neddylated and causing accumulation of CRL substrates such as p27, p53, and cyclin E, with consequent cell-cycle arrest, senescence, endoreduplication, and embryonic lethality [PMID:15299027, PMID:20974137]. Beyond the canonical deneddylase function, CSN5 acts as a CRM1-dependent nuclear-export adaptor through a leucine-rich NES — exemplified by driving nuclear export and proteasomal degradation of p27 — and serves as a substrate-specific stabilizing or destabilizing factor for diverse proteins including Smad4, Smad7, RUNX3, PD-L1, HK2, ZEB1, and NCoR, frequently through control of their ubiquitination and proteasomal turnover [PMID:11704659, PMID:11818334, PMID:14993265, PMID:27866850, PMID:27375289, PMID:31991125]. Through these activities CSN5 modulates TGF-β/Smad signaling, DNA repair via a p53→Rad51 axis, p21- and CDK2/cyclin E-dependent senescence, and a metabolic program that suppresses autophagic degradation of Mtch2 to favor glycolysis and limit ROS-driven DNA damage [PMID:11818334, PMID:14993265, PMID:20802511, PMID:23316279, PMID:34874913, PMID:31964807]. CSN5 itself is regulated by transcriptional induction downstream of NF-κB and STAT3 and is targeted for degradation by the CUL4B E3 ligase [PMID:27866850, PMID:23357576, PMID:21689417]. Its potentiation of MYC and CRL-dependent substrate turnover makes CSN5 isopeptidase activity rate-limiting for oncogenic transformation in vivo [PMID:18199546].","teleology":[{"year":2000,"claim":"Established an early non-deneddylase role for JAB1 as a transcriptional coactivator, framing CSN5 as more than a CRL regulator.","evidence":"Yeast/mammalian two-hybrid, GST pulldown, and reporter assays mapping JAB1 binding to PR and SRC-1","pmids":["10722692"],"confidence":"Medium","gaps":["No structural basis for coactivation defined","Relationship to CSN holocomplex not addressed"]},{"year":2001,"claim":"Defined a CSN-independent mechanism by which CSN5 controls substrate fate, identifying it as a CRM1 nuclear-export adaptor for p27.","evidence":"LMB inhibition, NES mutagenesis, dominant-negative truncation, fractionation, and Co-IP identifying a cytoplasmic CSN4-8 shuttle subcomplex","pmids":["11704659"],"confidence":"High","gaps":["Whether export adaptor function requires isopeptidase activity not resolved","Subcomplex composition only partially defined"]},{"year":2002,"claim":"Identified the JAMM metalloprotease motif as the molecular basis of CSN deneddylase activity, defining CSN5's core catalytic function.","evidence":"In vitro isopeptidase assays with active-site mutagenesis and metal chelation, plus genetic rescue in yeast and Drosophila","pmids":["12183637"],"confidence":"High","gaps":["Did not explain how monomeric CSN5 is kept inactive","Substrate repertoire beyond Cul1 not mapped"]},{"year":2002,"claim":"Connected CSN5 to TGF-β signaling by showing it destabilizes Smad4, establishing it as an antagonist of this pathway.","evidence":"Co-IP, overexpression, proteasome inhibitors, and TGF-β reporter assays","pmids":["11818334"],"confidence":"Medium","gaps":["E3 ligase mediating Smad4 ubiquitination not identified","Dependence on CSN holocomplex untested"]},{"year":2004,"claim":"Demonstrated CSN5 also targets the inhibitory Smad7 for export and degradation, showing it can both promote and antagonize TGF-β signaling depending on substrate.","evidence":"Reciprocal Co-IP, siRNA, immunofluorescence, FRAP, and phosphorylation assays","pmids":["14993265"],"confidence":"Medium","gaps":["Reconciliation of opposing Smad4 vs Smad7 effects unresolved","Context determining substrate choice unknown"]},{"year":2004,"claim":"Established the essentiality of CSN5 in vivo and tied its loss to CRL-substrate accumulation and a deneddylase-independent subcomplex defect.","evidence":"Jab1 knockout and heterozygous mice with p27/p53/cyclin E and neddylated Cul1 readouts in MEFs","pmids":["15299027"],"confidence":"High","gaps":["Distinct contributions of subcomplex vs holocomplex not fully separated","Direct substrate vs indirect effects not delineated"]},{"year":2006,"claim":"Linked CSN5 to apoptotic control via E2F1 and p53, broadening its role beyond proliferation into cell-death decisions.","evidence":"Y2H, Co-IP, shRNA depletion, and apoptosis/p53 assays mapping E2F1 marked-box binding","pmids":["16481464"],"confidence":"Medium","gaps":["Mechanism of p53 accumulation downstream of E2F1-Jab1 unclear","Catalytic requirement untested"]},{"year":2008,"claim":"Showed CSN5 isopeptidase activity is rate-limiting for oncogenic transformation, establishing therapeutic rationale for targeting its catalysis.","evidence":"Isopeptidase-dead mutant in primary human cells plus MYC/RAS transgenic mouse breast cancer model","pmids":["18199546"],"confidence":"High","gaps":["Direct CRL substrate driving transformation not pinpointed","Mechanism of MYC potentiation not molecularly defined"]},{"year":2010,"claim":"Confirmed the JAMM/deneddylase domain is essential for proliferation and linked CSN5 loss to p53-independent senescence and genome instability.","evidence":"Conditional MEF knockout with JAMM-domain rescue and DNA-repair/ChIP analysis of a p53→Rad51 axis","pmids":["20974137","20802511"],"confidence":"High","gaps":["How CSN5 controls p53 levels mechanistically not fully resolved","Direct vs CRL-mediated DNA repair role unclear"]},{"year":2013,"claim":"Resolved the structural basis of catalytic autoinhibition, explaining why monomeric CSN5 is inactive.","evidence":"X-ray crystallography of inactive monomer, MD simulation, AUC, and Ins-1 mutagenesis restoring activity","pmids":["23288897"],"confidence":"High","gaps":["Conformational change upon holocomplex assembly not captured at high resolution","Physiological trigger of monomer-dimer equilibrium unknown"]},{"year":2013,"claim":"Defined the CSN4-5-6-7 architecture and the CSN5-CSN6 MPN-MPN interface that positions the catalytic module within the complex.","evidence":"Bacterial reconstitution, pulldown, SEC, and ITC mapping pairwise and combinatorial interactions","pmids":["23086934"],"confidence":"High","gaps":["Full holocomplex assembly intermediates not all defined","How assembly relieves Ins-1 autoinhibition not shown structurally"]},{"year":2013,"claim":"Identified CUL4B as the E3 ligase that degrades CSN5, closing a feedback loop in which CSN5 regulates CRLs and a CRL regulates CSN5.","evidence":"siRNA, in vitro and in vivo ubiquitination assays, and CUL4B-null MEFs with BMP reporter","pmids":["23357576"],"confidence":"High","gaps":["Conditions selecting CUL4B-mediated turnover unknown","Whether degradation targets monomer or complexed CSN5 unclear"]},{"year":2014,"claim":"Demonstrated that CSN5-CSN6 MPN association is necessary but not sufficient for efficient CRL deneddylation, refining the activation model.","evidence":"Hybrid structural modeling, cross-linking mass spectrometry, and heterodimer reconstitution isopeptidase assays","pmids":["25144743"],"confidence":"High","gaps":["Which additional subunits complete activation not identified","Quantitative activation mechanism unresolved"]},{"year":2016,"claim":"Established CSN5 as a stabilizer of PD-L1 downstream of inflammatory signaling, linking it to tumor immune evasion.","evidence":"Co-IP, ubiquitination assay, NF-κB reporter, siRNA, and in vivo mouse tumor model","pmids":["27866850"],"confidence":"High","gaps":["Whether stabilization is via deneddylation or direct deubiquitination unclear","E3 ligase counteracted not defined"]},{"year":2016,"claim":"Showed CSN5 isopeptidase-dependent degradation of NCoR drives endocrine-therapy resistance, with catalytic inhibition restoring sensitivity.","evidence":"Co-IP, ubiquitination assay, isopeptidase-dead mutant, and in vitro/in vivo breast cancer models","pmids":["27375289"],"confidence":"High","gaps":["Direct vs CRL-mediated NCoR ubiquitination not separated"]},{"year":2019,"claim":"Placed CSN5-mediated p53 degradation under upstream control by Asrij/OCIAD1 