{"gene":"OTUD7B","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2010,"finding":"Cezanne/OTUD7B is the first deubiquitinase identified with preferential specificity for Lys11-linked ubiquitin chains. Crystallographic and NMR analyses of Lys11-linked diubiquitin revealed compact conformations with exposed Ile44, and in vitro assays demonstrated Cezanne's Lys11-linkage preference.","method":"In vitro DUB activity assay, X-ray crystallography, NMR spectroscopy","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus NMR plus in vitro biochemical assay, replicated across multiple orthogonal methods in one rigorous study","pmids":["20622874"],"is_preprint":false},{"year":2016,"finding":"Crystal structures of Cezanne alone, in complex with monoubiquitin, and in complex with Lys11-linked diubiquitin reveal the molecular basis of Lys11-linkage specificity: ubiquitin-assisted conformational changes activate the enzyme, all chain types interact with the S1 site, but only Lys11-linked chains can bind productively across the active site to stimulate catalytic turnover.","method":"X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, in vitro DUB activity assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures combined with HDX-MS and enzymatic assays, rigorous mechanistic dissection in one study","pmids":["27732584"],"is_preprint":false},{"year":2008,"finding":"Cezanne/OTUD7B suppresses canonical NF-κB activation downstream of TNF receptor signaling by deubiquitinating RIP1, reducing polyubiquitinated RIP1 at activated TNFRs. The catalytic cysteine (Cys209) is essential for this activity, as the C209 mutant loses NF-κB suppression. Cezanne is induced by TNFα, forming a negative feedback loop.","method":"siRNA knockdown, NF-κB luciferase reporter, overexpression with catalytic mutant, Co-IP, RIP1 ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, catalytic-mutant rescue, reporter assay, and loss-of-function in one study","pmids":["18178551"],"is_preprint":false},{"year":2013,"finding":"OTUD7B is a pivotal regulator of the non-canonical NF-κB pathway. In response to non-canonical NF-κB stimuli, OTUD7B binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant non-canonical NF-κB activation. OTUD7B deficiency in mice causes hyperactivation of non-canonical NF-κB without affecting canonical NF-κB.","method":"Mouse knockout, Co-IP, ubiquitination assay, NF-κB signaling readouts, genetic epistasis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout mouse model plus Co-IP plus ubiquitination assay, multiple orthogonal methods","pmids":["23334419"],"is_preprint":false},{"year":2017,"finding":"OTUD7B removes K63-linked polyubiquitin chains from GβL (MLST8), preventing GβL interaction with SIN1 that would disrupt mTORC2 assembly. TRAF2 E3 ligase promotes K63-linked polyubiquitination of GβL to favor mTORC1, while OTUD7B deubiquitinates GβL to promote GβL–SIN1 interaction and mTORC2 formation. Genetic deletion of Otud7b in mice suppresses AKT activation and Kras-driven lung tumorigenesis.","method":"Co-IP, ubiquitination assay, mouse genetic knockout, in vivo tumorigenesis model, site-directed mutagenesis (GβL K305R/K313R)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo mouse models, mutagenesis, multiple orthogonal methods replicated across human and mouse","pmids":["28489822"],"is_preprint":false},{"year":2016,"finding":"Otud7b facilitates TCR signaling by deubiquitinating Zap70 upon TCR ligation, preventing association of Zap70 with negative-regulatory phosphatases Sts1 and Sts2. Otud7b deficiency attenuates Zap70 activation and downstream pathways, impairing T cell activation and rendering mice refractory to T cell-mediated autoimmune responses.","method":"Mouse knockout, Co-IP, ubiquitination assay, T cell activation assays, autoimmune disease model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout, Co-IP, ubiquitination assay, and disease phenotype with mechanistic pathway placement","pmids":["26903241"],"is_preprint":false},{"year":2011,"finding":"Cezanne-1/OTUD7B