{"gene":"USP47","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2011,"finding":"USP47 is the major deubiquitylating enzyme responsible for deubiquitylation of DNA polymerase β (Pol β) in the cytoplasm, stabilizing newly synthesized Pol β that is used as a source for nuclear Pol β involved in 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, BER functional assays, cell viability assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (knockdown, ubiquitylation assays, BER assays) in a high-impact journal with strong mechanistic follow-up","pmids":["21362556"],"is_preprint":false},{"year":2009,"finding":"USP47 interacts with SCF(β-TrCP) E3 ubiquitin ligase; both β-TrCP1 and β-TrCP2 bind specifically to USP47, with point mutations in the β-TrCP WD-repeat region abolishing binding, indicating an E3-substrate-type interaction. Depletion of USP47 induces accumulation of Cdc25A, decreases cell survival, and augments cytotoxic effects of anticancer drugs.","method":"Co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, cell viability assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with mutagenesis validation and functional phenotype readout","pmids":["19966869"],"is_preprint":false},{"year":2015,"finding":"USP47 (and its Drosophila counterpart UBP64E) prevents β-catenin ubiquitination to promote Wnt signaling. USP47 inactivation by RNAi increases β-catenin ubiquitination, attenuates Wnt signaling, and represses cancer cell growth. β-TrCP promotes USP47 ubiquitination through interaction with an atypical motif in USP47, while USP47 also deubiquitinates itself. In Drosophila, UBP64E is required for Armadillo stabilization.","method":"RNAi library screen, ubiquitination assays, Wnt reporter assays, in vivo Drosophila wing studies","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods across mammalian and Drosophila systems, replicated mechanism","pmids":["26169834"],"is_preprint":false},{"year":2013,"finding":"USP47 is a katanin-p60-specific deubiquitinating enzyme that stabilizes katanin-p60 by counteracting CHIP (an E3 ubiquitin ligase that promotes proteasomal degradation of katanin-p60). USP47 promotes axonal growth of rat hippocampal neurons; bFGF treatment increases USP47 and katanin-p60 levels and decreases ubiquitinated katanin-p60, promoting axonal growth.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, neuronal culture axonal growth assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assays, and functional neuronal phenotype with defined mechanistic pathway","pmids":["23904609"],"is_preprint":false},{"year":2016,"finding":"In Drosophila, USP47 acts post-translationally to counteract proteasome-mediated degradation of MAPK, thereby maintaining MAPK half-life and signaling output. RNAi genetic interaction screening identified UBC6 (E2) and POE/UBR4 (E3 N-recognin) as enzymes opposing USP47 activity; KCMF1 is another component of this degradation module. USP47 thus counteracts the N-end rule pathway to control MAPK levels.","method":"RNAi-based genetic interaction screen (Drosophila), epistasis analysis, protein stability assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — systematic RNAi epistasis screen with multiple genetic validations in Drosophila ortholog","pmids":["27552662"],"is_preprint":false},{"year":2018,"finding":"USP47 (together with USP7) regulates NLRP3 inflammasome activation in macrophages. Chemical inhibition of USP7/USP47 blocks inflammasome formation by preventing ASC oligomerisation and speck formation, independently of transcription. The ubiquitination status of NLRP3 itself is altered by inhibition of USP7 and USP47. CRISPR/Cas9 knockdown of both USP7 and USP47 in THP-1 cells reduces inflammasome activation and IL-1β/IL-18 release.","method":"Pharmacological inhibition, CRISPR/Cas9 knockdown, ASC oligomerization/speck assays, cytokine release assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (inhibitor, CRISPR KO, functional readouts), highly cited","pmids":["30206189"],"is_preprint":false},{"year":2019,"finding":"USP47 interacts with SATB1 and mediates its deubiquitination and stabilization. USP47 deficiency impairs SATB1 transcriptional activity and inhibits colon cancer cell proliferation, migration, and tumorigenesis. SMURF2 functions as an E3 ubiquitin ligase promoting SATB1 degradation, and SMURF2 is negatively regulated by USP47 (USP47 depletion sensitizes cells to 5-FU).","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, mouse xenograft model","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assays, in vivo model with mechanistic pathway definition","pmids":["30742943"],"is_preprint":false},{"year":2019,"finding":"ERAP1 binds USP47, displaces USP47-associated βTrCP (the substrate-receptor subunit of SCFβTrCP), and promotes βTrCP degradation. This results in modulation of Gli transcription factors and enhancement of Hedgehog pathway activity. Genetic or pharmacological inhibition of ERAP1 suppresses Hh-dependent tumor growth in vitro and in vivo.","method":"Co-immunoprecipitation, protein stability assays, genetic inhibition (CRISPR/siRNA), in vivo tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical and genetic methods with in vivo validation","pmids":["31341163"],"is_preprint":false},{"year":2014,"finding":"KIFC3 (a minus end-directed kinesin motor) binds USP47 and recruits it to adherens junctions (AJs). USP47 at AJs prevents ubiquitination and Hakai E3-ligase-mediated degradation of E-cadherin. Depletion of KIFC3 or USP47 promotes cleavage of E-cadherin at a juxtamembrane region, producing a 90-kDa fragment and causing E-cadherin internalization; this process is inhibited by proteasome inhibitors.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence localization, proteasome inhibitor treatment, E-cadherin ubiquitination assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, functional localization with direct consequence, ubiquitination assays","pmids":["25253721"],"is_preprint":false},{"year":2021,"finding":"USP47 stabilizes Y-box binding protein 1 (YBX1) to promote DNA damage repair in CML cells. USP47 knockdown represses CML cell proliferation in vitro and in vivo; Usp47 knockout significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice and reduces Lin-Sca1+c-Kit+ CML stem/progenitor cells.","method":"siRNA/shRNA knockdown, Usp47 knockout mice, in vitro proliferation assays, CML mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO in vivo model with mechanistic substrate identification and functional phenotype","pmids":["33397955"],"is_preprint":false},{"year":2020,"finding":"USP47 deubiquitinates RPL11 (ribosomal protein L11), preventing its interaction with MDM2 under normal conditions. USP47 inhibition or miR-101-3p-mediated suppression leads to RPL11 translocation from nucleolus to nucleoplasm, enabling RPL11-MDM2 binding that suppresses MDM2 and stabilizes p53, inhibiting cancer cell proliferation. The catalytically inactive form of USP47 cannot restore these effects.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, catalytic mutant analysis, p53 pathway reporter assays, miRNA transfection","journal":"Cancers / Cancers (multiple papers)","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro deubiquitination, catalytic mutant validation, mechanistic pathway placement","pmids":["32370049","35205710"],"is_preprint":false},{"year":2020,"finding":"USP47 directly interacts with IK (a spliceosomal component) and stabilizes it through deubiquitination, preventing its proteasomal degradation. IK is required for proper splicing of ATM pre-mRNA; IK depletion leads to retention of intron 1 in ATM pre-mRNA and loss of ATM protein, impairing DNA damage repair. SMU1 absence induces IK ubiquitination; USP47 counteracts this.","method":"Co-immunoprecipitation, ubiquitination assays, RT-PCR splicing assays, siRNA knockdown","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assays with functional splicing readout, single lab","pmids":["32377397"],"is_preprint":false},{"year":2023,"finding":"USP47 deubiquitylates the transcriptional corepressor TLE3/Groucho to counteract XIAP-mediated monoubiquitylation of TLE, promoting Wnt-β-catenin signaling. USP47 interacts with TLE3 and XIAP, and inhibits XIAP-mediated ubiquitylation of TLE3 in vitro in a dose-dependent manner. USP47 acts downstream of the β-catenin destruction complex and is required for Wnt signaling in Drosophila, Xenopus, and human cells.","method":"Genome-scale RNAi screen (Drosophila cells), in vitro deubiquitylation assay, Co-immunoprecipitation, Wnt reporter assays, Xenopus and Drosophila in vivo assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted deubiquitylation assay, multiple organism validation, genome-scale screen","pmids":["36749823"],"is_preprint":false},{"year":2023,"finding":"Crystal structures of the USP47 catalytic domain in 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 and contribute to substrate selectivity. USP47 depletion inhibits cancer cell growth in a p53-dependent manner, enhanced by simultaneous USP7 knockdown.","method":"X-ray crystallography (free and ubiquitin-bound), in vitro DUB activity assays, siRNA knockdown, cancer cell growth assays","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation and in vitro enzymatic assays","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 triggers c-Myc protein accumulation and exacerbated hyperglycolysis in Tregs, compromising Treg homeostasis and function.","method":"Co-immunoprecipitation, ubiquitination assays, polyribosome/translation assays, Treg-specific conditional knockout mice, metabolic assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical assays with conditional KO in vivo model","pmids":["37788092"],"is_preprint":false},{"year":2023,"finding":"USP47 removes K63-linked polyubiquitin chains from TRAF3 and TRAF6, attenuating type I interferon signaling downstream of MAVS and upstream of TBK1. USP47 overexpression suppresses virus-induced ISRE and IFN-β activation and enhances viral replication; knockdown has opposite effects.","method":"Co-immunoprecipitation, K63-linkage-specific ubiquitination assays, dual-luciferase reporter assays, overexpression/knockdown in virus infection models","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and linkage-specific ubiquitination assays with functional reporter readout, single lab","pmids":["37001379"],"is_preprint":false},{"year":2022,"finding":"USP47 stabilizes BACH1 by direct binding and deubiquitination, promoting the Warburg effect and NSCLC development. USP47 deubiquitination of BACH1 leads to downstream transcriptional upregulation of Hk2 and Gapdh, enhancing glycolysis.