sequestration, defining a regulatory brake in stem-cell homeostasis.","evidence":"Asrij knockout mice, Co-IP, polyubiquitination assays, and Nutlin-3 rescue with transplantation","pmids":["30952670"],"confidence":"High","gaps":["Structural basis of OCIA-domain sequestration unknown","Whether sequestration blocks catalysis or interaction unclear"]},{"year":2020,"claim":"Integrated CSN5 into a metabolism-genome-stability axis by showing it suppresses Mtch2 autophagy to favor glycolysis and limit ROS-driven DNA damage in ESCs.","evidence":"Inducible CRISPR KO ESCs with metabolic, ROS, comet, DDR, and autophagy/Mtch2 readouts","pmids":["31964807"],"confidence":"High","gaps":["Mechanism by which CSN5 restrains Mtch2 autophagy not molecularly defined","Relationship to deneddylase activity unclear"]},{"year":2022,"claim":"Defined CSN5's tissue-specific requirement in myelinating glia, linking its loss to DNA-damage-induced, p21-dependent senescence and neuroinflammation.","evidence":"Oligodendrocyte-specific conditional KO mice with DNA-damage markers and p21 vs p16 genetic epistasis","pmids":["34874913"],"confidence":"High","gaps":["Direct DNA-repair substrate of CSN5 in glia unknown","Why p21 rather than p16 is selected unresolved"]},{"year":null,"claim":"How CSN5 selects between its CSN-dependent deneddylase activity and its many CSN-independent substrate-specific and adaptor functions in a given cellular context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model distinguishing holocomplex vs monomer/subcomplex substrate routing","Direct deubiquitinase vs CRL-mediated effects rarely separated for individual substrates","Structural transition from autoinhibited monomer to active holocomplex not captured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,5,7,9]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[21,27,44]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,45]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16,37,52]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,25,27]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,24]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,7,9,30]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10,11,24]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[12,47,50]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,52]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[32,50]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,52]}],"complexes":["COP9 signalosome (CSN)","CSN4-5-6-7 subcomplex"],"partners":["CSN6","P27","SMAD7","PD-L1","CUL4B","MIF","CDK2","RANBP9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92905","full_name":"COP9 signalosome complex subunit 5","aliases":["Jun activation domain-binding protein 1"],"length_aa":334,"mass_kda":37.6,"function":"Probable protease subunit 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 the 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, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8, 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. In the complex, it probably acts as the catalytic center that mediates the cleavage of Nedd8 from cullins. It however has no metalloprotease activity by itself and requires the other subunits of the CSN complex. Interacts directly with a large number of proteins that are regulated by the CSN complex, confirming a key role in the complex. Promotes the proteasomal degradation of BRSK2","subcellular_location":"Cytoplasm, cytosol; Nucleus; Cytoplasm, perinuclear region; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle","url":"https://www.uniprot.org/uniprotkb/Q92905/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/COPS5","classification":"Common Essential","n_dependent_lines":1202,"n_total_lines":1208,"dependency_fraction":0.9950331125827815},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDB1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COPS5","total_profiled":1310},"omim":[{"mim_id":"619596","title":"OCIA DOMAIN-CONTAINING PROTEIN 1; OCIAD1","url":"https://www.omim.org/entry/619596"},{"mim_id":"616750","title":"ZDHHC PALMITOYLTRANSFERASE 16; ZDHHC16","url":"https://www.omim.org/entry/616750"},{"mim_id":"614729","title":"COP9 SIGNALOSOME, SUBUNIT 6; COPS6","url":"https://www.omim.org/entry/614729"},{"mim_id":"611649","title":"MINDY LYSINE-48 DEUBIQUITINASE 3; MINDY3","url":"https://www.omim.org/entry/611649"},{"mim_id":"604850","title":"COP9 SIGNALOSOME, SUBUNIT 5; COPS5","url":"https://www.omim.org/entry/604850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COPS5"},"hgnc":{"alias_symbol":["JAB1","SGN5","MOV-34","CSN5"],"prev_symbol":[]},"alphafold":{"accession":"Q92905","domains":[{"cath_id":"3.40.140.10","chopping":"26-235","consensus_level":"high","plddt":88.4648,"start":26,"end":235},{"cath_id":"1.10.287","chopping":"252-329","consensus_level":"high","plddt":80.7883,"start":252,"end":329}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92905","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92905-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92905-F1-predicted_aligned_error_v6.png","plddt_mean":86.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COPS5","jax_strain_url":"https://www.jax.org/strain/search?query=COPS5"},"sequence":{"accession":"Q92905","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92905.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92905/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92905"}},"corpus_meta":[{"pmid":"27866850","id":"PMC_27866850","title":"Deubiquitination and Stabilization of PD-L1 by CSN5.","date":"2016","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/27866850","citation_count":677,"is_preprint":false},{"pmid":"12183637","id":"PMC_12183637","title":"Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1.","date":"2002","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12183637","citation_count":604,"is_preprint":false},{"pmid":"11704659","id":"PMC_11704659","title":"The cytoplasmic shuttling and subsequent degradation of p27Kip1 mediated by Jab1/CSN5 and the COP9 signalosome complex.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11704659","citation_count":252,"is_preprint":false},{"pmid":"31802034","id":"PMC_31802034","title":"Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/31802034","citation_count":198,"is_preprint":false},{"pmid":"33354502","id":"PMC_33354502","title":"Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5.","date":"2020","source":"Acta pharmaceutica Sinica. 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America","url":"https://pubmed.ncbi.nlm.nih.gov/31964807","citation_count":16,"is_preprint":false},{"pmid":"16483597","id":"PMC_16483597","title":"CSN5/Jab1 inhibits cardiac L-type Ca2+ channel activity through protein-protein interactions.","date":"2006","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/16483597","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48707,"output_tokens":13108,"usd":0.171371,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24984,"output_tokens":5566,"usd":0.132035,"stage2_stop_reason":"end_turn"},"total_usd":0.303406,"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\": 2002,\n      \"finding\": \"The JAMM (JAB1/MPN domain metalloenzyme) motif in the CSN5/Jab1 subunit underlies the COP9 signalosome's Nedd8 isopeptidase (deneddylase) activity. Metal chelators and point mutations within JAMM abolished CSN-dependent cleavage of Nedd8 from Cul1, yet had little effect on CSN complex assembly.\",\n      \"method\": \"In vitro isopeptidase assays, active-site mutagenesis, metal chelation; genetic rescue in yeast and Drosophila\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with mutagenesis, validated in two model organisms (yeast and Drosophila), widely replicated\",\n      \"pmids\": [\"12183637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Jab1/CSN5 functions as an adaptor between p27(Kip1) and CRM1 to drive CRM1-dependent nuclear export of p27 and its subsequent proteasomal degradation. Jab1/CSN5 contains a leucine-rich NES through which CRM1 binds; mutation of NES leucines abolishes CRM1 interaction, nuclear export, and p27 degradation. A cytoplasmic ~100 kDa sub-complex (CSN4-8, lacking CSN1-3) exists and is the shuttle form.