deubiquitinates EGFR, opposing CBL-mediated receptor ubiquitination and degradation, thereby enhancing EGFR signaling. Physical interaction between Cezanne-1 and EGFR was demonstrated, and EGFR transphosphorylates Cezanne-1. Both the catalytic and ubiquitin-binding domains of Cezanne-1 are required for these functions.","method":"RNA interference screen, Co-IP, ubiquitination assay, domain deletion/mutation analysis, EGFR degradation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, domain mutagenesis, ubiquitination assay, multiple orthogonal methods in one study","pmids":["22179831"],"is_preprint":false},{"year":2014,"finding":"Cezanne/OTUD7B regulates HIF-1α protein stability in a proteasome-independent manner dependent on the tumor suppressor pVHL, with hydroxylase activity dispensable. Loss of Cezanne decreases HIF-1α protein levels and target gene expression; data suggest chaperone-mediated autophagy as the degradation route when Cezanne is absent.","method":"siRNA knockdown, HIF-1α protein stability assay, inhibitor treatment (proteasome, hydroxylase), HIF-1α target gene expression","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, loss-of-function with mechanistic pathway exclusion, but no direct biochemical reconstitution of the Cezanne–HIF-1α interaction","pmids":["25355043"],"is_preprint":false},{"year":2015,"finding":"Cezanne/OTUD7B regulates HIF2α expression in an E2F1-dependent transcriptional manner: Cezanne controls the stability of the transcription factor E2F1, which directly drives HIF2α (EPAS1) promoter activity. Exogenous E2F1 rescues HIF2α transcript and protein when Cezanne is depleted.","method":"siRNA knockdown, rescue experiment with exogenous E2F1, qRT-PCR, promoter reporter assay, protein stability assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus rescue plus promoter assay, single lab but multiple orthogonal methods","pmids":["26148512"],"is_preprint":false},{"year":2013,"finding":"Cezanne/OTUD7B is induced in endothelial cells by hypoxia via p38 MAPK-dependent transcriptional and post-transcriptional mechanisms, and it suppresses NF-κB activation by deubiquitinating TRAF6 (removing Lys63-linked polyubiquitin). Genetic deletion of Cezanne in mice enhances renal inflammation and injury after ischemia-reperfusion.","method":"siRNA knockdown, mouse genetic knockout, TRAF6 ubiquitination assay, NF-κB activation assay, ischemia-reperfusion model","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout mouse model, TRAF6 ubiquitination assay, NF-κB readouts, multiple methods across in vitro and in vivo","pmids":["23564640"],"is_preprint":false},{"year":2018,"finding":"Cezanne/OTUD7B is a cell cycle-regulated DUB that antagonizes APC/C-mediated ubiquitination of mitotic substrates. Cezanne is specifically active against K11-linked ubiquitin chains formed by APC/C, binds APC/C substrates, and reverses their ubiquitination. Cezanne depletion accelerates APC/C substrate degradation and causes mitotic errors and micronuclei formation.","method":"siRNA depletion, ubiquitination assays, Co-IP with APC/C substrates, cell cycle analysis, microscopy for micronuclei","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple APC/C substrate interactions confirmed by Co-IP, K11-chain specificity assay, loss-of-function with defined mitotic phenotype, multiple orthogonal methods","pmids":["29973362"],"is_preprint":false},{"year":2019,"finding":"Cezanne/OTUD7B promotes recruitment of the Rap80/BRCA1-A complex to DNA damage sites by acting as a 'reader' of Lys63-linked polyubiquitin (via its UBA domain) and an 'eraser' of Lys11-linked ubiquitination (via its DUB activity). Its UBA domain selectively binds Lys63-linked chains; loss of Cezanne DUB activity increases Lys11 ubiquitination and impairs Rap80/BRCA1-A recruitment, Rad18, and 53BP1 recruitment.","method":"Ubiquitin-binding domain protein array screen, Co-IP, ubiquitination assay, ionizing radiation sensitivity assay, DNA repair assay","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitin-binding