{"gene":"USP47","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2011,"finding":"USP47 is the major deubiquitylating enzyme for DNA polymerase β (Pol β), stabilizing newly synthesized cytoplasmic Pol β that is used as a source for nuclear Pol β in DNA base excision repair (BER). Knockdown of USP47 increases ubiquitylated Pol β, decreases Pol β levels, and causes BER deficiency with accumulation of DNA strand breaks.","method":"siRNA knockdown, ubiquitylation assays, DNA damage assays, cell viability assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (knockdown, ubiquitylation assay, BER functional assay, DNA strand break measurement), published in high-quality journal with clear mechanistic readouts","pmids":["21362556"],"is_preprint":false},{"year":2009,"finding":"USP47 physically interacts with SCF(β-TrCP) E3 ubiquitin ligase via direct binding to both β-TrCP1 and β-TrCP2 WD-repeat regions (point mutations in WD-repeat abolished binding). Unlike canonical β-TrCP substrates, USP47 levels were not regulated by β-TrCP. Depletion of USP47 caused accumulation of Cdc25A and decreased cell survival.","method":"Co-immunoprecipitation, point mutagenesis, siRNA knockdown, cell survival assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis, single lab, functional phenotype confirmed","pmids":["19966869"],"is_preprint":false},{"year":2012,"finding":"USP47 (together with USP7) is a cysteine isopeptidase whose inhibition stabilizes p53 and decreases DNA polymerase β (Pol β) levels in cancer cells, leading to apoptosis. Selective dual small-molecule inhibitors of USP7 and USP47 were shown to inhibit USP7 in cells and induce elevated p53.","method":"Small molecule inhibition, cell-based p53/apoptosis assays, in vivo xenograft models","journal":"ACS medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzyme inhibition confirmed in cells with multiple readouts (p53 stabilization, apoptosis, in vivo), single lab","pmids":["24900381"],"is_preprint":false},{"year":2013,"finding":"USP47 deubiquitinates and stabilizes katanin-p60 (a microtubule-severing enzyme), antagonizing CHIP (an E3 ubiquitin ligase that promotes katanin-p60 degradation). USP47 overexpression promoted axonal growth in rat hippocampal neurons, while CHIP overexpression inhibited it. bFGF treatment increased USP47 and katanin-p60 levels and decreased ubiquitinated katanin-p60.","method":"Co-immunoprecipitation, ubiquitination assays, overexpression/knockdown in cultured neurons, bFGF treatment","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, epistasis between USP47 and CHIP on katanin-p60 stability, functional axonal growth readout with multiple orthogonal approaches","pmids":["23904609"],"is_preprint":false},{"year":2014,"finding":"Minus end-directed motor KIFC3 binds USP47 and recruits it to adherens junctions. Depletion of KIFC3 or USP47 promotes ubiquitination and cleavage of E-cadherin at a juxtamembrane region (producing a 90-kDa fragment), dependent on the E3 ligase Hakai, leading to E-cadherin internalization. Proteasome inhibitors blocked this cleavage.","method":"Co-immunoprecipitation, siRNA knockdown, E-cadherin ubiquitination assay, proteasome inhibitor treatment, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishing KIFC3-USP47 interaction, epistasis with Hakai E3 ligase, functional E-cadherin stability assay with multiple orthogonal approaches","pmids":["25253721"],"is_preprint":false},{"year":2015,"finding":"USP47 (and its Drosophila ortholog UBP64E) deubiquitinates β-catenin, preventing its ubiquitination and proteasomal degradation. RNAi inactivation of USP47 increased β-catenin ubiquitination, attenuated Wnt signaling, and repressed cancer cell growth. β-TrCP promotes USP47 ubiquitination via an atypical interaction motif, and USP47 also auto-deubiquitinates itself. In vivo, UBP64E is required for Armadillo stabilization and Wnt target gene expression in Drosophila wing.","method":"RNAi library screen, Co-immunoprecipitation, ubiquitination assays, Drosophila in vivo genetics","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi screen identification, Co-IP, ubiquitination assays, and in vivo Drosophila validation across two organisms","pmids":["26169834"],"is_preprint":false},{"year":2016,"finding":"Drosophila USP47 acts post-translationally to stabilize MAPK by counteracting its proteasome-mediated degradation. Genetic interaction RNAi screening identified UBC6 (E2), POE/UBR4 (N-recognin E3 ligase), and UFD4 as enzymes opposing USP47. KCMF1 was identified as another component of the POE-associated degradation module. These results place USP47 as counteracting the N-end rule pathway to maintain MAPK levels and RAS-MAPK signaling output.","method":"RNAi-based genetic interaction screen, epistasis analysis in Drosophila, MAPK level measurements","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic RNAi epistasis screen with genetic validation in Drosophila, multiple components identified and validated","pmids":["27552662"],"is_preprint":false},{"year":2018,"finding":"Chemical inhibition of USP7 and USP47 blocks NLRP3 inflammasome formation in macrophages, independently of transcription, by preventing ASC oligomerisation and speck formation. The ubiquitination status of NLRP3 is altered by inhibition of USP7/USP47. USP7 and USP47 activity increases in response to inflammasome activators. CRISPR/Cas9 knockdown of both USP7 and USP47 reduces inflammasome activation and IL-1β/IL-18 release.","method":"Chemical inhibition, CRISPR/Cas9 knockdown, ASC oligomerization assay, NLRP3 ubiquitination assay, cytokine measurement","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (pharmacological inhibition, CRISPR knockdown), functional inflammasome readouts with mechanistic ubiquitination analysis","pmids":["30206189"],"is_preprint":false},{"year":2018,"finding":"USP47 promotes β-TrCP stability and phosphorylation of RelA (NF-κB subunit) in gastric cancer cells. USP47 knockdown reduced cell viability and increased sensitivity to etoposide and camptothecin.","method":"Immunoblot, siRNA knockdown, MTT assay, Annexin V staining, PARP/caspase cleavage","journal":"Biomedicines","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, immunoblot-based evidence for β-TrCP stability, no direct deubiquitination assay of the relevant substrates shown","pmids":["29786670"],"is_preprint":false},{"year":2019,"finding":"ERAP1 binds USP47, displaces the USP47-associated β-TrCP (substrate-receptor of SCFβ-TrCP ubiquitin ligase), and promotes β-TrCP degradation. This results in modulation of Gli transcription factors (effectors of Hedgehog signaling) and enhancement of Hh pathway activity.","method":"Co-immunoprecipitation, pulldown, genetic and pharmacological inhibition in vitro and in vivo tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishing ERAP1-USP47-β-TrCP ternary complex, functional Hh signaling and Gli modulation, in vivo validation","pmids":["31341163"],"is_preprint":false},{"year":2019,"finding":"USP47 interacts with SATB1 and mediates its deubiquitination and stabilization. SMURF2 is an E3 ubiquitin ligase that promotes SATB1 degradation. USP47 negatively regulates SMURF2, and USP47 depletion sensitizes colon cancer cells to 5-FU-induced apoptosis.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, mouse xenograft model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays in single lab, functional tumor model, two orthogonal approaches","pmids":["30742943"],"is_preprint":false},{"year":2020,"finding":"USP47 interacts with and deubiquitinates IK (a spliceosomal component), preventing its proteolytic degradation via the 26S proteasome. USP47-mediated stabilization of IK is required for proper splicing of ATM pre-mRNA (particularly intron 1), and IK deficiency impairs DNA damage repair.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, pre-mRNA splicing assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP and ubiquitination assay linking USP47 to IK stabilization, functional splicing assay, single lab","pmids":["32377397"],"is_preprint":false},{"year":2020,"finding":"USP47 deubiquitinates ribosomal protein S2 (RPS2) that has been ubiquitinated by MDM2. Under normal conditions, USP47 inhibits the interaction between RPS2 and MDM2, alleviating RPS2-mediated MDM2 suppression and keeping p53 levels low. Under ribosomal stress, USP47 dissociation allows RPS2-MDM2 binding, suppresses MDM2, and induces p53 upregulation.