\",\n      \"method\": \"Leptomycin B inhibition, NES mutagenesis, dominant-negative Jab1 truncation, cell fractionation, glycerol gradient sedimentation, Co-IP\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, LMB inhibition, fractionation, dominant-negative) in single lab; mechanistically replicated in subsequent studies\",\n      \"pmids\": [\"11704659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Jab1/CSN5 directly interacts with Smad4 and induces its ubiquitination and proteasomal degradation, thereby antagonizing TGF-β signaling; ectopic Jab1 expression decreases endogenous Smad4 and inhibits TGF-β-induced gene transcription.\",\n      \"method\": \"Co-immunoprecipitation, ectopic overexpression, proteasome inhibitors (lactacystin, MG132), transcriptional reporter assays\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional reporter assay plus proteasome inhibitor validation, single lab\",\n      \"pmids\": [\"11818334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Jab1/CSN5 constitutively associates with Smad7 and promotes its translocation from nucleus to cytoplasm and proteasomal degradation, thereby releasing Smad7-mediated suppression of TGF-β signaling and enhancing Smad2 phosphorylation. siRNA knockdown of Jab1 stabilizes Smad7.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, siRNA knockdown, immunofluorescence localization, FRAP, phosphorylation assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA, and functional phosphorylation assays; single lab\",\n      \"pmids\": [\"14993265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of CSN5 in its catalytically inactive monomeric form reveals that the Ins-1 segment obstructs access to the substrate-binding site. A single mutation in Ins-1 is sufficient to restore isopeptidase activity. A dynamic monomer-dimer equilibrium exists both in vitro and in vivo and is functionally relevant for catalytic activation.\",\n      \"method\": \"X-ray crystallography, molecular dynamics simulation, in vitro isopeptidase assay, Ins-1 mutagenesis, analytical ultracentrifugation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro enzymatic validation in a single rigorous study\",\n      \"pmids\": [\"23288897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Association of the CSN5 and CSN6 MPN domains activates CSN5 isopeptidase activity; CSN5 alone is inactive due to an auto-inhibited catalytic domain conformation. The CSN5/CSN6 module is insufficient for efficient CRL deneddylation, indicating further subunits are required. The C-termini of CSN subunits likely form a helical bundle at the core, positioning the MPN catalytic module.\",\n      \"method\": \"Structural hybrid modeling, cross-linking/mass spectrometry, in vitro isopeptidase assay with CSN5/CSN6 heterodimer reconstitution\",\n      \"journal\": \"PloS One\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution of heterodimer combined with structural modeling and in vitro enzymatic assay\",\n      \"pmids\": [\"25144743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A CSN4-5-6-7 subcomplex was biochemically reconstituted; CSN5 associates with the CSN4-6-7 heterotrimer via MPN-MPN interaction between CSN5 and CSN6. PCI-PCI interactions between CSN4 and CSN7, and CSN6 C-terminus interactions with CSN4 and CSN7 further stabilize the subcomplex.\",\n      \"method\": \"Bacterial co-expression reconstitution, in vitro pulldown, biochemical and biophysical characterization (SEC, ITC)\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with multiple biophysical methods defining pairwise and combinatorial interactions\",\n      \"pmids\": [\"23086934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CSN5, induced by NF-κB p65 downstream of TNF-α, inhibits ubiquitination and proteasomal degradation of PD-L1, thereby stabilizing PD-L1 on cancer cells and suppressing anti-tumor T-cell immunity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, NF-κB reporter, in vivo mouse tumor model\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, NF-κB reporter, and in vivo validation; independently confirmed by multiple subsequent studies\",\n      \"pmids\": [\"27866850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CSN5 isopeptidase activity is required for breast epithelial transformation; CSN5 potentiates MYC transcriptional activity in a manner dependent on assembly of the full COP9 signalosome. Transgenic inhibition of CSN5 isopeptidase activity blocks MYC/RAS-driven breast cancer progression in vivo.\",\n      \"method\": \"Isopeptidase-dead mutant expression, oncogene transformation assays in primary human cells, transgenic mouse model\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue with catalytic mutant in primary cells and transgenic in vivo model; multiple orthogonal approaches\",\n      \"pmids\": [\"18199546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"COPS5 overexpression, through its isopeptidase activity, leads to ubiquitination and proteasomal degradation of NCoR (nuclear co-repressor for ERα), causing tamoxifen resistance. Genetic inhibition of COPS5 isopeptidase activity re-sensitizes resistant cells to tamoxifen.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, isopeptidase-dead COPS5 mutant, genomic amplification analysis, in vitro and in vivo breast cancer models\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isopeptidase mutant rescue, Co-IP, ubiquitination assay, and in vivo validation in single study\",\n      \"pmids\": [\"27375289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Jab1-null embryos die shortly after implantation. Jab1-/- embryonic cells lack other CSN components and accumulate p27, p53, and cyclin E, resulting in impaired proliferation and accelerated apoptosis. In Jab1+/- MEFs, the Jab1-containing small subcomplex (not the CSN holocomplex) is selectively reduced, and G0-to-S phase progression is delayed via inefficient p27 down-regulation, while deneddylated Cul1 levels are unchanged.\",\n      \"method\": \"Jab1 knockout mice (homologous recombination), embryo analysis, MEF proliferation assays, western blotting for p27/p53/cyclin E/neddylated Cul1\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null and heterozygous mouse models with defined molecular readouts; independently confirmed by Tian et al. 2010\",\n      \"pmids\": [\"15299027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Conditional knockout of CSN5/Jab1 in MEFs ceases proliferation; the JAMM/deneddylase domain is essential for this function. Loss of CSN5 enhances neddylation of cullins 1 and 4, alters cyclin E and p53 levels, blocks cell cycle at multiple points, initiates p53-independent senescence, and increases cell ploidy (endoreduplication).\",\n      \"method\": \"CRE-lox conditional MEF knockout, cell cycle analysis, neddylation western blot, JAMM-domain rescue experiments\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic KO with catalytic-domain rescue, multiple orthogonal cell-cycle readouts\",\n      \"pmids\": [\"20974137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss of Jab1 in mice causes early embryonic lethality due to accelerated apoptosis. Loss of Jab1 sensitizes cells to γ-radiation-induced apoptosis, increases spontaneous DNA damage, and causes homologous recombination (HR) defects correlated with reduced Rad51 and elevated p53 levels. Accumulated p53 binds the Rad51 promoter and suppresses its expression, representing the mechanistic link between Jab1 loss and HR deficiency.