domain array plus Co-IP plus functional DNA repair assays, single lab","pmids":["31699778"],"is_preprint":false},{"year":2020,"finding":"The N-terminal UBA domain of Cezanne/OTUD7B binds Lys63-linked polyubiquitin chains via Leu9 and Ser10 residues, and this binding is required for recruitment of Cezanne to the activated TNFR complex to suppress RIP1 polyubiquitination and NF-κB activation. Mutations at these UBA residues disrupt TNFR complex recruitment and dramatically reduce NF-κB inhibition.","method":"UBA domain truncation and point mutagenesis, Co-IP, ubiquitin-binding assay, NF-κB reporter assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with defined binding residues plus Co-IP plus reporter, single lab","pmids":["28817177"],"is_preprint":false},{"year":2020,"finding":"FIH1 (factor inhibiting HIF1) hydroxylates Asn35 within the N-terminal UBA-like domain of Cezanne in an oxygen-dependent manner, and this hydroxylation inhibits ubiquitin binding by UBACez. The UBACez domain binds Lys11-, Lys48-, Lys63-, and Met1-linked ubiquitin chains in vitro via a noncanonical surface, linking oxygen sensing to Cezanne substrate recruitment.","method":"Mass spectrometry identification of hydroxylation, in vitro ubiquitin-binding assay, mutagenesis, oxygen-dependent FIH1 assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct identification of PTM site, in vitro ubiquitin-binding reconstitution, mutagenesis, and FIH1 hydroxylation assay in one study","pmids":["31937588"],"is_preprint":false},{"year":2010,"finding":"DJ-1 (Park7) physically interacts with Cezanne/OTUD7B and inhibits its deubiquitinating activity. The interaction maps to the N-terminal 70 residues of DJ-1 and leads to enhanced NF-κB activation and increased cell survival, opposing Cezanne's negative regulatory role on NF-κB.","method":"Mass spectrometry, Co-IP of endogenous proteins, DUB activity assay, NF-κB nuclear translocation assay, mouse Park7-/- primary cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous Co-IP, DUB activity assay, genetic validation in knockout cells, single lab","pmids":["21097510"],"is_preprint":false},{"year":2022,"finding":"OTUD7B acts as a negative regulator of antiviral innate immunity by promoting IRF3 selective autophagic degradation. Mechanistically, OTUD7B interacts with IRF3 and deubiquitinates SQSTM1/p62 at K7 (removing K63-linked chains), enhancing SQSTM1 oligomerization to function as a cargo receptor for IRF3 autophagic degradation.","method":"Co-IP, ubiquitination assay (K63-chain removal), autophagy flux assay, siRNA knockdown, viral infection model","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific ubiquitination (K7) identification, loss-of-function, single lab with multiple methods","pmids":["35100065"],"is_preprint":false},{"year":2021,"finding":"OTUD7B deubiquitinates LSD1 at K226/K277 residues (K63-linked ubiquitin chains), controlling LSD1 binding partner specificity and stability. OTUD7B deficiency increases K63-linked ubiquitination of LSD1, disrupting the LSD1/CoREST complex and targeting LSD1 for p62-mediated proteolysis, impairing genome-wide LSD1 occupancy and promoting H3K4/H3K9 methylation changes that abrogate breast cancer metastasis.","method":"Co-IP, K63-ubiquitination assay with site-specific mutants (K226R/K277R), chromatin immunoprecipitation, ChIP-seq, cell invasion assay, xenograft","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific ubiquitination identification, Co-IP, ChIP-seq, in vivo model, single lab","pmids":["34050636"],"is_preprint":false},{"year":2021,"finding":"OTUD7B interacts with, deubiquitinates, and stabilizes estrogen receptor α (ERα) in a catalytic-activity-dependent manner, preventing ERα degradation. OTUD7B depletion decreases ERα protein level, ERα target gene expression, and ERα-positive breast cancer cell proliferation; overexpression of ERα rescues the OTUD7B-depletion phenotype.","method":"Co-IP, ubiquitination assay, rescue experiment with ERα overexpression, cell proliferation assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, rescue experiment, single lab","pmids":["34035221"],"is_preprint":false},{"year":2020,"finding":"OTUD7B directly binds to TRAF3 and deubiquitinates it via its OTU domain, inhibiting TRAF3 proteolysis and preventing NIK accumulation and non-canonical NF-κB pathway activation. A catalytic mutant (C194S/H358R) of OTUD7B fails to suppress LCL161-induced lung cancer cell invasion and migration, confirming that DUB activity is required.","method":"Co-IP, ubiquitination assay, luciferase reporter, shRNA silencing, overexpression of OTU catalytic mutant, in vivo metastasis model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, catalytic mutant validation, ubiquitination assay, in vivo model, single lab","pmids":["33198776"],"is_preprint":false},{"year":2019,"finding":"Reactive oxygen species (ROS) inactivate Cezanne/OTUD7B by oxidizing its catalytic cysteine residue, as demonstrated using ubiquitin-derived thiol-reactive probes (HA-UbVME) and a biotin-tagged cysteine-reactive probe (DCP-Bio1). DTT reactivates Cezanne activity, linking ROS-mediated cysteine oxidation to prolonged NF-κB activation in hepatocellular carcinoma cells.","method":"Activity-based probe assay (HA-UbVME), DCP-Bio1 biotin-cysteine probe, DTT reactivation assay, NF-κB reporter","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — activity-based probe assay confirming catalytic cysteine oxidation, single lab, single study","pmids":["31072419"],"is_preprint":false},{"year":2023,"finding":"OTUD7B interacts with and deubiquitinates YAP1, stabilizing it and promoting its transcriptional activity, including upregulation of NUAK2 and other YAP1 target genes, thereby accelerating gastric cancer progression.","method":"Co-IP, ubiquitination assay, xenograft model, qPCR of target genes","journal":"Digestive and liver disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, limited mechanistic detail in abstract","pmids":["37429790"],"is_preprint":false},{"year":2022,"finding":"Cezanne/OTUD7B drives vascular smooth muscle cell (VSMC) proliferation by deubiquitinating β-catenin, promoting β-catenin-dependent CCN1 expression. Wild-type but not catalytically inactive Cezanne (C209S mutant) increases VSMC proliferative ability and mobility. Global Cezanne deletion in mice reduced atherosclerotic plaque size but with reduced plaque stability.","method":"Overexpression of wild-type vs. C209S catalytic mutant, RNA-sequencing, Co-IP, mouse knockout, arterial injury model","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant comparison, RNA-seq, Co-IP, in vivo mouse model, single lab","pmids":["33599243"],"is_preprint":false},{"year":2023,"finding":"OTUD7B stabilizes TRAF2 in dendritic cells by removing K48-linked ubiquitin chains from TRAF2, preventing its proteasomal degradation. TRAF2 in turn facilitates K63-linked polyubiquitination of RIPK1, activating NF-κB and MAP kinases, IL-12 production, and anti-apoptotic gene expression. DC-specific OTUD7B deficiency causes DC apoptosis and failure to prime CD8+ T cells in a malaria infection model.","method":"Co-IP, K48-ubiquitination assay, DC-specific knockout mouse, infection model, NF-κB/MAPK signaling assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — DC-specific knockout mouse, Co-IP, linkage-specific ubiquitination assay, in vivo infection model, multiple orthogonal methods","pmids":["37516734"],"is_preprint":false},{"year":2020,"finding":"OTUD7B deubiquitinates KLF4, preventing its degradation and maintaining KLF4 protein levels in vascular smooth muscle cells. OTUD7B downregulation by plant-derived miRNAs (Sal-miR-1 and 3) reduces KLF4 deubiquitylation, leading to decreased KLF4 and increased NMHC IIA expression, promoting VSMC contractile phenotype and suppressing migration.","method":"Co-IP, ubiquitination assay, luciferase assay, ChIP, western blotting, carotid artery ligation model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP, in vivo vascular model, single lab","pmids":["32685020"],"is_preprint":false},{"year":2023,"finding":"Cezanne/OTUD7B