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, xenograft mouse model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay, stress-condition epistasis, functional tumor suppression readout, single lab","pmids":["32370049"],"is_preprint":false},{"year":2021,"finding":"USP47 stabilizes Y-box binding protein 1 (YBX1), contributing to DNA damage repair in CML cells. USP47 knockdown or knockout significantly inhibited BCR-ABL and BCR-ABL(T315I)-induced CML in mice and reduced Lin-Sca1+c-Kit+ CML stem/progenitor cells.","method":"Mechanistic studies (YBX1 stabilization), in vitro knockdown, in vivo CML mouse models, flow cytometry for stem cell populations","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse CML model with stem cell readout, YBX1 stabilization mechanistic link, single lab","pmids":["33397955"],"is_preprint":false},{"year":2021,"finding":"USP47 interacts with TCEA3 and mediates its deubiquitination, increasing intracellular TCEA3 levels. TCEA3 regulates pro-apoptotic Bax levels. USP47-TCEA3 axis modulates pyroptosis and apoptosis in response to doxorubicin in colorectal cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, apoptosis/pyroptosis assays","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and deubiquitination assay established substrate relationship, functional rescue experiments, single lab","pmids":["34630087"],"is_preprint":false},{"year":2022,"finding":"USP47 deubiquitinates and stabilizes BACH1 (BTB and CNC homology 1 transcription factor). USP47-stabilized BACH1 promotes the Warburg effect (glycolysis) in NSCLC by transcriptionally upregulating hexokinase 2 (Hk2) and GAPDH.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro/in vivo proliferation assays, glycolysis measurement","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional glycolysis and tumor growth readouts, single lab","pmids":["35141006"],"is_preprint":false},{"year":2022,"finding":"USP47 deubiquitinates RPL11, preventing its translocation from nucleolus to nucleoplasm. When USP47 is inhibited, RPL11 translocates to the nucleoplasm and interacts with MDM2, preventing MDM2-mediated proteasomal degradation of p53, thus inhibiting cell proliferation in a p53-dependent manner. The catalytically inactive USP47 form does not rescue this phenotype.","method":"miR-101-3p overexpression, USP47 overexpression with catalytically inactive mutant, Co-IP, immunofluorescence for RPL11 localization, cell proliferation assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytically inactive mutant used to confirm enzymatic requirement, Co-IP and subcellular localization with functional p53 readout, single lab","pmids":["35205710"],"is_preprint":false},{"year":2022,"finding":"USP47 removes K63-linked polyubiquitin chains from TRAF3 and TRAF6, acting downstream of MAVS and upstream of TBK1 in the antiviral innate immune signaling pathway, thereby attenuating type I interferon production and IFNB1 transcription.","method":"Co-immunoprecipitation, ubiquitin chain-type specific assays, overexpression/knockdown, luciferase reporter assay, viral replication assay","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K63-chain specific deubiquitination demonstrated, epistasis positioning (downstream MAVS, upstream TBK1), single lab","pmids":["37001379"],"is_preprint":false},{"year":2022,"finding":"USP47 inhibition leads to destabilization of mutant EZH2 protein through promotion of its ubiquitination. USP47 was identified as a novel regulator of mutant EZH2, and targeting USP47 leads to death of mutant EZH2-positive DLBCL cells in vitro and in vivo.","method":"Selectivity profiling, genetic knockdown, ubiquitination assay, in vitro and mouse model studies","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods including selectivity profiling, animal models, and ubiquitination assays, single lab","pmids":["35034955"],"is_preprint":false},{"year":2023,"finding":"Crystal structures of the USP47 catalytic domain (free and ubiquitin-bound states) reveal misaligned catalytic triads that become aligned upon ubiquitin binding (similar to USP7), enabling catalysis. Full-length USP47 shows higher deubiquitinase activity than the catalytic domain alone. BL1, BL2, and BL3 loops differ from USP7 in composition and length, contributing to substrate selectivity.","method":"X-ray crystallography, in vitro deubiquitinase activity assays, domain truncation experiments","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure determination with functional validation of catalytic mechanism and activity comparison between full-length and catalytic domain","pmids":["37740002"],"is_preprint":false},{"year":2023,"finding":"USP47 prevents YTHDF1 ubiquitination to attenuate the association of YTHDF1 with translation initiation machinery, thereby decreasing m6A-based c-Myc translation efficiency in regulatory T cells. USP47 ablation in Tregs caused c-Myc protein accumulation, exacerbated hyperglycolysis, compromised Treg homeostasis, and boosted antitumor immune responses.","method":"Co-immunoprecipitation, ubiquitination assay, Treg-specific knockout mouse, m6A translation efficiency assays, metabolic assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assay, in vivo Treg-specific KO model, translational regulation mechanism with multiple orthogonal methods","pmids":["37788092"],"is_preprint":false},{"year":2023,"finding":"USP47 deubiquitylates the transcriptional co-repressor Groucho/TLE, counteracting XIAP-mediated monoubiquitylation of TLE3. USP47 interacts with both TLE3 and XIAP but does not alter their amounts. USP47 inhibited XIAP-mediated ubiquitylation of TLE3 in vitro in a dose-dependent manner. This deubiquitylation is required for Wnt-β-catenin target gene expression in Drosophila, Xenopus, and human cells.","method":"Genome-scale RNAi screen in Drosophila, Co-immunoprecipitation, in vitro ubiquitylation assay, Xenopus and human cell epistasis experiments, Wnt reporter assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted ubiquitylation inhibition assay, replicated across three organisms (Drosophila, Xenopus, human cells), Co-IP and functional Wnt reporter","pmids":["36749823"],"is_preprint":false},{"year":2024,"finding":"USP47 deubiquitinates and stabilizes SIRT1 protein. SIRT1 in turn upregulates PPARα expression via deacetylation, thereby promoting osteogenic differentiation of bone marrow mesenchymal stem cells via the Wnt/β-catenin pathway.","method":"Ubiquitination assay, co-immunoprecipitation, siRNA knockdown, osteogenic differentiation assays (ALP activity, Alizarin Red staining)","journal":"Chemical biology & drug design","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay for USP47-SIRT1 substrate relationship, functional differentiation readout, single lab","pmids":["38373741"],"is_preprint":false},{"year":2024,"finding":"USP47 stabilizes IRF1 by deubiquitination, preventing its proteasomal degradation. Stabilized IRF1 binds the CXCL4 promoter to promote CXCL4 expression, which in turn promotes NLRP3 inflammasome-mediated pyroptosis and cardiac dysfunction in myocardial infarction.","method":"Co-immunoprecipitation, ubiquitination assay, luciferase reporter (IRF1-CXCL4 promoter binding), siRNA knockdown, MI mouse model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, promoter binding assay, in vivo rescue with IRF1 overexpression, single lab","pmids":["38850785"],"is_preprint":false},{"year":2025,"finding":"USP47 stabilizes c-Myc by preventing its proteasomal degradation through deubiquitination, thereby promoting NSCLC cell proliferation. USP47 inhibition destabilizes c-Myc and enhances the efficacy of the KRASG12C inhibitor Sotorasib in vitro and in vivo.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro proliferation assay, in vivo xenograft model, small molecule inhibitor (K-552)","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional in vivo validation, single lab","pmids":["40180254"],"is_preprint":false},{"year":2025,"finding":"USP47 modulates PD-L1 protein stability through deubiquitination. USP47 interacts with PD-L1 (Co-IP) and deubiquitinates it, preventing its degradation. USP47 inhibition reduces tumoral PD-L1 levels without affecting mRNA, and combination with anti-PD-1 therapy enhanced HCC tumor suppression in mouse models.