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, in vivo xenograft, glycolysis assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assays with functional metabolic readout, single lab","pmids":["35141006"],"is_preprint":false},{"year":2022,"finding":"USP47 regulates mutant EZH2 protein stability; inhibition of USP47 promotes ubiquitination and degradation of mutant EZH2. Targeting USP47 leads to death of mutant EZH2-positive cells in vitro and in vivo.","method":"Selectivity profiling, genetic studies (siRNA/KO), animal models, ubiquitination assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic substrate identification with in vivo validation, single lab","pmids":["35034955"],"is_preprint":false},{"year":2021,"finding":"USP47 binds TCEA3 (transcription elongation factor A3) and regulates its deubiquitination and intracellular stability. USP47 ectopic expression increases TCEA3 levels; TCEA3 regulates pro-apoptotic Bax levels, and the USP47-TCEA3 axis modulates doxorubicin-induced pyroptosis and apoptosis in colorectal cancer cells.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, apoptosis/pyroptosis assays","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assays with functional apoptosis readout, single lab","pmids":["34630087"],"is_preprint":false},{"year":2024,"finding":"USP47 stabilizes IRF1 through deubiquitination. IRF1 binds to the CXCL4 promoter to upregulate CXCL4, promoting NLRP3-mediated pyroptosis and impairing cardiac function in myocardial infarction. USP47 silencing increases IRF1 ubiquitination, decreases IRF1 and CXCL4, and reduces pyroptosis.","method":"Co-immunoprecipitation, ubiquitination assays, ChIP (IRF1-CXCL4 promoter binding), siRNA knockdown, MI mouse model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical assays with in vivo MI model, single lab","pmids":["38850785"],"is_preprint":false},{"year":2025,"finding":"USP47 stabilizes c-Myc by preventing its proteasomal degradation through deubiquitination, promoting NSCLC cell proliferation. A selective USP47 inhibitor (K-552) destabilizes c-Myc and enhances the efficacy of Sotorasib (KRASG12C inhibitor) in vitro and in vivo.","method":"siRNA knockdown, ubiquitination assays, in vitro/in vivo proliferation assays, virtual screening-derived inhibitor","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assays with in vivo model, single lab","pmids":["40180254"],"is_preprint":false},{"year":2025,"finding":"USP47 binds and deubiquitinates GluR1 (AMPAR subunit), inhibiting its degradation and enhancing excitatory postsynaptic transmission and dendritic spine maturation. USP47 knockdown reduces seizure frequency and duration in epileptic mice.","method":"Co-immunoprecipitation, ubiquitination assays, electrophysiology, dendritic spine imaging, epilepsy mouse model with USP47 knockdown","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assays, functional electrophysiology, and in vivo model, single lab","pmids":["40716012"],"is_preprint":false},{"year":2025,"finding":"USP47 binds, deubiquitinates, and stabilizes PRMT5 (protein arginine methyltransferase 5), which in turn upregulates O-GlcNAcase expression, reducing protein O-GlcNAcylation in cardiomyocytes and attenuating Ang II-induced cardiac hypertrophy.","method":"Co-immunoprecipitation, ubiquitination assays, adenovirus-mediated gain/loss-of-function, in vitro and in vivo cardiac hypertrophy models","journal":"Journal of cardiovascular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assays with in vivo model, single lab","pmids":["39436323"],"is_preprint":false},{"year":2025,"finding":"USP47 deubiquitinates PD-L1 to stabilize its protein expression in hepatocellular carcinoma cells. USP47 deficiency reduces PD-L1 protein without affecting its mRNA. USP47 inhibition combined with anti-PD-1 therapy enhances tumor suppression in HCC mouse models.","method":"Co-immunoprecipitation, ubiquitination assays, Western blot, siRNA knockdown, HCC mouse model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assays with in vivo model, single lab","pmids":["40494207"],"is_preprint":false},{"year":2026,"finding":"USP47 directly interacts with HDAC2, promotes its deubiquitination, and stabilizes its protein. HDAC2 acts as a transcriptional repressor of CYP1A1 by deacetylating H3K9/H3K27 at the CYP1A1 promoter, limiting 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, CS-induced mouse model","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods with in vivo model, single lab","pmids":["41529803"],"is_preprint":false},{"year":2026,"finding":"USP47 inhibits the ubiquitination and degradation of SIRT1, stabilizing its expression. SIRT1 then increases PPARα expression through deacetylation, promoting lipid metabolism and alleviating metabolic-associated fatty liver disease (MAFLD).","method":"Co-immunoprecipitation, ubiquitination assays, adenovirus-mediated overexpression/knockdown, HFD rat model, HepG2 cell model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assays with in vivo model, single lab","pmids":["41930505"],"is_preprint":false},{"year":2020,"finding":"USP47 is upregulated in MCF-10A cells undergoing TGFβ2-induced EMT (as identified by quantitative proteomics), and chemical inhibition of USP47 reduces expression of EMT markers and reverts morphological changes. USP47 acts in SNAIL stabilization during EMT.","method":"Quantitative proteomics (MRM), pharmacological inhibition (P5091), Western blot, morphological assays","journal":"Journal of proteomics","confidence":"Low","confidence_rationale":"Tier 3 — proteomics-based identification with inhibitor treatment, limited mechanistic follow-up","pmids":["32201364"],"is_preprint":false},{"year":2023,"finding":"USP47 deubiquitinates NNT (nicotinamide nucleotide transhydrogenase) to protect it from ubiquitin-mediated degradation; loss of USP47 decreases NNT levels, leading to increased mitochondrial ROS and impaired energy production in irradiated skin cells. Usp47 knockout mice show aggravated oxidative skin damage.","method":"Usp47 knockout mouse models, proteomic analysis, ubiquitination assays, ROS/mitochondrial function assays","journal":"Toxicology and applied pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse model with proteomic screen and functional validation, single lab","pmids":["37924851"],"is_preprint":false},{"year":2026,"finding":"NUP85 competitively binds USP47 to ASK1, deubiquitinates ASK1 at lysine residue 805, and regulates ASK1 activation, thereby promoting collagen deposition and endoplasmic reticulum stress in liver fibrosis. USP47 thus deubiquitinates ASK1 as part of the NUP85-USP47-ASK1 pathway.","method":"Co-immunoprecipitation, ubiquitination assays (site-specific K805), competitive binding assays, siRNA knockdown, liver fibrosis mouse model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — site-specific ubiquitination assay with competitive binding and in vivo model, single lab","pmids":["41903125"],"is_preprint":false},{"year":2025,"finding":"USP47 stabilizes NRP1 (neuropilin-1) by preventing its ubiquitination and degradation, activating the PI3K/Akt signaling pathway and promoting angiogenesis in gastric cancer.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, angiogenesis assays","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP and ubiquitination assay with limited mechanistic follow-up, single lab","pmids":["40499689"],"is_preprint":false},{"year":2024,"finding":"USP47 deubiquitinates and stabilizes SIRT1, which then enhances Wnt/β-catenin pathway activity by upregulating PPARα. USP47 knockdown suppresses Icariin-induced osteogenic differentiation of bone marrow mesenchymal stem cells.