stabilizes PIK3C3 (VPS34) by deubiquitinating K48-linked ubiquitination at Lysine 322, promoting autophagy. Additionally, Cezanne upregulates PIK3C2A transcription in a POLR2A-dependent manner as a compensatory PI3P-generating mechanism, and accelerates EGFR recycling, contributing to Osimertinib resistance in lung adenocarcinoma.","method":"Ubiquitination assay (K48, site-specific K322), Co-IP, POLR2A knockdown, autophagy flux assay, drug resistance assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific ubiquitination at K322 identified, Co-IP, functional autophagy assay, single lab","pmids":["37596251"],"is_preprint":false},{"year":2025,"finding":"OTUD7B deubiquitinates p53 (removing Mdm2-mediated and other K-linked polyubiquitin chains), stabilizing p53 and suppressing proteasomal degradation. OTUD7B overexpression suppresses HCC growth in cultures and xenografts through p53-dependent mitochondrial apoptosis (PUMA and BAX induction). OTUD7B expression is transcriptionally repressed via p53-dependent mechanisms, forming a mutual feedback loop.","method":"Mass spectrometry pulldown, Co-IP (endogenous, ectopic, mutant forms), ubiquitination assay, luciferase reporter, ChIP, shRNA knockdown, CRISPR-Cas9 knockout, xenograft","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including CRISPR knockout, Co-IP, ChIP, ubiquitination assay, and in vivo xenograft, single lab","pmids":["39990225"],"is_preprint":false},{"year":2023,"finding":"OTUD7B interacts with LEF1 through its UBA domain (interacting with LEF1's HMG domain) and promotes nuclear localization of LEF1, increasing LEF1–β-catenin interaction in the nucleus and activating Wnt target gene transcription. OTUD7B overexpression upregulates ~75% of tested Wnt target genes.","method":"DUB library screen, Co-IP with domain mutants, nuclear/cytoplasmic fractionation, qPCR array","journal":"Biomolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP with domain mapping and fractionation, single lab, limited mechanistic depth in abstract","pmids":["37371581"],"is_preprint":false},{"year":2024,"finding":"OTUD7B interacts with FOXM1 and reduces its polyubiquitylation, stabilizing FOXM1 protein in breast cancer cells. OTUD7B knockdown decreases FOXM1 protein and FOXM1 overexpression rescues the inhibitory effects of OTUD7B knockdown on breast cancer cell proliferation and stemness.","method":"Co-IP, ubiquitination assay, rescue experiment with FOXM1 overexpression, cell proliferation/sphere assays","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay, rescue experiment, single lab, single study","pmids":["38298430"],"is_preprint":false},{"year":2025,"finding":"BRCA1 protein stability is regulated in a cell cycle-dependent manner through K11-linked ubiquitination by APC/C (with Cdh1 recognizing a BRCA1 degron) and the E2 Ube2S, while Cezanne/OTUD7B counteracts this by removing K11-linked ubiquitin from BRCA1. Cezanne deficiency leads to increased BRCA1 K11-ubiquitination, decreased BRCA1 protein level, and increased cellular sensitivity to PARP inhibitors.","method":"Ubiquitination assay (K11-linkage specific), cell cycle analysis, PARP inhibitor sensitivity assay, genetic depletion of Cezanne/Ube2S/APC/C components","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — linkage-specific ubiquitination assay, genetic epistasis with APC/C-Cdh1 and Ube2S, functional drug sensitivity readout, single study","pmids":["41359628"],"is_preprint":false},{"year":2024,"finding":"OTUD7B interacts with and deubiquitinates VEGFA, stabilizing it and promoting vascular mimicry in non-small cell lung cancer. OTUD7B knockdown increases VEGFA ubiquitination and reduces VEGFA protein levels, suppressing vascular mimicry.","method":"Co-IP, ubiquitination assay, tube formation/vascular mimicry assay, luciferase reporter (miR-491-5p target site), xenograft","journal":"The journal of gene medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, functional context established but mechanistic depth