\",\n      \"method\": \"Jab1 knockout mice, γ-irradiation assays, comet assay, HR assay, chromatin immunoprecipitation for p53 on Rad51 promoter\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null model combined with ChIP-defined mechanistic pathway linking Jab1→p53→Rad51 promoter\",\n      \"pmids\": [\"20802511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"JAB1/CSN5 dual-regulates MIF-induced ERK signaling: JAB1 overexpression inhibits sustained (CD74-dependent) ERK phosphorylation by MIF, while JAB1 knockdown (siRNA) abolishes transient ERK activation by MIF. Transient MIF-ERK signaling requires a Src-type kinase upstream and minimum JAB1 levels.\",\n      \"method\": \"siRNA knockdown of JAB1, Src-deficient cells with Src re-expression, Src inhibitor PP2, genistein inhibition, ERK/Raf/MEK phosphorylation assays\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (Src-KO rescue) and pharmacological inhibition plus siRNA; single lab\",\n      \"pmids\": [\"16122907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The MPN domain of JAB1 (without requiring the JAMM catalytic motif) mediates direct binding to MIF. The MIF sequence MIF(50-65) and the MPN domain are sufficient for the MIF-JAB1 interaction, confirmed by endogenous Co-IP showing that MPN (via CSN6 as a proxy) mediates the interaction in mammalian cells.\",\n      \"method\": \"Yeast two-hybrid with domain deletions, in vitro CoIP, GST pulldown, MALDI-TOF mass spectrometry with nanobead affinity matrix\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping by Y2H and pulldown plus in vivo Co-IP; single lab, multiple methods\",\n      \"pmids\": [\"15757663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Jab1 acts as a specificity factor for E2F1-induced apoptosis: Jab1 binds E2F1 specifically (not other E2Fs) via the E2F1 marked box region, and co-expression of Jab1+E2F1 synergistically induces apoptosis coincident with p53 accumulation. Jab1 depletion impairs both E2F1-induced apoptosis and p53 induction.\",\n      \"method\": \"Yeast two-hybrid screen, Co-IP, shRNA depletion, apoptosis and cell cycle assays, p53 western blot\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H confirmed by Co-IP, functional rescue/depletion experiments; single lab\",\n      \"pmids\": [\"16481464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CSN5 is a critical regulator of both p53 and MDM2: CSN5 interacts with p53, promotes MDM2-mediated p53 ubiquitination, facilitates p53 nuclear export, and stabilizes MDM2 by reducing its self-ubiquitination. CSN5 also antagonizes p53 transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, nuclear export assay, transcriptional reporter, curcumin (CSN-kinase inhibitor) treatment\",\n      \"journal\": \"Journal of Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional ubiquitination/export/reporter assays; single lab\",\n      \"pmids\": [\"17879958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Thioredoxin (Trx) directly interacts with and negatively regulates Jab1, competing with p27(Kip1) for Jab1 binding; Trx inhibits both AP-1 transcriptional activation and p27 degradation through this interaction. The negative effect on AP-1 is Jab1-dependent.\",\n      \"method\": \"FRET, Co-immunoprecipitation, antisense knockdown of Jab1, competition binding assay, AP-1 reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET plus Co-IP plus competition assay plus Jab1-dependent reporter; single lab\",\n      \"pmids\": [\"15480426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CSN5-associated deubiquitinase activity (via its JAMM domain) regulates sorting of proteins into exosomes: CSN5 knockdown increases ubiquitinated and non-ubiquitinated exosomal proteins. JAMM-domain-deleted CSN5 increases ubiquitinated (but not non-ubiquitinated) exosomal Hsp70, and promotes HIV Gag sorting and HIV-1 release.\",\n      \"method\": \"siRNA knockdown, JAMM-deletion mutant expression, western blot of exosomal fractions, HIV-1 release assay\",\n      \"journal\": \"American Journal of Pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion mutant combined with siRNA and biochemical fractionation; single lab\",\n      \"pmids\": [\"19246649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"JAB1 interacts with IRE1α in the absence of ER stress, and this interaction is decreased upon ER stress induction. A JAB1 mutant that binds IRE1α constitutively down-regulates UPR signaling, suggesting JAB1 modulates the choice between UPR and apoptosis via its association/dissociation with IRE1α.\",\n      \"method\": \"Yeast two-hybrid, Co-immunoprecipitation, UPR reporter assay, mutant JAB1 expression\",\n      \"journal\": \"Neurochemistry International\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus Y2H and reporter assay; single lab, limited mechanistic depth\",\n      \"pmids\": [\"15234121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CSN5/Jab1 co-immunoprecipitates with ERα and overexpression of CSN5/Jab1 increases ligand-induced ERα proteasomal degradation. This requires CSN-associated kinase activity (blocked by curcumin) and nuclear export (blocked by leptomycin B) for estradiol-induced degradation.\",\n      \"method\": \"Co-immunoprecipitation, LMB/curcumin inhibition, proteasome inhibitor, ERα degradation assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus multiple pharmacological inhibitors dissecting pathway; single lab\",\n      \"pmids\": [\"15899841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"JAB1 interacts with both the progesterone receptor (PR) and steroid receptor coactivator 1 (SRC-1), stabilizing PR-SRC-1 complexes and potentiating the transcriptional activity of multiple SRC-1-associated transcription factors without altering PR or SRC-1 protein levels.\",\n      \"method\": \"Yeast two-hybrid, mammalian two-hybrid, GST pulldown, transcriptional reporter assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H confirmed by pulldown and functional reporter; single lab\",\n      \"pmids\": [\"10722692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Drosophila CSN5/JAB1, expressed in photoreceptor R cells, is required for lamina glial cell migration into the optic lobe target region. Missense mutations in CSN5 specifically disrupt R1-R6 axon targeting; protein-null alleles additionally impair R cell differentiation at an earlier stage.\",\n      \"method\": \"Drosophila genetic analysis, CSN5 missense and null alleles, immunostaining of optic lobe development\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic allelic series (missense vs null) establishing distinct developmental functions; complementary to Cope et al. 2002\",\n      \"pmids\": [\"11779478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In Drosophila oogenesis, CSN5/JAB1 is required for meiotic progression and axis specification. CSN5 mutations reduce Gurken protein accumulation and cause Vasa modification, phenocopying spindle-class DNA-repair genes. The phenotype is suppressed by mutations in the DNA-damage checkpoint kinase mei-41 or by abolishing double-strand breaks (mei-W68), linking CSN5 to meiotic DNA repair checkpoint control of Gurken translation.\",\n      \"method\": \"Drosophila genetic epistasis (mei-41 and mei-W68 suppressors), immunostaining for Gurken and Vasa, oocyte axis analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple suppressors firmly places CSN5 in a defined checkpoint pathway\",\n      \"pmids\": [\"12397113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CSN5, but not the CSN holocomplex, directly binds CDK2 in vivo and in vitro. CSN5 depletion enhances Akt-mediated CDK2 phosphorylation, causing cytoplasmic accumulation of CDK2/cyclin E and impaired Rb phosphorylation. Additional knockdown of CDK2 (reducing cyclin E) suppresses senescence in CSN5-depleted cells, and enforced cytoplasmic cyclin E alone induces premature senescence.