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, T cell killing assay, mouse HCC model with P5091 inhibitor","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and deubiquitination assay, mRNA vs protein level distinction, functional immune assay, in vivo model, single lab","pmids":["40494207"],"is_preprint":false},{"year":2025,"finding":"USP47 deubiquitinates FEN1 (flap endonuclease 1), stabilizing its protein levels. Mutant USP47 (Cys109Ser, catalytically inactive) did not stabilize FEN1. USP47 directly interacts with FEN1 (Co-IP, immunofluorescence). The natural compound rotenone physically interacts with USP47 and modulates USP47 expression and Ub-USP47 conjugation, reducing FEN1 stability.","method":"Co-immunoprecipitation, immunofluorescence, cycloheximide chase, deubiquitination assay, catalytic mutant (Cys109Ser), Biacore binding assay, xenograft model","journal":"Drug design, development and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant used to confirm enzymatic requirement, Co-IP and Biacore binding, multiple functional assays, single lab","pmids":["42112089"],"is_preprint":false},{"year":2025,"finding":"USP47 binds, deubiquitinates, and stabilizes PRMT5 (protein arginine methyltransferase 5), thereby upregulating O-GlcNAcase expression and inhibiting O-GlcNAcylation in cardiomyocytes. This mechanism attenuates Ang II-induced cardiac hypertrophy.","method":"Co-immunoprecipitation, ubiquitination assay, adenovirus-mediated gain/loss-of-function, cardiac hypertrophy in vitro and in vivo assays","journal":"Journal of cardiovascular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and deubiquitination assay, in vivo cardiac model, functional rescue by PRMT5 restoration, single lab","pmids":["39436323"],"is_preprint":false},{"year":2025,"finding":"USP47 deubiquitinates and stabilizes NRP1 (Neuropilin-1), preventing its ubiquitination and degradation, and activating the PI3K/Akt signaling pathway to promote angiogenesis in gastric cancer.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, angiogenesis assays","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, limited mechanistic depth in abstract","pmids":["40499689"],"is_preprint":false},{"year":2026,"finding":"USP47 directly interacts with HDAC2, promotes its deubiquitination, and enhances HDAC2 protein stability. Stabilized HDAC2 acts as a transcriptional repressor of CYP1A1 by deacetylating H3K9 and H3K27 at the CYP1A1 promoter, thereby reducing ROS-driven autophagy and protecting against cigarette smoke-induced skeletal muscle atrophy.","method":"Co-immunoprecipitation, ubiquitination assays, ChIP-qPCR, RNA-seq, gain/loss-of-function in mouse model and C2C12 cells","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay, ChIP-qPCR for downstream mechanism, in vivo mouse model, multiple orthogonal methods, single lab","pmids":["41529803"],"is_preprint":false},{"year":2026,"finding":"USP47 stabilizes SIRT1 through deubiquitination (inhibiting its ubiquitination and degradation). SIRT1 then upregulates PPARα expression via deacetylation to promote lipid metabolism and alleviate metabolic-associated fatty liver disease. SIRT1 inhibitor EX-527 reversed USP47 overexpression benefits.","method":"Co-immunoprecipitation, ubiquitination assay, rat HFD model, HepG2 OA model, gain/loss-of-function experiments, pharmacological inhibitor rescue","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and deubiquitination assay for USP47-SIRT1 axis, in vivo rat model, pharmacological epistasis, single lab","pmids":["41930505"],"is_preprint":false},{"year":2026,"finding":"USP47 competitively binds ASK1 (apoptosis signal-regulating kinase 1), deubiquitinating lysine residue 805 of ASK1. NUP85 competitively displaces USP47 from ASK1, promoting ASK1 activation and exacerbating collagen deposition and endoplasmic reticulum stress in liver fibrosis.","method":"Co-immunoprecipitation, ubiquitination assay (site-specific K805), competitive binding experiments, loss-of-function in liver fibrosis model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific deubiquitination of ASK1 K805, competitive binding mechanism, in vivo liver fibrosis model, single lab","pmids":["41903125"],"is_preprint":false},{"year":2023,"finding":"USP47 regulates cutaneous oxidative injury through stabilization of nicotinamide nucleotide transhydrogenase (NNT) by preventing its ubiquitin-mediated degradation. Loss of USP47 in mice aggravated radiation- and imiquimod-induced skin damage; knockdown of NNT increased mitochondrial ROS and disrupted mitochondrial membrane potential.","method":"Usp47 knockout mouse models, proteomic analysis, siRNA knockdown of NNT, mitochondrial ROS measurement","journal":"Toxicology and applied pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse model with proteomic identification of NNT, mechanistic ubiquitination link, functional mitochondrial readouts, single lab","pmids":["37924851"],"is_preprint":false},{"year":2025,"finding":"USP47 inhibits degradation of ubiquitinated GluR1 (AMPAR subunit), thereby enhancing excitatory postsynaptic transmission and increasing dendritic spine density/maturity. Elevated USP47 was found in epileptic mice, and USP47 knockdown reduced seizure frequency and duration.","method":"Electrophysiology, dendritic spine morphology analysis, ubiquitination assay, siRNA knockdown in epileptic mouse model","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay identifying GluR1 as substrate, electrophysiology functional readout, in vivo epilepsy model, single lab","pmids":["40716012"],"is_preprint":false}],"current_model":"USP47 is a cysteine deubiquitylase whose catalytic triads become aligned upon ubiquitin binding (as revealed by crystal structure), with its full-length form showing higher activity than the catalytic domain alone; it stabilizes a wide range of substrates — including DNA polymerase β, β-catenin, katanin-p60, BACH1, YBX1, SATB1, IK, RPS2/RPL11 (modulating p53 via MDM2), TRAF3/TRAF6 (attenuating antiviral IFN signaling), YTHDF1 (controlling m6A-dependent c-Myc translation in Tregs), TLE/Groucho (promoting Wnt-TCF transcription by opposing XIAP-mediated ubiquitylation), E-cadherin (via KIFC3-mediated recruitment to adherens junctions), PRMT5, NNT, ASK1, FEN1, HDAC2, SIRT1, PD-L1, NRP1, and GluR1 — through direct deubiquitination, placing USP47 as a central regulator of DNA repair, Wnt/β-catenin, Hedgehog, MAPK (N-end rule), NF-κB, NLRP3 inflammasome, antiviral immunity, Treg metabolism, axonal growth, adherens junction maintenance, and cancer cell proliferation pathways."},"narrative":{"mechanistic_narrative":"USP47 is a cysteine deubiquitylase that stabilizes a broad array of substrate proteins by removing ubiquitin chains and antagonizing their proteasomal degradation, positioning it as a central regulator across DNA repair, Wnt and Hedgehog signaling, immunity, and cell proliferation [PMID:21362556, PMID:26169834, PMID:36749823]. Crystal structures of its catalytic domain show that its catalytic triad is misaligned in the free state and becomes competent upon ubiquitin binding, and the full-length enzyme is more active than the isolated catalytic domain [PMID:37740002]. In genome maintenance, USP47 is the major deubiquitylase for DNA polymerase β, stabilizing the cytoplasmic pool that supplies nuclear base excision repair, and it likewise stabilizes FEN1 and the spliceosomal factor IK to support DNA damage repair [PMID:21362556, PMID:42112089, PMID:32377397]. USP47 functions in concert with the SCF(β-TrCP) ligase machinery: it binds β-TrCP1/2 directly and these interactions feed into Wnt/β-catenin and Hedgehog outputs, including direct deubiquitylation of β-catenin and of the Groucho/TLE co-repressor to promote Wnt-TCF target gene expression [PMID:19966869, PMID:26169834, PMID:31341163, PMID:36749823]. In the cytoplasm and at the cell cortex it stabilizes katanin-p60 to promote axonal growth and is recruited by the motor KIFC3 to deubiquitylate E-cadherin at adherens junctions [PMID:23904609, PMID:25253721]. USP47 also tunes immune and inflammatory signaling — it is required for NLRP3 inflammasome assembly, removes K63-linked chains from TRAF3/TRAF6 to attenuate type I interferon production, and in regulatory T cells stabilizes YTHDF1 to control m6A-dependent c-Myc translation [PMID:30206189, PMID:37001379, PMID:37788092]. A recurring theme in cancer is USP47-mediated stabilization of oncogenic and metabolic regulators including c-Myc, BACH1, YBX1, SATB1, and PD-L1, making it a recurrent therapeutic target whose pharmacological inhibition lowers these substrates and sensitizes tumors [PMID:40180254, PMID:35141006, PMID:33397955, PMID:30742943, PMID:40494207].","teleology":[{"year":2009,"claim":"Established USP47 as a physical partner of the SCF(β-TrCP) ligase, defining its connection to the ubiquitin–proteasome degradation machinery and to cell-cycle/survival control.","evidence":"Co-IP with point mutagenesis of β-TrCP WD-repeats and siRNA knockdown with survival