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, osteogenic differentiation assays","journal":"Chemical biology & drug design","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP and ubiquitination assay, limited mechanistic novelty beyond known SIRT1 substrate","pmids":["38373741"],"is_preprint":false},{"year":2018,"finding":"USP47 promotes β-TrCP stability and phosphorylation of RelA (NF-κB subunit) in gastric cancer cells, contributing to cell viability and chemoresistance. Knockdown of USP47 decreases metabolic activity and induces apoptotic cell death.","method":"Immunoblots, MTT assay, Annexin V staining, siRNA knockdown","journal":"Biomedicines","confidence":"Low","confidence_rationale":"Tier 3 — single Western blot-based finding with functional readout, limited mechanistic detail","pmids":["29786670"],"is_preprint":false}],"current_model":"USP47 is a cysteine deubiquitylase (USP family) whose catalytic triad becomes aligned upon ubiquitin binding; it stabilizes diverse substrates — including DNA polymerase β (BER), katanin-p60 (axonal growth), β-catenin/TLE (Wnt signaling), NLRP3/ASC (inflammasome), TRAF3/TRAF6 (antiviral immunity), MAPK (RAS signaling), SATB1, BACH1, YBX1, c-Myc, PRMT5, HDAC2, GluR1, PD-L1, and others — by removing ubiquitin chains to prevent proteasomal degradation, and it is itself regulated through interaction with SCF(β-TrCP) and by modulation of its own ubiquitination status."},"narrative":{"teleology":[{"year":2009,"claim":"Identifying USP47 as a physical partner of SCFβ-TrCP revealed that this DUB is itself subject to E3-ligase-mediated regulation, establishing a regulatory axis rather than a simple enzyme–substrate relationship.","evidence":"Reciprocal co-immunoprecipitation with β-TrCP1/2 WD-repeat point mutants, siRNA knockdown and cell viability in human cancer cells","pmids":["19966869"],"confidence":"High","gaps":["Whether β-TrCP ubiquitylates USP47 for degradation or modulates its activity was not resolved","No structural basis for the atypical binding motif"]},{"year":2011,"claim":"Demonstrating that USP47 is the principal DUB for cytoplasmic Pol β established a direct connection between deubiquitylation and base excision repair fidelity, the first well-defined physiological substrate pathway for USP47.","evidence":"siRNA knockdown, ubiquitylation assays, and BER functional assays in human cells","pmids":["21362556"],"confidence":"High","gaps":["How USP47 selectively recognizes newly synthesized Pol β over mature nuclear Pol β was unknown","Whether other DUBs partially compensate in vivo"]},{"year":2013,"claim":"Identification of katanin-p60 as a USP47 substrate linked deubiquitylation to microtubule severing and axonal growth, broadening USP47's roles beyond DNA repair into neuronal biology.","evidence":"Co-IP, ubiquitination assays, siRNA knockdown, and axonal growth assays in rat hippocampal neurons","pmids":["23904609"],"confidence":"High","gaps":["Whether USP47–katanin-p60 axis operates in CNS contexts beyond bFGF stimulation","In vivo neuronal phenotype of Usp47 knockout not tested"]},{"year":2014,"claim":"Showing that KIFC3 recruits USP47 to adherens junctions to protect E-cadherin from Hakai-mediated degradation established a spatial targeting mechanism for USP47 activity at cell–cell contacts.","evidence":"Co-IP, immunofluorescence localization, E-cadherin ubiquitination and cleavage assays in epithelial cells","pmids":["25253721"],"confidence":"High","gaps":["Whether USP47 directly deubiquitylates E-cadherin or acts indirectly through Hakai was not fully resolved","In vivo junctional phenotype not examined"]},{"year":2015,"claim":"Demonstrating that USP47 deubiquitylates β-catenin to promote Wnt signaling, conserved from Drosophila to mammals, placed USP47 as a positive Wnt pathway regulator and revealed β-TrCP-mediated autoregulation of USP47 ubiquitination.","evidence":"RNAi screen, Wnt reporter assays, in vivo Drosophila wing phenotypes, ubiquitination assays","pmids":["26169834"],"confidence":"High","gaps":["Whether USP47 acts at the destruction complex or downstream was not distinguished at this stage"]},{"year":2016,"claim":"Systematic epistasis screening in Drosophila revealed that USP47 counteracts the N-end rule pathway (UBC6/POE-UBR4/KCMF1) to maintain MAPK protein levels, establishing USP47 as a post-translational stabilizer of RAS–MAPK signaling output.","evidence":"RNAi genetic interaction screen, epistasis analysis, and MAPK stability assays in Drosophila","pmids":["27552662"],"confidence":"High","gaps":["Mammalian validation of the N-end rule mechanism for MAPK was not provided","Identity of the specific MAPK ubiquitin chain type was not determined"]},{"year":2018,"claim":"Pharmacological and genetic evidence that USP47 (together with USP7) deubiquitylates NLRP3 and is required for ASC speck formation extended USP47's roles to innate immune inflammasome regulation.","evidence":"USP7/USP47 inhibitor, CRISPR knockdown in THP-1 macrophages, ASC oligomerization and IL-1β/IL-18 release assays","pmids":["30206189"],"confidence":"High","gaps":["Individual contributions of USP7 versus USP47 were not fully separated","Direct deubiquitylation of ASC by USP47 was not reconstituted in vitro"]},{"year":2019,"claim":"Two studies expanded USP47's substrate repertoire to include SATB1 (stabilized for colon cancer transcription programs) and revealed that ERAP1 competes with β-TrCP for USP47 binding to modulate Hedgehog signaling, uncovering a protein-competition regulatory mechanism.","evidence":"Co-IP, ubiquitination assays, xenograft models (SATB1); CRISPR/siRNA, protein stability assays, tumor models (ERAP1–β-TrCP–USP47)","pmids":["30742943","31341163"],"confidence":"High","gaps":["Structural basis for ERAP1 displacement of β-TrCP from USP47 remains unknown","Whether ERAP1 regulation of USP47 operates outside Hedgehog-driven tumors"]},{"year":2020,"claim":"Identification of RPL11 deubiquitylation by USP47 connected USP47 to the ribosomal stress–MDM2–p53 axis, demonstrating that USP47 prevents RPL11 nucleolar-to-nucleoplasmic translocation and thereby suppresses p53 activation under basal conditions.","evidence":"Catalytic-dead mutant analysis, ubiquitination assays, p53 pathway reporters, miR-101-3p transfection","pmids":["32370049","35205710"],"confidence":"High","gaps":["Whether USP47 acts on other ribosomal stress sensors","In vivo validation of the RPL11–p53 axis via Usp47 knockout"]},{"year":2020,"claim":"Demonstrating that USP47 stabilizes IK (spliceosomal component) to maintain proper ATM pre-mRNA splicing linked USP47 for the first time to RNA processing and the DNA damage response via a splicing intermediate.","evidence":"Co-IP, ubiquitination assays, RT-PCR splicing analysis, siRNA knockdown","pmids":["32377397"],"confidence":"Medium","gaps":["Single-lab finding; independent replication needed","Whether USP47 regulates splicing of transcripts beyond ATM"]},{"year":2021,"claim":"USP47 stabilization of YBX1 in CML cells, with Usp47 knockout significantly inhibiting CML driven by BCR-ABL and the T315I gatekeeper mutant in mice, established USP47 as a therapeutic vulnerability in drug-resistant leukemia.","evidence":"Usp47 knockout mice, BCR-ABL CML model, shRNA/siRNA, Lin⁻Sca1⁺c-Kit⁺ stem cell analysis","pmids":["33397955"],"confidence":"High","gaps":["Whether USP47 inhibition is tolerated long-term in vivo","Whether YBX1 is the sole CML-relevant substrate"]},{"year":2023,"claim":"Crystal structures of free and ubiquitin-bound USP47 catalytic domain resolved the activation mechanism: the catalytic triad is misaligned until ubiquitin binding induces conformational rearrangement, explaining substrate-dependent activation analogous to USP7.","evidence":"X-ray crystallography (free and Ub-bound forms), in vitro DUB activity assays comparing full-length vs. catalytic domain","pmids":["37740002"],"confidence":"High","gaps":["No structure of full-length USP47 with regulatory domains","Structural basis for substrate selectivity beyond BL loop differences not resolved"]},{"year":2023,"claim":"Reconstituted in vitro deubiquitylation of TLE3 by USP47, counteracting XIAP-mediated monoubiquitylation, definitively placed USP47 downstream of the β-catenin destruction complex in Wnt signaling and resolved the earlier ambiguity about its pathway position.","evidence":"In vitro deubiquitylation assay, genome-scale RNAi screen, Xenopus/Drosophila/human cell Wnt reporter validation","pmids":["36749823"],"confidence":"High","gaps":["Whether β-catenin and TLE3 deubiquitylation are independent or coordinated events","Quantitative contribution of USP47 versus other Wnt-regulatory DUBs in vivo"]},{"year":2023,"claim":"Discovery that USP47 deubiquitylates YTHDF1 to attenuate m6A-dependent c-Myc translation in regulatory T cells revealed a non-degradative function—modifying reader-protein interactions—and linked USP47 to Treg metabolic fitness and immune homeostasis.","evidence":"Treg-specific conditional knockout mice, polyribosome profiling, ubiquitination assays, metabolic assays","pmids":["37788092"],"confidence":"High","gaps":["Whether USP47 regulation of YTHDF1 extends to other m6A targets beyond c-Myc","Ubiquitin chain type on YTHDF1 not specified"]},{"year":2023,"claim":"Showing that USP47 removes K63-linked polyubiquitin from TRAF3 and TRAF6 to dampen type I interferon signaling identified USP47 as a negative regulator of antiviral innate immunity, extending its chain-type specificity beyond K48.","evidence":"K63-linkage-specific ubiquitination assays, dual-luciferase ISRE/IFN-β reporters, overexpression/knockdown in virus infection models","pmids":["37001379"],"confidence":"Medium","gaps":["In vivo viral challenge in Usp47 knockout mice not performed","Direct in vitro cleavage of K63 chains not reconstituted"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for how full-length USP47's non-catalytic domains regulate activity and substrate selection; the physiological hierarchy among its many reported substrates in different tissues; and whether selective USP47 inhibitors can achieve therapeutic windows in cancer and immune disease.