\",\n      \"method\": \"Co-IP (in vivo and in vitro), siRNA double knockdown, cytoplasmic cyclin E overexpression, SA-β-gal senescence assay, Rb phosphorylation assay\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro Co-IP plus genetic epistasis (double KD); single lab\",\n      \"pmids\": [\"23316279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Jab1/CSN5 induces nuclear export and proteasomal degradation of RUNX3. The nuclear export is controlled by CSN-associated kinases, and cytoplasmic RUNX3 is rapidly degraded via the proteasome pathway.\",\n      \"method\": \"Co-immunoprecipitation, nuclear export assay (LMB inhibition), proteasome inhibitor, overexpression/knockdown\",\n      \"journal\": \"Journal of Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus LMB and proteasome inhibitor validation; single lab\",\n      \"pmids\": [\"19350572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COPS5 interacts with RanBP9 (confirmed by Co-IP in neuronal and non-neuronal cells and mouse brain) and increases RanBP9 protein stability (half-life). Overexpression of COPS5 increases amyloid-β generation via increased sAPP-β, and siRNA knockdown of COPS5 reduces Aβ generation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, APP processing assays (ELISA for Aβ, western blot for sAPP-α/β), protein half-life assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H confirmed by Co-IP in multiple cell types and mouse brain, plus functional Aβ assays; single lab\",\n      \"pmids\": [\"23926111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JAB1 interacts with unphosphorylated STAT3 in the nucleus (demonstrated by Co-IP from nuclear extract) and positively regulates its DNA-binding activity. JAB1 knockdown decreases unphosphorylated STAT3 DNA-binding and reduces expression of MDR1, NANOG, and VEGF (STAT3 target genes).\",\n      \"method\": \"Nuclear fractionation, Co-immunoprecipitation from nuclear extract, siRNA knockdown, STAT3 DNA-binding ELISA, qPCR of target genes\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear Co-IP plus functional DNA-binding and target gene assays; single lab\",\n      \"pmids\": [\"23911788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Jab1 directly interacts with the West Nile virus capsid protein (WNVCp) and promotes its CRM1-dependent nuclear export to the cytoplasm and subsequent proteasomal degradation, preventing WNVCp-induced G2 cell cycle arrest. The first 15 aa of WNVCp (including P5/P8) are required for interaction.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, GST pulldown, immunofluorescence, LMB inhibition, deletion/point mutant analysis, flow cytometry\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (Y2H, pulldown, CoIP) plus LMB and functional cell-cycle assay; single lab\",\n      \"pmids\": [\"16882664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Jab1 directly interacts with and acts as a pro-apoptotic co-activator for BclGs (a BH3-only protein). Jab1 competes with Bcl-XL/Bcl-2 for BclGs binding, promotes Bax translocation to mitochondria, cytochrome c release, and caspase-3 activation. JAB1 knockdown reduces BclGs-induced apoptosis.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, GST pulldown, competition binding assay, RNAi knockdown, apoptosis assays (caspase, cytochrome c)\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H confirmed by Co-IP/pulldown plus competition assay and RNAi rescue; single lab\",\n      \"pmids\": [\"18006276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CUL4B E3 ubiquitin ligase (as part of DDB1-CUL4B-ROC1 complex) targets Jab1/CSN5 for polyubiquitination and proteasomal degradation. RNAi depletion of CUL4B impairs Jab1 degradation; in vitro and in vivo ubiquitination assays confirm CUL4B promotes Jab1 polyubiquitination. This degradation is independent of CUL4A. In Cul4b-deficient mouse fibroblasts, Jab1 accumulates and BMP signaling is aberrantly activated.\",\n      \"method\": \"siRNA knockdown of CUL4B, in vitro ubiquitination assay, in vivo ubiquitination assay, CUL4B-null MEFs, BMP signaling reporter\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro and in vivo ubiquitination assays combined with genetic null model and specific functional pathway readout\",\n      \"pmids\": [\"23357576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Jab1/CSN5 is required for normal Schwann cell proliferation and axonal sorting. Loss of Jab1 in Schwann cells increases p27 levels causing cell cycle defects and aberrant differentiation; genetic reduction of p27 in Jab1-null Schwann cells rescues cell number, differentiation, axonal sorting, and dysmyelinating neuropathy.\",\n      \"method\": \"Schwann-cell-specific Jab1 conditional knockout mice, genetic epistasis with p27 knockout, nerve morphology, cell cycle analysis\",\n      \"journal\": \"Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with genetic rescue (p27 KO epistasis) demonstrating causal pathway in vivo\",\n      \"pmids\": [\"24344238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Oligodendrocyte-specific deletion of JAB1/CSN5 causes DNA damage and defective DNA repair, leading to a p21CIP1-dependent senescence-like phenotype that triggers chronic neuroinflammation and oxidative stress. Deletion of p21CIP1 (but not p16INK4a) ameliorates the disease, linking CSN5 to senescence pathway selection in myelinating glia.\",\n      \"method\": \"Oligodendrocyte-specific Jab1 conditional KO mice, DNA damage markers, SA-β-gal, microglia inhibition, p21/p16 genetic epistasis\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with genetic epistasis (p21 vs p16) defining pathway; rigorous in vivo model\",\n      \"pmids\": [\"34874913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"JAB1 overexpression in hematopoietic cells promotes myeloproliferative disease in vivo; stable JAB1 transgenic mice have larger stem cell populations with higher transplantable proliferative potential. JAB1 interacts with the histone methyltransferase SMYD3, and together they suppress p16(INK4a) transcription.\",\n      \"method\": \"Jab1 transgenic mice, bone marrow transplantation, Co-IP (JAB1-SMYD3), p16 promoter reporter assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic in vivo model plus Co-IP and promoter assay; single lab\",\n      \"pmids\": [\"18667426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CSN5/Jab1 inhibits cardiac L-type Ca2+ channel (α1C subunit) activity through direct protein-protein interaction with the II-III linker of α1C. Silencing CSN5 with siRNA in COS7 cells activates L-type Ca2+ channel current. CSN5 and α1C co-immunoprecipitate from rat heart and co-localize in sarcolemmal membranes and transverse tubules.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from cardiac tissue, siRNA knockdown, electrophysiology (patch clamp), immunofluorescence co-localization\",\n      \"journal\": \"Journal of Molecular and Cellular Cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H confirmed by tissue Co-IP plus electrophysiology functional assay; single lab\",\n      \"pmids\": [\"16483597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CSN5 directly binds ZEB1 and decreases its ubiquitination, enhancing ZEB1 protein stability. This promotes RCC cell EMT, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro migration/invasion, in vivo xenograft\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay and functional rescue; single lab\",\n      \"pmids\": [\"28479251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Jab1/Csn5 mediates proteasome-dependent degradation of the CDK inhibitor p57(KIP2) through direct physical interaction in HCC cells, independently of Skp2 and Akt pathways.\",\n      \"method\": \"Co-immunoprecipitation, 26S proteasome inhibitor treatment, siRNA knockdown, in vitro interaction assay, in vivo xenograft\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus proteasome inhibitor plus pathway-specificity controls (Skp2/Akt); single lab\",\n      \"pmids\": [\"26606000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Asrij/OCIAD1 sequesters CSN5 via its conserved OCIA domain, preventing CSN5-mediated p53 ubiquitination and degradation. Loss of Asrij in mouse HSCs leads to increased CSN5-mediated p53 ubiquitination, reduced p53 levels, and HSC over-proliferation; Nutlin-3 treatment restores p53 and normalizes HSC frequencies.