readout","pmids":["19966869"],"confidence":"Medium","gaps":["Direct deubiquitylation of a substrate not yet demonstrated","How USP47 modulates β-TrCP function mechanistically unclear"]},{"year":2011,"claim":"Identified the first bona fide USP47 substrate, DNA polymerase β, linking the enzyme to base excision repair fidelity.","evidence":"siRNA knockdown, ubiquitylation assays, and DNA strand-break/BER functional assays","pmids":["21362556"],"confidence":"High","gaps":["Site of deubiquitylation on Pol β not mapped","In vitro reconstitution with purified components not shown"]},{"year":2013,"claim":"Showed USP47 directly antagonizes a specific E3 ligase (CHIP) to stabilize katanin-p60, demonstrating a deubiquitylase–ligase counterbalance with a developmental phenotype.","evidence":"Reciprocal Co-IP, ubiquitination assays, and axonal-growth assays in cultured neurons with bFGF stimulation","pmids":["23904609"],"confidence":"High","gaps":["Chain type removed not defined","Upstream regulation of USP47 by bFGF not resolved"]},{"year":2014,"claim":"Revealed spatial control of USP47 activity, with motor KIFC3 recruiting it to adherens junctions to protect E-cadherin from Hakai-mediated cleavage.","evidence":"Co-IP, siRNA knockdown, E-cadherin ubiquitination assay, and immunofluorescence","pmids":["25253721"],"confidence":"High","gaps":["Direct vs indirect deubiquitylation of E-cadherin not distinguished","Structural basis of KIFC3 binding unknown"]},{"year":2015,"claim":"Defined USP47 as a Wnt pathway component that deubiquitylates β-catenin, validated across species, and uncovered its reciprocal regulation by and auto-deubiquitylation within the β-TrCP system.","evidence":"RNAi screen, Co-IP, ubiquitination assays, and Drosophila in vivo genetics","pmids":["26169834"],"confidence":"High","gaps":["Stoichiometry between USP47 self-regulation and substrate turnover unclear"]},{"year":2016,"claim":"Positioned USP47 as a counter-force to the N-end rule (UBR4/POE) degradation module to maintain MAPK levels and RAS-MAPK output.","evidence":"RNAi-based genetic interaction/epistasis screen in Drosophila with MAPK level measurements","pmids":["27552662"],"confidence":"High","gaps":["Direct biochemical deubiquitylation of MAPK not shown","Conservation in mammalian cells not tested here"]},{"year":2018,"claim":"Extended USP47 function into innate immunity by showing it is required for NLRP3 inflammasome assembly and ASC speck formation.","evidence":"Chemical inhibition, CRISPR/Cas9 knockdown, ASC oligomerization and NLRP3 ubiquitination assays, cytokine measurement","pmids":["30206189"],"confidence":"High","gaps":["Inhibitors target both USP7 and USP47, limiting USP47-specific attribution","Direct NLRP3 substrate relationship not isolated"]},{"year":2019,"claim":"Connected USP47 to Hedgehog signaling through an ERAP1–USP47–β-TrCP ternary complex that controls Gli activity, and to SATB1 stabilization in cancer.","evidence":"Co-IP, pulldown, and in vitro/in vivo tumor models; separate SATB1 Co-IP/ubiquitination work","pmids":["31341163","30742943"],"confidence":"High","gaps":["Whether USP47 catalytic activity is required for the ERAP1 effect not separated from scaffolding"]},{"year":2020,"claim":"Linked USP47 to ribosomal-stress p53 signaling and to splicing fidelity, stabilizing RPS2 and the spliceosomal factor IK that ensures correct ATM pre-mRNA splicing.","evidence":"Co-IP, ubiquitination assays, splicing assays, and xenograft models","pmids":["32370049","32377397"],"confidence":"Medium","gaps":["Single-lab evidence for each substrate","Catalytic dependence of RPS2 effect not formally tested"]},{"year":2022,"claim":"Defined the catalytic mechanism: ubiquitin binding aligns the misaligned catalytic triad and full-length enzyme exceeds the isolated catalytic domain in activity; in parallel, multiple oncogenic/immune substrates (BACH1, RPL11/p53, TRAF3/6, EZH2) were established.","evidence":"X-ray crystallography with deubiquitinase assays; plus Co-IP/ubiquitination assays and catalytically inactive mutant controls across substrate studies","pmids":["37740002","35141006","35205710","37001379","35034955"],"confidence":"High","gaps":["No full-length structure to explain higher activity","Substrate-specific recognition determinants in BL loops not mapped to individual substrates"]},{"year":2023,"claim":"Showed USP47 controls Treg metabolism via YTHDF1-dependent m6A c-Myc translation and deubiquitylates the Groucho/TLE co-repressor to drive Wnt target gene expression, broadening its regulatory reach into translation and transcriptional co-repression.","evidence":"Treg-specific knockout mouse, m6A translation/metabolic assays; genome-scale RNAi screen with in vitro ubiquitylation inhibition across three organisms","pmids":["37788092","36749823"],"confidence":"High","gaps":["Direct YTHDF1 deubiquitylation site not mapped","Relative contribution of β-catenin vs TLE deubiquitylation to Wnt output unresolved"]},{"year":2025,"claim":"Consolidated USP47 as a cancer therapeutic target, stabilizing c-Myc and PD-L1, with inhibition synergizing with KRAS-G12C inhibition and anti-PD-1 therapy.","evidence":"Co-IP, ubiquitination assays, T cell killing assays, and in vivo xenograft/HCC models with small-molecule inhibitors","pmids":["40180254","40494207"],"confidence":"Medium","gaps":["Single-lab evidence per substrate","Inhibitor selectivity over USP7 not fully resolved in some studies"]},{"year":2026,"claim":"Expanded the substrate landscape into tissue-protective and pathological roles, stabilizing SIRT1, HDAC2, ASK1, PRMT5, NNT and GluR1 across liver, cardiac, muscle, skin and neuronal contexts.","evidence":"Co-IP, site-specific (ASK1 K805) and catalytic-mutant ubiquitination assays, ChIP-qPCR, electrophysiology, and in vivo disease models","pmids":["41930505","41529803","41903125","39436323","37924851","40716012"],"confidence":"Medium","gaps":["Each substrate rests on single-lab evidence","Whether one cell type uses one dominant substrate axis is unclear"]},{"year":null,"claim":"How USP47 achieves substrate selectivity among its many reported targets and how its activity is spatially and temporally regulated remain open.","evidence":"No full-length or substrate-bound structure and no unifying recruitment/selectivity model across substrates in the corpus","pmids":[],"confidence":"Medium","gaps":["No substrate-recognition code linking BL loops to specific substrates","Regulation of USP47 catalytic activation in vivo undefined","Most substrate claims are single-lab"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,5,19,21,26]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,19,26]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,9,16]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,11,26]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,9,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,17,20]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,5,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,12,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,15,24,25]}],"complexes":[],"partners":["BTRC","FBXW11","KIFC3","ERAP1","XIAP","TLE3","ASK1","PRMT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96K76","full_name":"Ubiquitin carboxyl-terminal hydrolase 47","aliases":["Deubiquitinating enzyme 47","Ubiquitin thioesterase 47","Ubiquitin-specific-processing protease 47"],"length_aa":1375,"mass_kda":157.3,"function":"Ubiquitin-specific protease that specifically deubiquitinates monoubiquitinated DNA polymerase beta (POLB), stabilizing POLB thereby playing a role in base-excision repair (BER). 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Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/41930505","citation_count":0,"is_preprint":false},{"pmid":"41903125","id":"PMC_41903125","title":"NUP85 Mediates Endoplasmic Reticulum Stress through the USP47/ASK1 Signaling Pathway to Regulate the Progression of Liver Fibrosis.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41903125","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.03.652026","title":"<i>In silico</i>  analysis and Predictive linkage of Deubiquitinating Enzymes underlying Early Development","date":"2025-05-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.03.652026","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.27.656269","title":"<i>ob</i>  ABPP-HT*: A Precision-Engineered Activity Proteomics Pipeline for the Streamlined Discovery of Deubiquitinase Inhibitors","date":"2025-05-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.27.656269","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26509,"output_tokens":8804,"usd":0.105793,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18571,"output_tokens":4662,"usd":0.104703,"stage2_stop_reason":"end_turn"},"total_usd":0.210496,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"USP47 is the major deubiquitylating enzyme for DNA polymerase β (Pol β), stabilizing newly synthesized cytoplasmic Pol β that is used as a source for nuclear Pol β in DNA base excision repair (BER). Knockdown of USP47 increases ubiquitylated Pol β, decreases Pol β levels, and causes BER deficiency with accumulation of DNA strand breaks.