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length USP47 structure available","No systematic comparison of substrate affinities","No clinical-stage USP47 inhibitor with characterized selectivity"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,5,6,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,27,28]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,9,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4,7,12,14,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,15,19,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,18,19]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[8]}],"complexes":[],"partners":["BTRC","POLB","KATNA1","CTNNB1","TLE3","YTHDF1","YBX1","RPL11"],"other_free_text":[]},"mechanistic_narrative":"USP47 is a cysteine deubiquitylase of the USP family that stabilizes a broad range of substrates by removing ubiquitin chains to prevent their proteasomal degradation, thereby regulating DNA repair, Wnt signaling, MAPK signaling, inflammasome activation, innate immunity, neuronal development, and metabolic homeostasis. Structural studies reveal that its catalytic triad is misaligned in the free state and becomes activated upon ubiquitin binding, a mechanism shared with USP7; full-length USP47 exhibits higher catalytic activity than the isolated catalytic domain, with substrate selectivity conferred by divergent BL1–BL3 loops [PMID:37740002]. USP47 stabilizes DNA polymerase β to maintain base excision repair [PMID:21362556], deubiquitylates both β-catenin and the corepressor TLE3/Groucho to promote Wnt pathway output [PMID:26169834, PMID:36749823], counteracts N-end-rule-mediated MAPK degradation [PMID:27552662], deubiquitylates NLRP3/ASC to enable inflammasome assembly [PMID:30206189], removes K63-linked ubiquitin from TRAF3/TRAF6 to attenuate type I interferon signaling [PMID:37001379], and stabilizes katanin-p60 to promote axonal growth [PMID:23904609]. USP47 itself is regulated through interaction with the SCFβ-TrCP E3 ligase, which binds USP47 through an atypical degron motif and modulates its ubiquitination status, while ERAP1 can displace β-TrCP from USP47 to redirect Hedgehog signaling [PMID:19966869, PMID:31341163]."},"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). Acts as a regulator of cell growth and genome integrity. May also indirectly regulate CDC25A expression at a transcriptional level","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96K76/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/USP47","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/USP47","total_profiled":1310},"omim":[{"mim_id":"614460","title":"UBIQUITIN-SPECIFIC PROTEASE 47; USP47","url":"https://www.omim.org/entry/614460"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/USP47"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96K76","domains":[{"cath_id":"3.10.20.90","chopping":"41-138","consensus_level":"medium","plddt":81.5199,"start":41,"end":138},{"cath_id":"3.10.20.90","chopping":"606-700","consensus_level":"high","plddt":88.7945,"start":606,"end":700},{"cath_id":"3.10.20.90","chopping":"714-797","consensus_level":"high","plddt":88.1786,"start":714,"end":797},{"cath_id":"3.10.20.90","chopping":"1226-1327","consensus_level":"medium","plddt":91.0155,"start":1226,"end":1327}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96K76","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96K76-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96K76-F1-predicted_aligned_error_v6.png","plddt_mean":71.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=USP47","jax_strain_url":"https://www.jax.org/strain/search?query=USP47"},"sequence":{"accession":"Q96K76","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96K76.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96K76/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96K76"}},"corpus_meta":[{"pmid":"30206189","id":"PMC_30206189","title":"USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation.","date":"2018","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/30206189","citation_count":156,"is_preprint":false},{"pmid":"24900381","id":"PMC_24900381","title":"Selective Dual Inhibitors of the Cancer-Related Deubiquitylating Proteases USP7 and USP47.","date":"2012","source":"ACS medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/24900381","citation_count":146,"is_preprint":false},{"pmid":"21362556","id":"PMC_21362556","title":"USP47 is a deubiquitylating enzyme that regulates base excision repair by controlling steady-state levels of DNA polymerase β.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21362556","citation_count":103,"is_preprint":false},{"pmid":"25429829","id":"PMC_25429829","title":"MicroRNA-204-5p inhibits gastric cancer cell proliferation by downregulating USP47 and RAB22A.","date":"2014","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25429829","citation_count":94,"is_preprint":false},{"pmid":"26169834","id":"PMC_26169834","title":"Deubiquitinase USP47/UBP64E Regulates β-Catenin Ubiquitination and Degradation and Plays a Positive Role in Wnt Signaling.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26169834","citation_count":77,"is_preprint":false},{"pmid":"30742943","id":"PMC_30742943","title":"Reversible regulation of SATB1 ubiquitination by USP47 and SMURF2 mediates colon cancer cell proliferation and tumor progression.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30742943","citation_count":73,"is_preprint":false},{"pmid":"19966869","id":"PMC_19966869","title":"The ubiquitin-specific protease USP47 is a novel beta-TRCP interactor regulating cell 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31233752","citation_count":46,"is_preprint":false},{"pmid":"37788092","id":"PMC_37788092","title":"USP47 inhibits m6A-dependent c-Myc translation to maintain regulatory T cell metabolic and functional homeostasis.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37788092","citation_count":39,"is_preprint":false},{"pmid":"23904609","id":"PMC_23904609","title":"USP47 and C terminus of Hsp70-interacting protein (CHIP) antagonistically regulate katanin-p60-mediated axonal growth.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23904609","citation_count":39,"is_preprint":false},{"pmid":"27552662","id":"PMC_27552662","title":"The Deubiquitinase USP47 Stabilizes MAPK by Counteracting the Function of the N-end Rule ligase POE/UBR4 in Drosophila.","date":"2016","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/27552662","citation_count":36,"is_preprint":false},{"pmid":"31925813","id":"PMC_31925813","title":"Spatial transcriptomics identifies spatially dysregulated expression of GRM3 and USP47 in amyotrophic lateral sclerosis.","date":"2020","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/31925813","citation_count":35,"is_preprint":false},{"pmid":"32201364","id":"PMC_32201364","title":"Proteomics analysis reveals the role of ubiquitin specific protease (USP47) in Epithelial to Mesenchymal Transition (EMT) induced by TGFβ2 in breast cells.","date":"2020","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/32201364","citation_count":31,"is_preprint":false},{"pmid":"34630087","id":"PMC_34630087","title":"USP47-Mediated Deubiquitination and Stabilization of TCEA3 Attenuates Pyroptosis and Apoptosis of Colorectal Cancer Cells Induced by Chemotherapeutic Doxorubicin.","date":"2021","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34630087","citation_count":30,"is_preprint":false},{"pmid":"25253721","id":"PMC_25253721","title":"Minus end-directed motor KIFC3 suppresses E-cadherin degradation by recruiting USP47 to adherens junctions.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25253721","citation_count":28,"is_preprint":false},{"pmid":"34030041","id":"PMC_34030041","title":"USP47 maintains the stemness of colorectal cancer cells and is inhibited by parthenolide.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34030041","citation_count":27,"is_preprint":false},{"pmid":"31526052","id":"PMC_31526052","title":"MicroRNA-204-5p Inhibits Ovarian Cancer Cell Proliferation by Down-Regulating USP47.","date":"2019","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/31526052","citation_count":26,"is_preprint":false},{"pmid":"35678979","id":"PMC_35678979","title":"LncRNA ZNF883-Mediated NLRP3 Inflammasome Activation and Epilepsy Development Involve USP47 Upregulation.","date":"2022","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35678979","citation_count":25,"is_preprint":false},{"pmid":"32379981","id":"PMC_32379981","title":"Long non-coding RNA DSCAM-AS1 upregulates USP47 expression through sponging miR-101-3p to accelerate osteosarcoma progression.","date":"2020","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/32379981","citation_count":22,"is_preprint":false},{"pmid":"33576460","id":"PMC_33576460","title":"Long non‑coding RNA KCNQ1OT1 promotes nasopharyngeal carcinoma cell cisplatin resistance via the miR‑454/USP47 axis.","date":"2021","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33576460","citation_count":22,"is_preprint":false},{"pmid":"32370049","id":"PMC_32370049","title":"USP47 Promotes Tumorigenesis by Negative Regulation of p53 through Deubiquitinating Ribosomal Protein S2.