\",\n      \"method\": \"Asrij knockout mice, Co-IP of Asrij-CSN5 interaction, polyubiquitination assays, Nutlin-3 rescue, transplantation studies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with biochemical Co-IP and pharmacological rescue (Nutlin-3) confirming mechanism in vivo\",\n      \"pmids\": [\"30952670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CSN5 knockdown in HCC cells causes accumulation of neddylated Cullin 1, alters SKP2, p53, p27, and NF-κB protein levels, induces apoptosis, and inhibits cell cycle progression. Systemic delivery of CSN5 siRNA via lipid nanoparticles suppresses orthotopic HCC xenograft growth in vivo.\",\n      \"method\": \"siRNA knockdown, neddylation western blot, transcriptomic analysis, in vivo xenograft with siRNA nanoparticle delivery\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple molecular readouts and in vivo validation; single lab\",\n      \"pmids\": [\"21499307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Stat3 and C/EBP-β transcriptionally regulate Jab1/CSN5 expression in breast cancer cells. Stat3 and C/EBP-β directly bind overlapping sites in the Jab1 promoter; Src/Stat3/IL-6 axis activates Jab1 transcription. Re-activation of Stat3 in normal mammary epithelial cells is sufficient to reactivate Jab1 expression.\",\n      \"method\": \"5'-deletion reporter assays, mutational analysis of promoter binding sites, EMSA, ChIP, Stat3 and Src siRNA knockdown, IL-6 stimulation\",\n      \"journal\": \"Breast Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus EMSA plus mutational reporter analysis; single lab\",\n      \"pmids\": [\"21689417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"COPS5 and LASP1 synergistically interact (SH3 domain of LASP1 binds the MPN domain of COPS5, confirmed by GST pulldown) to promote ubiquitination and degradation of 14-3-3σ and activate PI3K/Akt signaling, driving CRC cell proliferation, migration, and invasion.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown (domain mapping), Co-IP, siRNA knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"International Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapped pulldown plus Co-IP plus functional assays in vitro/in vivo; single lab\",\n      \"pmids\": [\"29226323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CSN5 directly binds HK2 (hexokinase 2) and inhibits its ubiquitin-proteasome-mediated degradation, thereby stabilizing HK2 and promoting glycolysis. Silencing CSN5 decreases HK2 protein, glucose uptake, and glycolytic flux; HK2 re-expression rescues glycolysis in CSN5 knockdown cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, HK2 rescue overexpression, glycolysis assays, in vivo xenograft\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus epistatic rescue; single lab\",\n      \"pmids\": [\"31991125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CSN5 directly binds survivin and decreases its ubiquitination, enhancing survivin protein stability in NSCLC cells; the tumor-promoting effects of CSN5 are at least partially mediated through this survivin stabilization.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, cell growth/apoptosis assays\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus ubiquitination assay; single lab, limited validation\",\n      \"pmids\": [\"29596838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CSN5 directly binds FOXM1 and decreases its ubiquitination, enhancing FOXM1 protein stability and thereby promoting MMP2 expression to drive pancreatic cancer invasion and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro/in vivo invasion assays\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus ubiquitination assay; single lab\",\n      \"pmids\": [\"30352219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"JAB1 directly binds the HLH domain of HAND2 and augments HAND2 transcriptional activity by enhancing HAND2 DNA binding rather than by recruiting a transcriptional activation domain.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, domain-deletion mapping, transcriptional reporter assay, DNA-binding assay\",\n      \"journal\": \"Journal of Neuroscience Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H confirmed by Co-IP, functional reporter and DNA-binding assay with domain mapping; single lab\",\n      \"pmids\": [\"15139020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"p8 directly interacts with Jab1 (confirmed by His6-pulldown and Co-IP) and is required for Jab1-mediated nuclear-to-cytoplasmic translocation of p27 and its subsequent degradation. p8 knockdown strongly inhibits Jab1-induced p27 degradation.\",\n      \"method\": \"Yeast two-hybrid, His6-pulldown, Co-immunoprecipitation, siRNA knockdown of p8, p27 localization/degradation assay\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H confirmed by two biochemical methods plus siRNA functional assay; single lab\",\n      \"pmids\": [\"16300740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NRBP (nuclear receptor binding protein) interacts with Jab1 in vivo and inhibits Jab1-induced c-Jun phosphorylation and AP-1 activation, acting as a negative regulator of Jab1-mediated transcription.\",\n      \"method\": \"Co-immunoprecipitation, AP-1 reporter assay, overexpression in mammalian cells\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus reporter assay; single lab, limited mechanistic depth\",\n      \"pmids\": [\"17052710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Jab1/CSN5 positively regulates Rad51 through a p53-dependent pathway, and elevated Rad51 confers cellular resistance to cisplatin and radiation in NPC cells. Jab1 knockdown reduces Rad51 and sensitizes cells to DNA-damaging agents.\",\n      \"method\": \"siRNA knockdown, Rad51 overexpression rescue, cisplatin/radiation survival assays, p53 pathway analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (Rad51 rescue of Jab1 KD), confirmed in three NPC cell lines; single lab\",\n      \"pmids\": [\"22797071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CSN5 affects β-catenin signaling in CRC cells via regulation of the SIAH-1 E3 ubiquitin ligase: CSN5 promotes SIAH-1 degradation in a deNEDDylase-dependent manner, and β-catenin and SIAH-1 both form protein complexes with CSN5.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, deNEDDylase inhibitor (MLN-4924), qPCR and western blot for SIAH-1 and β-catenin\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus pharmacological deNEDDylase inhibition confirming mechanism; single lab\",\n      \"pmids\": [\"24882689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"5-HT6 receptor (5-HT6R) physically interacts with Jab1 (confirmed by GST pulldown, FRET, Co-IP). Jab1 siRNA decreases 5-HT6R cell membrane expression and 5-HT6R-mediated signaling. 5-HT6R activation induces Jab1 nuclear translocation and increased c-Jun phosphorylation.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, FRET, Co-immunoprecipitation, siRNA knockdown, immunocytochemistry\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding confirmation methods (FRET, GST pulldown, Co-IP) plus functional siRNA; single lab\",\n      \"pmids\": [\"20093369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cops5 is essential for genomic stability in mouse ESCs: it suppresses autophagic degradation of Mtch2 to direct cellular metabolism toward glycolysis, minimizing ROS and endogenous DNA damage. Independently, Cops5 is required for DNA damage repair (DDR) activities. Loss of Cops5 causes elevated ROS, DNA damage accumulation, p53-dependent G2/M arrest, and apoptosis.