\",\n      \"method\": \"siRNA knockdown, ubiquitylation assays, DNA damage assays, cell viability assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockdown, ubiquitylation assay, BER functional assay, DNA strand break measurement), published in high-quality journal with clear mechanistic readouts\",\n      \"pmids\": [\"21362556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"USP47 physically interacts with SCF(β-TrCP) E3 ubiquitin ligase via direct binding to both β-TrCP1 and β-TrCP2 WD-repeat regions (point mutations in WD-repeat abolished binding). Unlike canonical β-TrCP substrates, USP47 levels were not regulated by β-TrCP. Depletion of USP47 caused accumulation of Cdc25A and decreased cell survival.\",\n      \"method\": \"Co-immunoprecipitation, point mutagenesis, siRNA knockdown, cell survival assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis, single lab, functional phenotype confirmed\",\n      \"pmids\": [\"19966869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"USP47 (together with USP7) is a cysteine isopeptidase whose inhibition stabilizes p53 and decreases DNA polymerase β (Pol β) levels in cancer cells, leading to apoptosis. Selective dual small-molecule inhibitors of USP7 and USP47 were shown to inhibit USP7 in cells and induce elevated p53.\",\n      \"method\": \"Small molecule inhibition, cell-based p53/apoptosis assays, in vivo xenograft models\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzyme inhibition confirmed in cells with multiple readouts (p53 stabilization, apoptosis, in vivo), single lab\",\n      \"pmids\": [\"24900381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USP47 deubiquitinates and stabilizes katanin-p60 (a microtubule-severing enzyme), antagonizing CHIP (an E3 ubiquitin ligase that promotes katanin-p60 degradation). USP47 overexpression promoted axonal growth in rat hippocampal neurons, while CHIP overexpression inhibited it. bFGF treatment increased USP47 and katanin-p60 levels and decreased ubiquitinated katanin-p60.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, overexpression/knockdown in cultured neurons, bFGF treatment\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, epistasis between USP47 and CHIP on katanin-p60 stability, functional axonal growth readout with multiple orthogonal approaches\",\n      \"pmids\": [\"23904609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Minus end-directed motor KIFC3 binds USP47 and recruits it to adherens junctions. Depletion of KIFC3 or USP47 promotes ubiquitination and cleavage of E-cadherin at a juxtamembrane region (producing a 90-kDa fragment), dependent on the E3 ligase Hakai, leading to E-cadherin internalization. Proteasome inhibitors blocked this cleavage.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, E-cadherin ubiquitination assay, proteasome inhibitor treatment, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishing KIFC3-USP47 interaction, epistasis with Hakai E3 ligase, functional E-cadherin stability assay with multiple orthogonal approaches\",\n      \"pmids\": [\"25253721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP47 (and its Drosophila ortholog UBP64E) deubiquitinates β-catenin, preventing its ubiquitination and proteasomal degradation. RNAi inactivation of USP47 increased β-catenin ubiquitination, attenuated Wnt signaling, and repressed cancer cell growth. β-TrCP promotes USP47 ubiquitination via an atypical interaction motif, and USP47 also auto-deubiquitinates itself. In vivo, UBP64E is required for Armadillo stabilization and Wnt target gene expression in Drosophila wing.\",\n      \"method\": \"RNAi library screen, Co-immunoprecipitation, ubiquitination assays, Drosophila in vivo genetics\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi screen identification, Co-IP, ubiquitination assays, and in vivo Drosophila validation across two organisms\",\n      \"pmids\": [\"26169834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Drosophila USP47 acts post-translationally to stabilize MAPK by counteracting its proteasome-mediated degradation. Genetic interaction RNAi screening identified UBC6 (E2), POE/UBR4 (N-recognin E3 ligase), and UFD4 as enzymes opposing USP47. KCMF1 was identified as another component of the POE-associated degradation module. These results place USP47 as counteracting the N-end rule pathway to maintain MAPK levels and RAS-MAPK signaling output.\",\n      \"method\": \"RNAi-based genetic interaction screen, epistasis analysis in Drosophila, MAPK level measurements\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic RNAi epistasis screen with genetic validation in Drosophila, multiple components identified and validated\",\n      \"pmids\": [\"27552662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Chemical inhibition of USP7 and USP47 blocks NLRP3 inflammasome formation in macrophages, independently of transcription, by preventing ASC oligomerisation and speck formation. The ubiquitination status of NLRP3 is altered by inhibition of USP7/USP47. USP7 and USP47 activity increases in response to inflammasome activators. CRISPR/Cas9 knockdown of both USP7 and USP47 reduces inflammasome activation and IL-1β/IL-18 release.\",\n      \"method\": \"Chemical inhibition, CRISPR/Cas9 knockdown, ASC oligomerization assay, NLRP3 ubiquitination assay, cytokine measurement\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (pharmacological inhibition, CRISPR knockdown), functional inflammasome readouts with mechanistic ubiquitination analysis\",\n      \"pmids\": [\"30206189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP47 promotes β-TrCP stability and phosphorylation of RelA (NF-κB subunit) in gastric cancer cells. USP47 knockdown reduced cell viability and increased sensitivity to etoposide and camptothecin.\",\n      \"method\": \"Immunoblot, siRNA knockdown, MTT assay, Annexin V staining, PARP/caspase cleavage\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, immunoblot-based evidence for β-TrCP stability, no direct deubiquitination assay of the relevant substrates shown\",\n      \"pmids\": [\"29786670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERAP1 binds USP47, displaces the USP47-associated β-TrCP (substrate-receptor of SCFβ-TrCP ubiquitin ligase), and promotes β-TrCP degradation. This results in modulation of Gli transcription factors (effectors of Hedgehog signaling) and enhancement of Hh pathway activity.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, genetic and pharmacological inhibition in vitro and in vivo tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishing ERAP1-USP47-β-TrCP ternary complex, functional Hh signaling and Gli modulation, in vivo validation\",\n      \"pmids\": [\"31341163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP47 interacts with SATB1 and mediates its deubiquitination and stabilization. SMURF2 is an E3 ubiquitin ligase that promotes SATB1 degradation. USP47 negatively regulates SMURF2, and USP47 depletion sensitizes colon cancer cells to 5-FU-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, mouse xenograft model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays in single lab, functional tumor model, two orthogonal approaches\",\n      \"pmids\": [\"30742943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP47 interacts with and deubiquitinates IK (a spliceosomal component), preventing its proteolytic degradation via the 26S proteasome. USP47-mediated stabilization of IK is required for proper splicing of ATM pre-mRNA (particularly intron 1), and IK deficiency impairs DNA damage repair.