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32370049","citation_count":22,"is_preprint":false},{"pmid":"35141006","id":"PMC_35141006","title":"USP47 stabilizes BACH1 to promote the Warburg effect and non-small cell lung cancer development via stimulating Hk2 and Gapdh transcription.","date":"2022","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35141006","citation_count":22,"is_preprint":false},{"pmid":"33489876","id":"PMC_33489876","title":"E2F7 Transcriptionally Inhibits MicroRNA-199b Expression to Promote USP47, Thereby Enhancing Colon Cancer Tumor Stem Cell Activity and Promoting the Occurrence of Colon Cancer.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33489876","citation_count":22,"is_preprint":false},{"pmid":"29786670","id":"PMC_29786670","title":"Deubiquitinylase USP47 Promotes RelA Phosphorylation and Survival in Gastric Cancer Cells.","date":"2018","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/29786670","citation_count":21,"is_preprint":false},{"pmid":"32761659","id":"PMC_32761659","title":"USP47 promotes apoptosis in rat myocardial cells after ischemia/reperfusion injury via NF-κB activation.","date":"2020","source":"Biotechnology and applied biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32761659","citation_count":20,"is_preprint":false},{"pmid":"35205710","id":"PMC_35205710","title":"MicroRNA-101-3p Suppresses Cancer Cell Growth by Inhibiting the USP47-Induced Deubiquitination of RPL11.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/35205710","citation_count":19,"is_preprint":false},{"pmid":"35034955","id":"PMC_35034955","title":"Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2.","date":"2022","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/35034955","citation_count":19,"is_preprint":false},{"pmid":"31982568","id":"PMC_31982568","title":"Gga-miR-30d regulates infectious bronchitis virus infection by targeting USP47 in HD11 cells.","date":"2020","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31982568","citation_count":17,"is_preprint":false},{"pmid":"32377397","id":"PMC_32377397","title":"Deubiquitinase USP47-stabilized splicing factor IK regulates the splicing of ATM pre-mRNA.","date":"2020","source":"Cell death 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design","url":"https://pubmed.ncbi.nlm.nih.gov/38373741","citation_count":9,"is_preprint":false},{"pmid":"37740002","id":"PMC_37740002","title":"Structural and functional characterization of USP47 reveals a hot spot for inhibitor design.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37740002","citation_count":8,"is_preprint":false},{"pmid":"37001379","id":"PMC_37001379","title":"Deubiquitinase USP47 attenuates virus-induced type I interferon signaling.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37001379","citation_count":7,"is_preprint":false},{"pmid":"37564825","id":"PMC_37564825","title":"Upregulation of ubiquitin carboxy‑terminal hydrolase 47 (USP47) in papillary thyroid carcinoma ex vivo and reduction of tumor cell malignant behaviors after USP47 knockdown by stabilizing SATB1 expression in vitro.","date":"2023","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/37564825","citation_count":7,"is_preprint":false},{"pmid":"40180254","id":"PMC_40180254","title":"Targeting USP47 enhances the efficacy of KRAS inhibitor in KRASG12C mutated non-small cell lung cancer by controlling deubiquitination of c-Myc.","date":"2025","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/40180254","citation_count":5,"is_preprint":false},{"pmid":"39436323","id":"PMC_39436323","title":"Deubiquitinase USP47 Ameliorates Cardiac Hypertrophy Through Reducing Protein O-GlcNAcylation.","date":"2025","source":"Journal of cardiovascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39436323","citation_count":4,"is_preprint":false},{"pmid":"37924851","id":"PMC_37924851","title":"Ubiquitin-specific peptidase 47 (USP47) regulates cutaneous oxidative injury through nicotinamide nucleotide transhydrogenase (NNT).","date":"2023","source":"Toxicology and applied 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immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40494207","citation_count":2,"is_preprint":false},{"pmid":"38334226","id":"PMC_38334226","title":"[Retracted] Long non‑coding RNA KCNQ1OT1 promotes nasopharyngeal carcinoma cell cisplatin resistance via the miR‑454/USP47 axis.","date":"2024","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38334226","citation_count":1,"is_preprint":false},{"pmid":"40499689","id":"PMC_40499689","title":"USP47 enhances NRP1-mediated angiogenesis to promote gastric cancer progression.","date":"2025","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40499689","citation_count":0,"is_preprint":false},{"pmid":"41930505","id":"PMC_41930505","title":"USP47 alleviates metabolic-associated fatty liver disease by activating the PPARα signaling pathway through the stabilization of SIRT1.","date":"2026","source":"Biochimica et biophysica acta. 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":"41529803","id":"PMC_41529803","title":"USP47 stabilizes HDAC2 to ameliorate cigarette smoke-induced skeletal muscle atrophy by suppressing CYP1A1/ROS-mediated autophagy.","date":"2026","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41529803","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":25267,"output_tokens":7749,"usd":0.096018},"stage2":{"model":"claude-opus-4-6","input_tokens":11581,"output_tokens":3946,"usd":0.234832},"total_usd":0.33085,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"USP47 is the major deubiquitylating enzyme responsible for deubiquitylation of DNA polymerase β (Pol β) in the cytoplasm, stabilizing newly synthesized Pol β that is used as a source for nuclear Pol β involved in 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, BER functional assays, cell viability assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (knockdown, ubiquitylation assays, BER assays) in a high-impact journal with strong mechanistic follow-up\",\n      \"pmids\": [\"21362556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"USP47 interacts with SCF(β-TrCP) E3 ubiquitin ligase; both β-TrCP1 and β-TrCP2 bind specifically to USP47, with point mutations in the β-TrCP WD-repeat region abolishing binding, indicating an E3-substrate-type interaction. Depletion of USP47 induces accumulation of Cdc25A, decreases cell survival, and augments cytotoxic effects of anticancer drugs.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown, cell viability assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with mutagenesis validation and functional phenotype readout\",\n      \"pmids\": [\"19966869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP47 (and its Drosophila counterpart UBP64E) prevents β-catenin ubiquitination to promote Wnt signaling. USP47 inactivation by RNAi increases β-catenin ubiquitination, attenuates Wnt signaling, and represses cancer cell growth. β-TrCP promotes USP47 ubiquitination through interaction with an atypical motif in USP47, while USP47 also deubiquitinates itself. In Drosophila, UBP64E is required for Armadillo stabilization.\",\n      \"method\": \"RNAi library screen, ubiquitination assays, Wnt reporter assays, in vivo Drosophila wing studies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across mammalian and Drosophila systems, replicated mechanism\",\n      \"pmids\": [\"26169834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USP47 is a katanin-p60-specific deubiquitinating enzyme that stabilizes katanin-p60 by counteracting CHIP (an E3 ubiquitin ligase that promotes proteasomal degradation of katanin-p60). USP47 promotes axonal growth of rat hippocampal neurons; bFGF treatment increases USP47 and katanin-p60 levels and decreases ubiquitinated katanin-p60, promoting axonal growth.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, neuronal culture axonal growth assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assays, and functional neuronal phenotype with defined mechanistic pathway\",\n      \"pmids\": [\"23904609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Drosophila, USP47 acts post-translationally to counteract proteasome-mediated degradation of MAPK, thereby maintaining MAPK half-life and signaling output. RNAi genetic interaction screening identified UBC6 (E2) and POE/UBR4 (E3 N-recognin) as enzymes opposing USP47 activity; KCMF1 is another component of this degradation module. USP47 thus counteracts the N-end rule pathway to control MAPK levels.\",\n      \"method\": \"RNAi-based genetic interaction screen (Drosophila), epistasis analysis, protein stability assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic RNAi epistasis screen with multiple genetic validations in Drosophila ortholog\",\n      \"pmids\": [\"27552662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP47 (together with USP7) regulates NLRP3 inflammasome activation in macrophages. Chemical inhibition of USP7/USP47 blocks inflammasome formation by preventing ASC oligomerisation and speck formation, independently of transcription. The ubiquitination status of NLRP3 itself is altered by inhibition of USP7 and USP47. CRISPR/Cas9 knockdown of both USP7 and USP47 in THP-1 cells reduces inflammasome activation and IL-1β/IL-18 release.