\",\n      \"method\": \"Inducible CRISPR/Cas9 Cops5 KO ESCs, metabolic assays, ROS measurement, comet assay, DDR marker analysis, autophagy/Mtch2 western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible genetic KO with multiple orthogonal mechanistic readouts (metabolism, autophagy, ROS, DDR); single lab but comprehensive study\",\n      \"pmids\": [\"31964807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Jab1 interacts with and stabilizes Thioredoxin (Trx) protein; ectopic Jab1 expression increases Trx expression, while Jab1 silencing reduces it. Jab1 also transcriptionally regulates Trx.\",\n      \"method\": \"Co-immunoprecipitation, western blot, siRNA knockdown, ectopic overexpression, qRT-PCR for Trx mRNA\",\n      \"journal\": \"Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus bidirectional expression manipulation; single lab\",\n      \"pmids\": [\"28270496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In endothelial cells, CSN5 forms a super-complex with IKK that dissociates upon TNF-α stimulation. CSN5 silencing enhances TNF-α-induced IκBα degradation and NF-κB activity, increases chemokine/adhesion molecule expression, and promotes monocyte arrest. CSN5 overexpression has reverse effects, indicating CSN5 is a negative regulator of NF-κB in endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation (CSN-IKK super-complex), siRNA knockdown, luciferase NF-κB reporter, flow cytometry, monocyte adhesion assay\",\n      \"journal\": \"Thrombosis and Haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of CSN-IKK complex plus bidirectional manipulation and functional adhesion assay; single lab\",\n      \"pmids\": [\"23636414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CSN5i-3 (pharmacological CSN5 inhibitor) causes endothelial barrier disruption by activating NF-κB pathway, inducing RhoB (and to lesser extent RhoA) expression and activation, and consequent Rho/ROCK-dependent MLC activation and endothelial contraction. This establishes that sustained CRL neddylation (via CSN5 inhibition) drives NF-κB→RhoB axis in endothelial cells.\",\n      \"method\": \"CSN5i-3 pharmacological inhibition, RhoGTPase activity assays, NF-κB reporter, ROCK inhibitor, endothelial permeability assay in vitro and in vivo\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with pathway inhibitor rescue and in vivo validation; single lab\",\n      \"pmids\": [\"31148579\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COPS5/CSN5/JAB1 is the catalytic subunit of the COP9 signalosome (CSN), carrying a JAMM-motif metalloprotease that deneddylates cullin-RING E3 ubiquitin ligases (CRLs); its isopeptidase activity is autoinhibited in the free monomer by the Ins-1 loop and is activated upon assembly into the CSN holocomplex (especially via MPN-MPN interaction with CSN6), enabling it to regulate CRL activity and the stability of diverse substrates including p27, p53, Smad4, Smad7, RUNX3, NCoR, PD-L1, HK2, ZEB1, and RanBP9 through deubiquitination or nuclear export/proteasomal degradation; independently of the CSN, CSN5 also functions as a nuclear-export adaptor (via its CRM1-binding NES), a transcriptional co-activator (for AP-1/c-Jun, HAND2, unphosphorylated STAT3), and a regulator of DNA repair (via Rad51/p53 axis), senescence (via CDK2/cyclin E and p21), and cellular metabolism (via suppression of Mtch2 autophagic degradation to promote glycolysis and minimize ROS in embryonic stem cells).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"COPS5 (CSN5/JAB1) is the catalytic subunit of the COP9 signalosome (CSN) and the cell's principal deneddylase for cullin-RING E3 ubiquitin ligases, thereby acting as a master regulator of protein stability across proliferation, DNA repair, and metabolism [#0, #11]. Its enzymatic activity is encoded by a JAMM-motif metalloprotease that cleaves Nedd8 from Cul1; metal chelation or active-site mutation abolishes this activity without disrupting complex assembly [#0]. In the free monomer this isopeptidase is autoinhibited by the Ins-1 segment occluding the substrate site, and a single Ins-1 mutation restores activity [#4]; productive catalysis is unlocked upon assembly into the CSN, where an MPN-MPN interaction between CSN5 and CSN6 within a CSN4-5-6-7 module activates the enzyme, though that module alone is insufficient for efficient CRL deneddylation [#5, #6]. Genetic loss of CSN5 disrupts the entire CSN, leaving cullins hyper-neddylated and causing accumulation of CRL substrates such as p27, p53, and cyclin E, with consequent cell-cycle arrest, senescence, endoreduplication, and embryonic lethality [#10, #11]. Beyond the canonical deneddylase function, CSN5 acts as a CRM1-dependent nuclear-export adaptor through a leucine-rich NES — exemplified by driving nuclear export and proteasomal degradation of p27 — and serves as a substrate-specific stabilizing or destabilizing factor for diverse proteins including Smad4, Smad7, RUNX3, PD-L1, HK2, ZEB1, and NCoR, frequently through control of their ubiquitination and proteasomal turnover [#1, #2, #3, #7, #9, #41]. Through these activities CSN5 modulates TGF-β/Smad signaling, DNA repair via a p53→Rad51 axis, p21- and CDK2/cyclin E-dependent senescence, and a metabolic program that suppresses autophagic degradation of Mtch2 to favor glycolysis and limit ROS-driven DNA damage [#2, #3, #12, #24, #32, #50]. CSN5 itself is regulated by transcriptional induction downstream of NF-κB and STAT3 and is targeted for degradation by the CUL4B E3 ligase [#7, #30, #39]. Its potentiation of MYC and CRL-dependent substrate turnover makes CSN5 isopeptidase activity rate-limiting for oncogenic transformation in vivo [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established an early non-deneddylase role for JAB1 as a transcriptional coactivator, framing CSN5 as more than a CRL regulator.\",\n      \"evidence\": \"Yeast/mammalian two-hybrid, GST pulldown, and reporter assays mapping JAB1 binding to PR and SRC-1\",\n      \"pmids\": [\"10722692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for coactivation defined\", \"Relationship to CSN holocomplex not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined a CSN-independent mechanism by which CSN5 controls substrate fate, identifying it as a CRM1 nuclear-export adaptor for p27.\",\n      \"evidence\": \"LMB inhibition, NES mutagenesis, dominant-negative truncation, fractionation, and Co-IP identifying a cytoplasmic CSN4-8 shuttle subcomplex\",\n      \"pmids\": [\"11704659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether export adaptor function requires isopeptidase activity not resolved\", \"Subcomplex composition only partially defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the JAMM metalloprotease motif as the molecular basis of CSN deneddylase activity, defining CSN5's core catalytic function.\",\n      \"evidence\": \"In vitro isopeptidase assays with active-site mutagenesis and metal chelation, plus genetic rescue in yeast and Drosophila\",\n      \"pmids\": [\"12183637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain how monomeric CSN5 is kept inactive\", \"Substrate repertoire beyond Cul1 not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected CSN5 to TGF-β signaling by showing it destabilizes Smad4, establishing it as an antagonist of this pathway.\",\n      \"evidence\": \"Co-IP, overexpression, proteasome inhibitors, and TGF-β reporter assays\",\n      \"pmids\": [\"11818334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating Smad4 ubiquitination not identified\", \"Dependence on CSN holocomplex untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated CSN5 also targets the inhibitory Smad7 for export and degradation, showing it can both promote and antagonize TGF-β signaling depending on substrate.