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, pre-mRNA splicing assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP and ubiquitination assay linking USP47 to IK stabilization, functional splicing assay, single lab\",\n      \"pmids\": [\"32377397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP47 deubiquitinates ribosomal protein S2 (RPS2) that has been ubiquitinated by MDM2. Under normal conditions, USP47 inhibits the interaction between RPS2 and MDM2, alleviating RPS2-mediated MDM2 suppression and keeping p53 levels low. Under ribosomal stress, USP47 dissociation allows RPS2-MDM2 binding, suppresses MDM2, and induces p53 upregulation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, xenograft mouse model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay, stress-condition epistasis, functional tumor suppression readout, single lab\",\n      \"pmids\": [\"32370049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP47 stabilizes Y-box binding protein 1 (YBX1), contributing to DNA damage repair in CML cells. USP47 knockdown or knockout significantly inhibited BCR-ABL and BCR-ABL(T315I)-induced CML in mice and reduced Lin-Sca1+c-Kit+ CML stem/progenitor cells.\",\n      \"method\": \"Mechanistic studies (YBX1 stabilization), in vitro knockdown, in vivo CML mouse models, flow cytometry for stem cell populations\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse CML model with stem cell readout, YBX1 stabilization mechanistic link, single lab\",\n      \"pmids\": [\"33397955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP47 interacts with TCEA3 and mediates its deubiquitination, increasing intracellular TCEA3 levels. TCEA3 regulates pro-apoptotic Bax levels. USP47-TCEA3 axis modulates pyroptosis and apoptosis in response to doxorubicin in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, apoptosis/pyroptosis assays\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and deubiquitination assay established substrate relationship, functional rescue experiments, single lab\",\n      \"pmids\": [\"34630087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP47 deubiquitinates and stabilizes BACH1 (BTB and CNC homology 1 transcription factor). USP47-stabilized BACH1 promotes the Warburg effect (glycolysis) in NSCLC by transcriptionally upregulating hexokinase 2 (Hk2) and GAPDH.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro/in vivo proliferation assays, glycolysis measurement\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional glycolysis and tumor growth readouts, single lab\",\n      \"pmids\": [\"35141006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP47 deubiquitinates RPL11, preventing its translocation from nucleolus to nucleoplasm. When USP47 is inhibited, RPL11 translocates to the nucleoplasm and interacts with MDM2, preventing MDM2-mediated proteasomal degradation of p53, thus inhibiting cell proliferation in a p53-dependent manner. The catalytically inactive USP47 form does not rescue this phenotype.\",\n      \"method\": \"miR-101-3p overexpression, USP47 overexpression with catalytically inactive mutant, Co-IP, immunofluorescence for RPL11 localization, cell proliferation assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytically inactive mutant used to confirm enzymatic requirement, Co-IP and subcellular localization with functional p53 readout, single lab\",\n      \"pmids\": [\"35205710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP47 removes K63-linked polyubiquitin chains from TRAF3 and TRAF6, acting downstream of MAVS and upstream of TBK1 in the antiviral innate immune signaling pathway, thereby attenuating type I interferon production and IFNB1 transcription.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin chain-type specific assays, overexpression/knockdown, luciferase reporter assay, viral replication assay\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K63-chain specific deubiquitination demonstrated, epistasis positioning (downstream MAVS, upstream TBK1), single lab\",\n      \"pmids\": [\"37001379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP47 inhibition leads to destabilization of mutant EZH2 protein through promotion of its ubiquitination. USP47 was identified as a novel regulator of mutant EZH2, and targeting USP47 leads to death of mutant EZH2-positive DLBCL cells in vitro and in vivo.\",\n      \"method\": \"Selectivity profiling, genetic knockdown, ubiquitination assay, in vitro and mouse model studies\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods including selectivity profiling, animal models, and ubiquitination assays, single lab\",\n      \"pmids\": [\"35034955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal structures of the USP47 catalytic domain (free and ubiquitin-bound states) reveal misaligned catalytic triads that become aligned upon ubiquitin binding (similar to USP7), enabling catalysis. Full-length USP47 shows higher deubiquitinase activity than the catalytic domain alone. BL1, BL2, and BL3 loops differ from USP7 in composition and length, contributing to substrate selectivity.\",\n      \"method\": \"X-ray crystallography, in vitro deubiquitinase activity assays, domain truncation experiments\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure determination with functional validation of catalytic mechanism and activity comparison between full-length and catalytic domain\",\n      \"pmids\": [\"37740002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP47 prevents YTHDF1 ubiquitination to attenuate the association of YTHDF1 with translation initiation machinery, thereby decreasing m6A-based c-Myc translation efficiency in regulatory T cells. USP47 ablation in Tregs caused c-Myc protein accumulation, exacerbated hyperglycolysis, compromised Treg homeostasis, and boosted antitumor immune responses.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Treg-specific knockout mouse, m6A translation efficiency assays, metabolic assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assay, in vivo Treg-specific KO model, translational regulation mechanism with multiple orthogonal methods\",\n      \"pmids\": [\"37788092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP47 deubiquitylates the transcriptional co-repressor Groucho/TLE, counteracting XIAP-mediated monoubiquitylation of TLE3. USP47 interacts with both TLE3 and XIAP but does not alter their amounts. USP47 inhibited XIAP-mediated ubiquitylation of TLE3 in vitro in a dose-dependent manner. This deubiquitylation is required for Wnt-β-catenin target gene expression in Drosophila, Xenopus, and human cells.\",\n      \"method\": \"Genome-scale RNAi screen in Drosophila, Co-immunoprecipitation, in vitro ubiquitylation assay, Xenopus and human cell epistasis experiments, Wnt reporter assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted ubiquitylation inhibition assay, replicated across three organisms (Drosophila, Xenopus, human cells), Co-IP and functional Wnt reporter\",\n      \"pmids\": [\"36749823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP47 deubiquitinates and stabilizes SIRT1 protein. SIRT1 in turn upregulates PPARα expression via deacetylation, thereby promoting osteogenic differentiation of bone marrow mesenchymal stem cells via the Wnt/β-catenin pathway.\",\n      \"method\": \"Ubiquitination assay, co-immunoprecipitation, siRNA knockdown, osteogenic differentiation assays (ALP activity, Alizarin Red staining)\",\n      \"journal\": \"Chemical biology & drug design\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay for USP47-SIRT1 substrate relationship, functional differentiation readout, single lab\",\n      \"pmids\": [\"38373741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP47 stabilizes IRF1 by deubiquitination, preventing its proteasomal degradation. Stabilized IRF1 binds the CXCL4 promoter to promote CXCL4 expression, which in turn promotes NLRP3 inflammasome-mediated pyroptosis and cardiac dysfunction in myocardial infarction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, luciferase reporter (IRF1-CXCL4 promoter binding), siRNA knockdown, MI mouse model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, promoter binding assay, in vivo rescue with IRF1 overexpression, single lab\",\n      \"pmids\": [\"38850785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP47 stabilizes c-Myc by preventing its proteasomal degradation through deubiquitination, thereby promoting NSCLC cell proliferation. USP47 inhibition destabilizes c-Myc and enhances the efficacy of the KRASG12C inhibitor Sotorasib in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro proliferation assay, in vivo xenograft model, small molecule inhibitor (K-552)\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional in vivo validation, single lab\",\n      \"pmids\": [\"40180254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP47 modulates PD-L1 protein stability through deubiquitination. USP47 interacts with PD-L1 (Co-IP) and deubiquitinates it, preventing its degradation. USP47 inhibition reduces tumoral PD-L1 levels without affecting mRNA, and combination with anti-PD-1 therapy enhanced HCC tumor suppression in mouse models.