\",\n      \"method\": \"Pharmacological inhibition, CRISPR/Cas9 knockdown, ASC oligomerization/speck assays, cytokine release assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (inhibitor, CRISPR KO, functional readouts), highly cited\",\n      \"pmids\": [\"30206189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"USP47 interacts with SATB1 and mediates its deubiquitination and stabilization. USP47 deficiency impairs SATB1 transcriptional activity and inhibits colon cancer cell proliferation, migration, and tumorigenesis. SMURF2 functions as an E3 ubiquitin ligase promoting SATB1 degradation, and SMURF2 is negatively regulated by USP47 (USP47 depletion sensitizes cells to 5-FU).\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, mouse xenograft model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assays, in vivo model with mechanistic pathway definition\",\n      \"pmids\": [\"30742943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ERAP1 binds USP47, displaces USP47-associated βTrCP (the substrate-receptor subunit of SCFβTrCP), and promotes βTrCP degradation. This results in modulation of Gli transcription factors and enhancement of Hedgehog pathway activity. Genetic or pharmacological inhibition of ERAP1 suppresses Hh-dependent tumor growth in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assays, genetic inhibition (CRISPR/siRNA), in vivo tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical and genetic methods with in vivo validation\",\n      \"pmids\": [\"31341163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KIFC3 (a minus end-directed kinesin motor) binds USP47 and recruits it to adherens junctions (AJs). USP47 at AJs prevents ubiquitination and Hakai E3-ligase-mediated degradation of E-cadherin. Depletion of KIFC3 or USP47 promotes cleavage of E-cadherin at a juxtamembrane region, producing a 90-kDa fragment and causing E-cadherin internalization; this process is inhibited by proteasome inhibitors.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence localization, proteasome inhibitor treatment, E-cadherin ubiquitination assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, functional localization with direct consequence, ubiquitination assays\",\n      \"pmids\": [\"25253721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP47 stabilizes Y-box binding protein 1 (YBX1) to promote DNA damage repair in CML cells. USP47 knockdown represses CML cell proliferation in vitro and in vivo; Usp47 knockout significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice and reduces Lin-Sca1+c-Kit+ CML stem/progenitor cells.\",\n      \"method\": \"siRNA/shRNA knockdown, Usp47 knockout mice, in vitro proliferation assays, CML mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in vivo model with mechanistic substrate identification and functional phenotype\",\n      \"pmids\": [\"33397955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP47 deubiquitinates RPL11 (ribosomal protein L11), preventing its interaction with MDM2 under normal conditions. USP47 inhibition or miR-101-3p-mediated suppression leads to RPL11 translocation from nucleolus to nucleoplasm, enabling RPL11-MDM2 binding that suppresses MDM2 and stabilizes p53, inhibiting cancer cell proliferation. The catalytically inactive form of USP47 cannot restore these effects.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, catalytic mutant analysis, p53 pathway reporter assays, miRNA transfection\",\n      \"journal\": \"Cancers / Cancers (multiple papers)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro deubiquitination, catalytic mutant validation, mechanistic pathway placement\",\n      \"pmids\": [\"32370049\", \"35205710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP47 directly interacts with IK (a spliceosomal component) and stabilizes it through deubiquitination, preventing its proteasomal degradation. IK is required for proper splicing of ATM pre-mRNA; IK depletion leads to retention of intron 1 in ATM pre-mRNA and loss of ATM protein, impairing DNA damage repair. SMU1 absence induces IK ubiquitination; USP47 counteracts this.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, RT-PCR splicing assays, siRNA knockdown\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assays with functional splicing readout, single lab\",\n      \"pmids\": [\"32377397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP47 deubiquitylates the transcriptional corepressor TLE3/Groucho to counteract XIAP-mediated monoubiquitylation of TLE, promoting Wnt-β-catenin signaling. USP47 interacts with TLE3 and XIAP, and inhibits XIAP-mediated ubiquitylation of TLE3 in vitro in a dose-dependent manner. USP47 acts downstream of the β-catenin destruction complex and is required for Wnt signaling in Drosophila, Xenopus, and human cells.\",\n      \"method\": \"Genome-scale RNAi screen (Drosophila cells), in vitro deubiquitylation assay, Co-immunoprecipitation, Wnt reporter assays, Xenopus and Drosophila in vivo assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted deubiquitylation assay, multiple organism validation, genome-scale screen\",\n      \"pmids\": [\"36749823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal structures of the USP47 catalytic domain in 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 and contribute to substrate selectivity. USP47 depletion inhibits cancer cell growth in a p53-dependent manner, enhanced by simultaneous USP7 knockdown.\",\n      \"method\": \"X-ray crystallography (free and ubiquitin-bound), in vitro DUB activity assays, siRNA knockdown, cancer cell growth assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation and in vitro enzymatic assays\",\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 triggers c-Myc protein accumulation and exacerbated hyperglycolysis in Tregs, compromising Treg homeostasis and function.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, polyribosome/translation assays, Treg-specific conditional knockout mice, metabolic assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical assays with conditional KO in vivo model\",\n      \"pmids\": [\"37788092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP47 removes K63-linked polyubiquitin chains from TRAF3 and TRAF6, attenuating type I interferon signaling downstream of MAVS and upstream of TBK1. USP47 overexpression suppresses virus-induced ISRE and IFN-β activation and enhances viral replication; knockdown has opposite effects.\",\n      \"method\": \"Co-immunoprecipitation, K63-linkage-specific ubiquitination assays, dual-luciferase reporter assays, overexpression/knockdown in virus infection models\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and linkage-specific ubiquitination assays with functional reporter readout, single lab\",\n      \"pmids\": [\"37001379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP47 stabilizes BACH1 by direct binding and deubiquitination, promoting the Warburg effect and NSCLC development. USP47 deubiquitination of BACH1 leads to downstream transcriptional upregulation of Hk2 and Gapdh, enhancing glycolysis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, in vivo xenograft, glycolysis assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assays with functional metabolic readout, single lab\",\n      \"pmids\": [\"35141006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP47 regulates mutant EZH2 protein stability; inhibition of USP47 promotes ubiquitination and degradation of mutant EZH2. Targeting USP47 leads to death of mutant EZH2-positive cells in vitro and in vivo.\",\n      \"method\": \"Selectivity profiling, genetic studies (siRNA/KO), animal models, ubiquitination assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic substrate identification with in vivo validation, single lab\",\n      \"pmids\": [\"35034955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP47 binds TCEA3 (transcription elongation factor A3) and regulates its deubiquitination and intracellular stability. USP47 ectopic expression increases TCEA3 levels; TCEA3 regulates pro-apoptotic Bax levels, and the USP47-TCEA3 axis modulates doxorubicin-induced pyroptosis and apoptosis in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, apoptosis/pyroptosis assays\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assays with functional apoptosis readout, single lab\",\n      \"pmids\": [\"34630087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP47 stabilizes IRF1 through deubiquitination. IRF1 binds to the CXCL4 promoter to upregulate CXCL4, promoting NLRP3-mediated pyroptosis and impairing cardiac function in myocardial infarction. USP47 silencing increases IRF1 ubiquitination, decreases IRF1 and CXCL4, and reduces pyroptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, ChIP (IRF1-CXCL4 promoter binding), siRNA knockdown, MI mouse model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical assays with in vivo MI model, 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, promoting NSCLC cell proliferation. A selective USP47 inhibitor (K-552) destabilizes c-Myc and enhances the efficacy of Sotorasib (KRASG12C inhibitor) in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, ubiquitination assays, in vitro/in vivo proliferation assays, virtual screening-derived inhibitor\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assays with in vivo model, single lab\",\n      \"pmids\": [\"40180254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP47 binds and deubiquitinates GluR1 (AMPAR subunit), inhibiting its degradation and enhancing excitatory postsynaptic transmission and dendritic spine maturation. USP47 knockdown reduces seizure frequency and duration in epileptic mice.