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA, immunofluorescence, FRAP, and phosphorylation assays\",\n      \"pmids\": [\"14993265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of opposing Smad4 vs Smad7 effects unresolved\", \"Context determining substrate choice unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the essentiality of CSN5 in vivo and tied its loss to CRL-substrate accumulation and a deneddylase-independent subcomplex defect.\",\n      \"evidence\": \"Jab1 knockout and heterozygous mice with p27/p53/cyclin E and neddylated Cul1 readouts in MEFs\",\n      \"pmids\": [\"15299027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinct contributions of subcomplex vs holocomplex not fully separated\", \"Direct substrate vs indirect effects not delineated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linked CSN5 to apoptotic control via E2F1 and p53, broadening its role beyond proliferation into cell-death decisions.\",\n      \"evidence\": \"Y2H, Co-IP, shRNA depletion, and apoptosis/p53 assays mapping E2F1 marked-box binding\",\n      \"pmids\": [\"16481464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of p53 accumulation downstream of E2F1-Jab1 unclear\", \"Catalytic requirement untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed CSN5 isopeptidase activity is rate-limiting for oncogenic transformation, establishing therapeutic rationale for targeting its catalysis.\",\n      \"evidence\": \"Isopeptidase-dead mutant in primary human cells plus MYC/RAS transgenic mouse breast cancer model\",\n      \"pmids\": [\"18199546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CRL substrate driving transformation not pinpointed\", \"Mechanism of MYC potentiation not molecularly defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Confirmed the JAMM/deneddylase domain is essential for proliferation and linked CSN5 loss to p53-independent senescence and genome instability.\",\n      \"evidence\": \"Conditional MEF knockout with JAMM-domain rescue and DNA-repair/ChIP analysis of a p53→Rad51 axis\",\n      \"pmids\": [\"20974137\", \"20802511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CSN5 controls p53 levels mechanistically not fully resolved\", \"Direct vs CRL-mediated DNA repair role unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the structural basis of catalytic autoinhibition, explaining why monomeric CSN5 is inactive.\",\n      \"evidence\": \"X-ray crystallography of inactive monomer, MD simulation, AUC, and Ins-1 mutagenesis restoring activity\",\n      \"pmids\": [\"23288897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational change upon holocomplex assembly not captured at high resolution\", \"Physiological trigger of monomer-dimer equilibrium unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the CSN4-5-6-7 architecture and the CSN5-CSN6 MPN-MPN interface that positions the catalytic module within the complex.\",\n      \"evidence\": \"Bacterial reconstitution, pulldown, SEC, and ITC mapping pairwise and combinatorial interactions\",\n      \"pmids\": [\"23086934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full holocomplex assembly intermediates not all defined\", \"How assembly relieves Ins-1 autoinhibition not shown structurally\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified CUL4B as the E3 ligase that degrades CSN5, closing a feedback loop in which CSN5 regulates CRLs and a CRL regulates CSN5.\",\n      \"evidence\": \"siRNA, in vitro and in vivo ubiquitination assays, and CUL4B-null MEFs with BMP reporter\",\n      \"pmids\": [\"23357576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conditions selecting CUL4B-mediated turnover unknown\", \"Whether degradation targets monomer or complexed CSN5 unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that CSN5-CSN6 MPN association is necessary but not sufficient for efficient CRL deneddylation, refining the activation model.\",\n      \"evidence\": \"Hybrid structural modeling, cross-linking mass spectrometry, and heterodimer reconstitution isopeptidase assays\",\n      \"pmids\": [\"25144743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which additional subunits complete activation not identified\", \"Quantitative activation mechanism unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established CSN5 as a stabilizer of PD-L1 downstream of inflammatory signaling, linking it to tumor immune evasion.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, NF-κB reporter, siRNA, and in vivo mouse tumor model\",\n      \"pmids\": [\"27866850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether stabilization is via deneddylation or direct deubiquitination unclear\", \"E3 ligase counteracted not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed CSN5 isopeptidase-dependent degradation of NCoR drives endocrine-therapy resistance, with catalytic inhibition restoring sensitivity.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, isopeptidase-dead mutant, and in vitro/in vivo breast cancer models\",\n      \"pmids\": [\"27375289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs CRL-mediated NCoR ubiquitination not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed CSN5-mediated p53 degradation under upstream control by Asrij/OCIAD1 sequestration, defining a regulatory brake in stem-cell homeostasis.\",\n      \"evidence\": \"Asrij knockout mice, Co-IP, polyubiquitination assays, and Nutlin-3 rescue with transplantation\",\n      \"pmids\": [\"30952670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of OCIA-domain sequestration unknown\", \"Whether sequestration blocks catalysis or interaction unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Integrated CSN5 into a metabolism-genome-stability axis by showing it suppresses Mtch2 autophagy to favor glycolysis and limit ROS-driven DNA damage in ESCs.\",\n      \"evidence\": \"Inducible CRISPR KO ESCs with metabolic, ROS, comet, DDR, and autophagy/Mtch2 readouts\",\n      \"pmids\": [\"31964807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CSN5 restrains Mtch2 autophagy not molecularly defined\", \"Relationship to deneddylase activity unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined CSN5's tissue-specific requirement in myelinating glia, linking its loss to DNA-damage-induced, p21-dependent senescence and neuroinflammation.\",\n      \"evidence\": \"Oligodendrocyte-specific conditional KO mice with DNA-damage markers and p21 vs p16 genetic epistasis\",\n      \"pmids\": [\"34874913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DNA-repair substrate of CSN5 in glia unknown\", \"Why p21 rather than p16 is selected unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CSN5 selects between its CSN-dependent deneddylase activity and its many CSN-independent substrate-specific and adaptor functions in a given cellular context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model distinguishing holocomplex vs monomer/subcomplex substrate routing\", \"Direct deubiquitinase vs CRL-mediated effects rarely separated for individual substrates\", \"Structural transition from autoinhibited monomer to active holocomplex not captured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 5, 7, 9]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [21, 27, 44]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 45]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 37, 52]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 25, 27]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 7, 9, 30]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10, 11, 24]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [12, 47, 50]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 52]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [32, 50]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 52]}\n    ],\n    \"complexes\": [\n      \"COP9 signalosome (CSN)\",\n      \"CSN4-5-6-7 subcomplex\"\n    ],\n    \"partners\": [\n      \"CSN6\",\n      \"p27\",\n      \"Smad7\",\n      \"PD-L1\",\n      \"CUL4B\",\n      \"MIF\",\n      \"CDK2\",\n      \"RanBP9\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}