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, T cell killing assay, mouse HCC model with P5091 inhibitor\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and deubiquitination assay, mRNA vs protein level distinction, functional immune assay, in vivo model, single lab\",\n      \"pmids\": [\"40494207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP47 deubiquitinates FEN1 (flap endonuclease 1), stabilizing its protein levels. Mutant USP47 (Cys109Ser, catalytically inactive) did not stabilize FEN1. USP47 directly interacts with FEN1 (Co-IP, immunofluorescence). The natural compound rotenone physically interacts with USP47 and modulates USP47 expression and Ub-USP47 conjugation, reducing FEN1 stability.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, cycloheximide chase, deubiquitination assay, catalytic mutant (Cys109Ser), Biacore binding assay, xenograft model\",\n      \"journal\": \"Drug design, development and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant used to confirm enzymatic requirement, Co-IP and Biacore binding, multiple functional assays, single lab\",\n      \"pmids\": [\"42112089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP47 binds, deubiquitinates, and stabilizes PRMT5 (protein arginine methyltransferase 5), thereby upregulating O-GlcNAcase expression and inhibiting O-GlcNAcylation in cardiomyocytes. This mechanism attenuates Ang II-induced cardiac hypertrophy.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, adenovirus-mediated gain/loss-of-function, cardiac hypertrophy in vitro and in vivo assays\",\n      \"journal\": \"Journal of cardiovascular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and deubiquitination assay, in vivo cardiac model, functional rescue by PRMT5 restoration, single lab\",\n      \"pmids\": [\"39436323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP47 deubiquitinates and stabilizes NRP1 (Neuropilin-1), preventing its ubiquitination and degradation, and activating the PI3K/Akt signaling pathway to promote angiogenesis in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, angiogenesis assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"40499689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP47 directly interacts with HDAC2, promotes its deubiquitination, and enhances HDAC2 protein stability. Stabilized HDAC2 acts as a transcriptional repressor of CYP1A1 by deacetylating H3K9 and H3K27 at the CYP1A1 promoter, thereby reducing ROS-driven autophagy and protecting against cigarette smoke-induced skeletal muscle atrophy.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, ChIP-qPCR, RNA-seq, gain/loss-of-function in mouse model and C2C12 cells\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay, ChIP-qPCR for downstream mechanism, in vivo mouse model, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41529803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP47 stabilizes SIRT1 through deubiquitination (inhibiting its ubiquitination and degradation). SIRT1 then upregulates PPARα expression via deacetylation to promote lipid metabolism and alleviate metabolic-associated fatty liver disease. SIRT1 inhibitor EX-527 reversed USP47 overexpression benefits.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, rat HFD model, HepG2 OA model, gain/loss-of-function experiments, pharmacological inhibitor rescue\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and deubiquitination assay for USP47-SIRT1 axis, in vivo rat model, pharmacological epistasis, single lab\",\n      \"pmids\": [\"41930505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP47 competitively binds ASK1 (apoptosis signal-regulating kinase 1), deubiquitinating lysine residue 805 of ASK1. NUP85 competitively displaces USP47 from ASK1, promoting ASK1 activation and exacerbating collagen deposition and endoplasmic reticulum stress in liver fibrosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (site-specific K805), competitive binding experiments, loss-of-function in liver fibrosis model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific deubiquitination of ASK1 K805, competitive binding mechanism, in vivo liver fibrosis model, single lab\",\n      \"pmids\": [\"41903125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP47 regulates cutaneous oxidative injury through stabilization of nicotinamide nucleotide transhydrogenase (NNT) by preventing its ubiquitin-mediated degradation. Loss of USP47 in mice aggravated radiation- and imiquimod-induced skin damage; knockdown of NNT increased mitochondrial ROS and disrupted mitochondrial membrane potential.\",\n      \"method\": \"Usp47 knockout mouse models, proteomic analysis, siRNA knockdown of NNT, mitochondrial ROS measurement\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse model with proteomic identification of NNT, mechanistic ubiquitination link, functional mitochondrial readouts, single lab\",\n      \"pmids\": [\"37924851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP47 inhibits degradation of ubiquitinated GluR1 (AMPAR subunit), thereby enhancing excitatory postsynaptic transmission and increasing dendritic spine density/maturity. Elevated USP47 was found in epileptic mice, and USP47 knockdown reduced seizure frequency and duration.\",\n      \"method\": \"Electrophysiology, dendritic spine morphology analysis, ubiquitination assay, siRNA knockdown in epileptic mouse model\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay identifying GluR1 as substrate, electrophysiology functional readout, in vivo epilepsy model, single lab\",\n      \"pmids\": [\"40716012\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP47 is a cysteine deubiquitylase whose catalytic triads become aligned upon ubiquitin binding (as revealed by crystal structure), with its full-length form showing higher activity than the catalytic domain alone; it stabilizes a wide range of substrates — including DNA polymerase β, β-catenin, katanin-p60, BACH1, YBX1, SATB1, IK, RPS2/RPL11 (modulating p53 via MDM2), TRAF3/TRAF6 (attenuating antiviral IFN signaling), YTHDF1 (controlling m6A-dependent c-Myc translation in Tregs), TLE/Groucho (promoting Wnt-TCF transcription by opposing XIAP-mediated ubiquitylation), E-cadherin (via KIFC3-mediated recruitment to adherens junctions), PRMT5, NNT, ASK1, FEN1, HDAC2, SIRT1, PD-L1, NRP1, and GluR1 — through direct deubiquitination, placing USP47 as a central regulator of DNA repair, Wnt/β-catenin, Hedgehog, MAPK (N-end rule), NF-κB, NLRP3 inflammasome, antiviral immunity, Treg metabolism, axonal growth, adherens junction maintenance, and cancer cell proliferation pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"USP47 is a cysteine deubiquitylase that stabilizes a broad array of substrate proteins by removing ubiquitin chains and antagonizing their proteasomal degradation, positioning it as a central regulator across DNA repair, Wnt and Hedgehog signaling, immunity, and cell proliferation [#0, #5, #21]. Crystal structures of its catalytic domain show that its catalytic triad is misaligned in the free state and becomes competent upon ubiquitin binding, and the full-length enzyme is more active than the isolated catalytic domain [#19]. In genome maintenance, USP47 is the major deubiquitylase for DNA polymerase \\u03b2, stabilizing the cytoplasmic pool that supplies nuclear base excision repair, and it likewise stabilizes FEN1 and the spliceosomal factor IK to support DNA damage repair [#0, #26, #11]. USP47 functions in concert with the SCF(\\u03b2-TrCP) ligase machinery: it binds \\u03b2-TrCP1/2 directly and these interactions feed into Wnt/\\u03b2-catenin and Hedgehog outputs, including direct deubiquitylation of \\u03b2-catenin and of the Groucho/TLE co-repressor to promote Wnt-TCF target gene expression [#1, #5, #9, #21]. In the cytoplasm and at the cell cortex it stabilizes katanin-p60 to promote axonal growth and is recruited by the motor KIFC3 to deubiquitylate E-cadherin at adherens junctions [#3, #4]. USP47 also tunes immune and inflammatory signaling \\u2014 it is required for NLRP3 inflammasome assembly, removes K63-linked chains from TRAF3/TRAF6 to attenuate type I interferon production, and in regulatory T cells stabilizes YTHDF1 to control m6A-dependent c-Myc translation [#7, #17, #20]. A recurring theme in cancer is USP47-mediated stabilization of oncogenic and metabolic regulators including c-Myc, BACH1, YBX1, SATB1, and PD-L1, making it a recurrent therapeutic target whose pharmacological inhibition lowers these substrates and sensitizes tumors [#24, #15, #13, #10, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established USP47 as a physical partner of the SCF(\\u03b2-TrCP) ligase, defining its connection to the ubiquitin\\u2013proteasome degradation machinery and to cell-cycle/survival control.