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, electrophysiology, dendritic spine imaging, epilepsy mouse model with USP47 knockdown\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assays, functional electrophysiology, and in vivo model, single lab\",\n      \"pmids\": [\"40716012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP47 binds, deubiquitinates, and stabilizes PRMT5 (protein arginine methyltransferase 5), which in turn upregulates O-GlcNAcase expression, reducing protein O-GlcNAcylation in cardiomyocytes and attenuating Ang II-induced cardiac hypertrophy.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, adenovirus-mediated gain/loss-of-function, in vitro and in vivo cardiac hypertrophy models\",\n      \"journal\": \"Journal of cardiovascular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assays with in vivo model, single lab\",\n      \"pmids\": [\"39436323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP47 deubiquitinates PD-L1 to stabilize its protein expression in hepatocellular carcinoma cells. USP47 deficiency reduces PD-L1 protein without affecting its mRNA. USP47 inhibition combined with anti-PD-1 therapy enhances tumor suppression in HCC mouse models.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, Western blot, siRNA knockdown, HCC mouse model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assays with in vivo model, single lab\",\n      \"pmids\": [\"40494207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP47 directly interacts with HDAC2, promotes its deubiquitination, and stabilizes its protein. HDAC2 acts as a transcriptional repressor of CYP1A1 by deacetylating H3K9/H3K27 at the CYP1A1 promoter, limiting 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, CS-induced mouse model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with in vivo model, single lab\",\n      \"pmids\": [\"41529803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP47 inhibits the ubiquitination and degradation of SIRT1, stabilizing its expression. SIRT1 then increases PPARα expression through deacetylation, promoting lipid metabolism and alleviating metabolic-associated fatty liver disease (MAFLD).\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, adenovirus-mediated overexpression/knockdown, HFD rat model, HepG2 cell model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assays with in vivo model, single lab\",\n      \"pmids\": [\"41930505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP47 is upregulated in MCF-10A cells undergoing TGFβ2-induced EMT (as identified by quantitative proteomics), and chemical inhibition of USP47 reduces expression of EMT markers and reverts morphological changes. USP47 acts in SNAIL stabilization during EMT.\",\n      \"method\": \"Quantitative proteomics (MRM), pharmacological inhibition (P5091), Western blot, morphological assays\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — proteomics-based identification with inhibitor treatment, limited mechanistic follow-up\",\n      \"pmids\": [\"32201364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP47 deubiquitinates NNT (nicotinamide nucleotide transhydrogenase) to protect it from ubiquitin-mediated degradation; loss of USP47 decreases NNT levels, leading to increased mitochondrial ROS and impaired energy production in irradiated skin cells. Usp47 knockout mice show aggravated oxidative skin damage.\",\n      \"method\": \"Usp47 knockout mouse models, proteomic analysis, ubiquitination assays, ROS/mitochondrial function assays\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with proteomic screen and functional validation, single lab\",\n      \"pmids\": [\"37924851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NUP85 competitively binds USP47 to ASK1, deubiquitinates ASK1 at lysine residue 805, and regulates ASK1 activation, thereby promoting collagen deposition and endoplasmic reticulum stress in liver fibrosis. USP47 thus deubiquitinates ASK1 as part of the NUP85-USP47-ASK1 pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (site-specific K805), competitive binding assays, siRNA knockdown, liver fibrosis mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific ubiquitination assay with competitive binding and in vivo model, single lab\",\n      \"pmids\": [\"41903125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP47 stabilizes NRP1 (neuropilin-1) by preventing its ubiquitination and degradation, activating the PI3K/Akt signaling pathway and promoting angiogenesis in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, angiogenesis assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP and ubiquitination assay with limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"40499689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP47 deubiquitinates and stabilizes SIRT1, which then enhances Wnt/β-catenin pathway activity by upregulating PPARα. USP47 knockdown suppresses Icariin-induced osteogenic differentiation of bone marrow mesenchymal stem cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, osteogenic differentiation assays\",\n      \"journal\": \"Chemical biology & drug design\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP and ubiquitination assay, limited mechanistic novelty beyond known SIRT1 substrate\",\n      \"pmids\": [\"38373741\"],\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, contributing to cell viability and chemoresistance. Knockdown of USP47 decreases metabolic activity and induces apoptotic cell death.\",\n      \"method\": \"Immunoblots, MTT assay, Annexin V staining, siRNA knockdown\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Western blot-based finding with functional readout, limited mechanistic detail\",\n      \"pmids\": [\"29786670\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"USP47 is a cysteine deubiquitylase (USP family) whose catalytic triad becomes aligned upon ubiquitin binding; it stabilizes diverse substrates — including DNA polymerase β (BER), katanin-p60 (axonal growth), β-catenin/TLE (Wnt signaling), NLRP3/ASC (inflammasome), TRAF3/TRAF6 (antiviral immunity), MAPK (RAS signaling), SATB1, BACH1, YBX1, c-Myc, PRMT5, HDAC2, GluR1, PD-L1, and others — by removing ubiquitin chains to prevent proteasomal degradation, and it is itself regulated through interaction with SCF(β-TrCP) and by modulation of its own ubiquitination status.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"USP47 is a cysteine deubiquitylase of the USP family that stabilizes a broad range of substrates by removing ubiquitin chains to prevent their proteasomal degradation, thereby regulating DNA repair, Wnt signaling, MAPK signaling, inflammasome activation, innate immunity, neuronal development, and metabolic homeostasis. Structural studies reveal that its catalytic triad is misaligned in the free state and becomes activated upon ubiquitin binding, a mechanism shared with USP7; full-length USP47 exhibits higher catalytic activity than the isolated catalytic domain, with substrate selectivity conferred by divergent BL1–BL3 loops [PMID:37740002]. USP47 stabilizes DNA polymerase β to maintain base excision repair [PMID:21362556], deubiquitylates both β-catenin and the corepressor TLE3/Groucho to promote Wnt pathway output [PMID:26169834, PMID:36749823], counteracts N-end-rule-mediated MAPK degradation [PMID:27552662], deubiquitylates NLRP3/ASC to enable inflammasome assembly [PMID:30206189], removes K63-linked ubiquitin from TRAF3/TRAF6 to attenuate type I interferon signaling [PMID:37001379], and stabilizes katanin-p60 to promote axonal growth [PMID:23904609]. USP47 itself is regulated through interaction with the SCFβ-TrCP E3 ligase, which binds USP47 through an atypical degron motif and modulates its ubiquitination status, while ERAP1 can displace β-TrCP from USP47 to redirect Hedgehog signaling [PMID:19966869, PMID:31341163].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying USP47 as a physical partner of SCFβ-TrCP revealed that this DUB is itself subject to E3-ligase-mediated regulation, establishing a regulatory axis rather than a simple enzyme–substrate relationship.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation with β-TrCP1/2 WD-repeat point mutants, siRNA knockdown and cell viability in human cancer cells\",\n      \"pmids\": [\"19966869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether β-TrCP ubiquitylates USP47 for degradation or modulates its activity was not resolved\", \"No structural basis for the atypical binding motif\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that USP47 is the principal DUB for cytoplasmic Pol β established a direct connection between deubiquitylation and base excision repair fidelity, the first well-defined physiological substrate pathway for USP47.