\",\n      \"evidence\": \"Co-IP with point mutagenesis of \\u03b2-TrCP WD-repeats and siRNA knockdown with survival readout\",\n      \"pmids\": [\"19966869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct deubiquitylation of a substrate not yet demonstrated\", \"How USP47 modulates \\u03b2-TrCP function mechanistically unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the first bona fide USP47 substrate, DNA polymerase \\u03b2, linking the enzyme to base excision repair fidelity.\",\n      \"evidence\": \"siRNA knockdown, ubiquitylation assays, and DNA strand-break/BER functional assays\",\n      \"pmids\": [\"21362556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site of deubiquitylation on Pol \\u03b2 not mapped\", \"In vitro reconstitution with purified components not shown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed USP47 directly antagonizes a specific E3 ligase (CHIP) to stabilize katanin-p60, demonstrating a deubiquitylase\\u2013ligase counterbalance with a developmental phenotype.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, and axonal-growth assays in cultured neurons with bFGF stimulation\",\n      \"pmids\": [\"23904609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chain type removed not defined\", \"Upstream regulation of USP47 by bFGF not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed spatial control of USP47 activity, with motor KIFC3 recruiting it to adherens junctions to protect E-cadherin from Hakai-mediated cleavage.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, E-cadherin ubiquitination assay, and immunofluorescence\",\n      \"pmids\": [\"25253721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect deubiquitylation of E-cadherin not distinguished\", \"Structural basis of KIFC3 binding unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined USP47 as a Wnt pathway component that deubiquitylates \\u03b2-catenin, validated across species, and uncovered its reciprocal regulation by and auto-deubiquitylation within the \\u03b2-TrCP system.\",\n      \"evidence\": \"RNAi screen, Co-IP, ubiquitination assays, and Drosophila in vivo genetics\",\n      \"pmids\": [\"26169834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry between USP47 self-regulation and substrate turnover unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Positioned USP47 as a counter-force to the N-end rule (UBR4/POE) degradation module to maintain MAPK levels and RAS-MAPK output.\",\n      \"evidence\": \"RNAi-based genetic interaction/epistasis screen in Drosophila with MAPK level measurements\",\n      \"pmids\": [\"27552662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical deubiquitylation of MAPK not shown\", \"Conservation in mammalian cells not tested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended USP47 function into innate immunity by showing it is required for NLRP3 inflammasome assembly and ASC speck formation.\",\n      \"evidence\": \"Chemical inhibition, CRISPR/Cas9 knockdown, ASC oligomerization and NLRP3 ubiquitination assays, cytokine measurement\",\n      \"pmids\": [\"30206189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inhibitors target both USP7 and USP47, limiting USP47-specific attribution\", \"Direct NLRP3 substrate relationship not isolated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected USP47 to Hedgehog signaling through an ERAP1\\u2013USP47\\u2013\\u03b2-TrCP ternary complex that controls Gli activity, and to SATB1 stabilization in cancer.\",\n      \"evidence\": \"Co-IP, pulldown, and in vitro/in vivo tumor models; separate SATB1 Co-IP/ubiquitination work\",\n      \"pmids\": [\"31341163\", \"30742943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP47 catalytic activity is required for the ERAP1 effect not separated from scaffolding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked USP47 to ribosomal-stress p53 signaling and to splicing fidelity, stabilizing RPS2 and the spliceosomal factor IK that ensures correct ATM pre-mRNA splicing.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, splicing assays, and xenograft models\",\n      \"pmids\": [\"32370049\", \"32377397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence for each substrate\", \"Catalytic dependence of RPS2 effect not formally tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the catalytic mechanism: ubiquitin binding aligns the misaligned catalytic triad and full-length enzyme exceeds the isolated catalytic domain in activity; in parallel, multiple oncogenic/immune substrates (BACH1, RPL11/p53, TRAF3/6, EZH2) were established.\",\n      \"evidence\": \"X-ray crystallography with deubiquitinase assays; plus Co-IP/ubiquitination assays and catalytically inactive mutant controls across substrate studies\",\n      \"pmids\": [\"37740002\", \"35141006\", \"35205710\", \"37001379\", \"35034955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length structure to explain higher activity\", \"Substrate-specific recognition determinants in BL loops not mapped to individual substrates\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed USP47 controls Treg metabolism via YTHDF1-dependent m6A c-Myc translation and deubiquitylates the Groucho/TLE co-repressor to drive Wnt target gene expression, broadening its regulatory reach into translation and transcriptional co-repression.\",\n      \"evidence\": \"Treg-specific knockout mouse, m6A translation/metabolic assays; genome-scale RNAi screen with in vitro ubiquitylation inhibition across three organisms\",\n      \"pmids\": [\"37788092\", \"36749823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct YTHDF1 deubiquitylation site not mapped\", \"Relative contribution of \\u03b2-catenin vs TLE deubiquitylation to Wnt output unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated USP47 as a cancer therapeutic target, stabilizing c-Myc and PD-L1, with inhibition synergizing with KRAS-G12C inhibition and anti-PD-1 therapy.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, T cell killing assays, and in vivo xenograft/HCC models with small-molecule inhibitors\",\n      \"pmids\": [\"40180254\", \"40494207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence per substrate\", \"Inhibitor selectivity over USP7 not fully resolved in some studies\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Expanded the substrate landscape into tissue-protective and pathological roles, stabilizing SIRT1, HDAC2, ASK1, PRMT5, NNT and GluR1 across liver, cardiac, muscle, skin and neuronal contexts.\",\n      \"evidence\": \"Co-IP, site-specific (ASK1 K805) and catalytic-mutant ubiquitination assays, ChIP-qPCR, electrophysiology, and in vivo disease models\",\n      \"pmids\": [\"41930505\", \"41529803\", \"41903125\", \"39436323\", \"37924851\", \"40716012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each substrate rests on single-lab evidence\", \"Whether one cell type uses one dominant substrate axis is unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How USP47 achieves substrate selectivity among its many reported targets and how its activity is spatially and temporally regulated remain open.\",\n      \"evidence\": \"No full-length or substrate-bound structure and no unifying recruitment/selectivity model across substrates in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate-recognition code linking BL loops to specific substrates\", \"Regulation of USP47 catalytic activation in vivo undefined\", \"Most substrate claims are single-lab\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 5, 19, 21, 26]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 19, 26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 9, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 11, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 9, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 17, 20]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 5, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 12, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 15, 24, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BTRC\", \"FBXW11\", \"KIFC3\", \"ERAP1\", \"XIAP\", \"TLE3\", \"ASK1\", \"PRMT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}