\",\n      \"evidence\": \"siRNA knockdown, ubiquitylation assays, and BER functional assays in human cells\",\n      \"pmids\": [\"21362556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP47 selectively recognizes newly synthesized Pol β over mature nuclear Pol β was unknown\", \"Whether other DUBs partially compensate in vivo\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of katanin-p60 as a USP47 substrate linked deubiquitylation to microtubule severing and axonal growth, broadening USP47's roles beyond DNA repair into neuronal biology.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, siRNA knockdown, and axonal growth assays in rat hippocampal neurons\",\n      \"pmids\": [\"23904609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP47–katanin-p60 axis operates in CNS contexts beyond bFGF stimulation\", \"In vivo neuronal phenotype of Usp47 knockout not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that KIFC3 recruits USP47 to adherens junctions to protect E-cadherin from Hakai-mediated degradation established a spatial targeting mechanism for USP47 activity at cell–cell contacts.\",\n      \"evidence\": \"Co-IP, immunofluorescence localization, E-cadherin ubiquitination and cleavage assays in epithelial cells\",\n      \"pmids\": [\"25253721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP47 directly deubiquitylates E-cadherin or acts indirectly through Hakai was not fully resolved\", \"In vivo junctional phenotype not examined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that USP47 deubiquitylates β-catenin to promote Wnt signaling, conserved from Drosophila to mammals, placed USP47 as a positive Wnt pathway regulator and revealed β-TrCP-mediated autoregulation of USP47 ubiquitination.\",\n      \"evidence\": \"RNAi screen, Wnt reporter assays, in vivo Drosophila wing phenotypes, ubiquitination assays\",\n      \"pmids\": [\"26169834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP47 acts at the destruction complex or downstream was not distinguished at this stage\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Systematic epistasis screening in Drosophila revealed that USP47 counteracts the N-end rule pathway (UBC6/POE-UBR4/KCMF1) to maintain MAPK protein levels, establishing USP47 as a post-translational stabilizer of RAS–MAPK signaling output.\",\n      \"evidence\": \"RNAi genetic interaction screen, epistasis analysis, and MAPK stability assays in Drosophila\",\n      \"pmids\": [\"27552662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian validation of the N-end rule mechanism for MAPK was not provided\", \"Identity of the specific MAPK ubiquitin chain type was not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Pharmacological and genetic evidence that USP47 (together with USP7) deubiquitylates NLRP3 and is required for ASC speck formation extended USP47's roles to innate immune inflammasome regulation.\",\n      \"evidence\": \"USP7/USP47 inhibitor, CRISPR knockdown in THP-1 macrophages, ASC oligomerization and IL-1β/IL-18 release assays\",\n      \"pmids\": [\"30206189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contributions of USP7 versus USP47 were not fully separated\", \"Direct deubiquitylation of ASC by USP47 was not reconstituted in vitro\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies expanded USP47's substrate repertoire to include SATB1 (stabilized for colon cancer transcription programs) and revealed that ERAP1 competes with β-TrCP for USP47 binding to modulate Hedgehog signaling, uncovering a protein-competition regulatory mechanism.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, xenograft models (SATB1); CRISPR/siRNA, protein stability assays, tumor models (ERAP1–β-TrCP–USP47)\",\n      \"pmids\": [\"30742943\", \"31341163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for ERAP1 displacement of β-TrCP from USP47 remains unknown\", \"Whether ERAP1 regulation of USP47 operates outside Hedgehog-driven tumors\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of RPL11 deubiquitylation by USP47 connected USP47 to the ribosomal stress–MDM2–p53 axis, demonstrating that USP47 prevents RPL11 nucleolar-to-nucleoplasmic translocation and thereby suppresses p53 activation under basal conditions.\",\n      \"evidence\": \"Catalytic-dead mutant analysis, ubiquitination assays, p53 pathway reporters, miR-101-3p transfection\",\n      \"pmids\": [\"32370049\", \"35205710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP47 acts on other ribosomal stress sensors\", \"In vivo validation of the RPL11–p53 axis via Usp47 knockout\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that USP47 stabilizes IK (spliceosomal component) to maintain proper ATM pre-mRNA splicing linked USP47 for the first time to RNA processing and the DNA damage response via a splicing intermediate.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, RT-PCR splicing analysis, siRNA knockdown\",\n      \"pmids\": [\"32377397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding; independent replication needed\", \"Whether USP47 regulates splicing of transcripts beyond ATM\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"USP47 stabilization of YBX1 in CML cells, with Usp47 knockout significantly inhibiting CML driven by BCR-ABL and the T315I gatekeeper mutant in mice, established USP47 as a therapeutic vulnerability in drug-resistant leukemia.\",\n      \"evidence\": \"Usp47 knockout mice, BCR-ABL CML model, shRNA/siRNA, Lin⁻Sca1⁺c-Kit⁺ stem cell analysis\",\n      \"pmids\": [\"33397955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP47 inhibition is tolerated long-term in vivo\", \"Whether YBX1 is the sole CML-relevant substrate\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Crystal structures of free and ubiquitin-bound USP47 catalytic domain resolved the activation mechanism: the catalytic triad is misaligned until ubiquitin binding induces conformational rearrangement, explaining substrate-dependent activation analogous to USP7.\",\n      \"evidence\": \"X-ray crystallography (free and Ub-bound forms), in vitro DUB activity assays comparing full-length vs. catalytic domain\",\n      \"pmids\": [\"37740002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of full-length USP47 with regulatory domains\", \"Structural basis for substrate selectivity beyond BL loop differences not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reconstituted in vitro deubiquitylation of TLE3 by USP47, counteracting XIAP-mediated monoubiquitylation, definitively placed USP47 downstream of the β-catenin destruction complex in Wnt signaling and resolved the earlier ambiguity about its pathway position.\",\n      \"evidence\": \"In vitro deubiquitylation assay, genome-scale RNAi screen, Xenopus/Drosophila/human cell Wnt reporter validation\",\n      \"pmids\": [\"36749823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether β-catenin and TLE3 deubiquitylation are independent or coordinated events\", \"Quantitative contribution of USP47 versus other Wnt-regulatory DUBs in vivo\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that USP47 deubiquitylates YTHDF1 to attenuate m6A-dependent c-Myc translation in regulatory T cells revealed a non-degradative function—modifying reader-protein interactions—and linked USP47 to Treg metabolic fitness and immune homeostasis.\",\n      \"evidence\": \"Treg-specific conditional knockout mice, polyribosome profiling, ubiquitination assays, metabolic assays\",\n      \"pmids\": [\"37788092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether USP47 regulation of YTHDF1 extends to other m6A targets beyond c-Myc\", \"Ubiquitin chain type on YTHDF1 not specified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that USP47 removes K63-linked polyubiquitin from TRAF3 and TRAF6 to dampen type I interferon signaling identified USP47 as a negative regulator of antiviral innate immunity, extending its chain-type specificity beyond K48.\",\n      \"evidence\": \"K63-linkage-specific ubiquitination assays, dual-luciferase ISRE/IFN-β reporters, overexpression/knockdown in virus infection models\",\n      \"pmids\": [\"37001379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo viral challenge in Usp47 knockout mice not performed\", \"Direct in vitro cleavage of K63 chains not reconstituted\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for how full-length USP47's non-catalytic domains regulate activity and substrate selection; the physiological hierarchy among its many reported substrates in different tissues; and whether selective USP47 inhibitors can achieve therapeutic windows in cancer and immune disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length USP47 structure available\", \"No systematic comparison of substrate affinities\", \"No clinical-stage USP47 inhibitor with characterized selectivity\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 9, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 7, 12, 14, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 15, 19, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 18, 19]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"BTRC\",\n      \"POLB\",\n      \"KATNA1\",\n      \"CTNNB1\",\n      \"TLE3\",\n      \"YTHDF1\",\n      \"YBX1\",\n      \"RPL11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}