limited","pmids":["39376029"],"is_preprint":false},{"year":2025,"finding":"OTUD7B stabilizes HNF4α by removing K48-linked ubiquitin chains, preventing its proteasomal degradation. OTUD7B-HNF4α interaction regulates fatty acid oxidation-related gene expression and suppresses ferroptosis and cardiac hypertrophy in response to pressure overload.","method":"Co-IP, K48-ubiquitination assay, transcriptome analysis, cardiomyocyte-specific knockout/overexpression, TAC mouse model","journal":"Biomarker research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K48-linkage-specific ubiquitination assay, in vivo cardiomyocyte-specific models, single lab","pmids":["40158182"],"is_preprint":false},{"year":2024,"finding":"OTUD7B deubiquitinates β-catenin by removing K48-linked ubiquitin chains, preventing its proteasomal degradation and activating β-catenin/Wnt signaling in hepatocytes. OTUD7B overexpression reduces hepatic lipid deposition and inflammation in NAFLD mouse models, with NR4A2 identified as a transcriptional regulator of OTUD7B.","method":"Co-IP, K48-ubiquitination assay, TopFlash reporter, adenoviral overexpression in NAFLD mouse model, ChIP-seq data analysis","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination assay, reporter assay, in vivo model, single lab","pmids":["39520879"],"is_preprint":false},{"year":2025,"finding":"OTUD7B restricts TNF-induced NF-κB and MAPK activation in astrocytes through sequential K63- and K48-deubiquitination of RIPK1. Additionally, OTUD7B prevents proteasomal degradation of GFAP through K48-deubiquitination of GFAP. In EAE (MS model), astrocytic OTUD7B deficiency increases chemokine expression and CD4+ T cell recruitment to inflammatory lesions.","method":"RNA-sequencing of isolated astrocytes, spatial transcriptomics, Co-IP, K63/K48-ubiquitination assays, astrocyte-specific knockout mouse, EAE model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — astrocyte-specific knockout, linkage-specific ubiquitination assays for two distinct substrates, spatial transcriptomics, multiple orthogonal methods, in vivo disease model","pmids":["41115891"],"is_preprint":false},{"year":2025,"finding":"OTUD7B deubiquitinates SERCA2a by removing K63-linked ubiquitin at K628 through its catalytic site C194, promoting SERCA2a–phospholamban (PLN) interaction and restricting SERCA2a activity in Ca2+ handling, thereby driving hypertrophic response in cardiomyocytes. Cardiomyocyte-specific OTUD7B deletion mitigated, while overexpression exacerbated, cardiac hypertrophy in Ang II and TAC models.","method":"Quantitative ubiquitinome analysis, site-directed mutagenesis (K628, C194), Co-IP, cardiomyocyte-specific knockout and overexpression mouse models, TAC/Ang II models","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — quantitative ubiquitinome, site-directed mutagenesis identifying catalytic site and substrate ubiquitination site, Co-IP, in vivo cardiomyocyte-specific models, multiple orthogonal methods","pmids":["41695487"],"is_preprint":false},{"year":2025,"finding":"β-hydroxybutyrylation of OTUD7B at lysine 511 impairs its DUB activity toward APC/C substrates, resulting in impaired APC/C substrate degradation, reduced cytoplasmic double-stranded DNA accumulation, and attenuated cGAS-STING activation, contributing to immune suppression in enzalutamide-resistant prostate cancer.","method":"β-hydroxybutyrylation identification (mass spectrometry implied), APC/C substrate degradation assay, cGAS-STING pathway readout, cell line and in vivo models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — site-specific PTM identification (K511), functional DUB activity readout, single lab, limited mechanistic reconstitution detail in abstract","pmids":["40393641"],"is_preprint":false},{"year":2025,"finding":"OTUD7B deubiquitinates Lox-1, preventing its ubiquitin-mediated degradation and stabilizing Lox-1 protein in macrophages (THP-1 and U937 cells). OTUD7B knockdown reduces Lox-1 levels and impairs oxLDL uptake; Lox-1 overexpression rescues oxLDL uptake in OTUD7B-deficient cells.","method":"Co-IP, ubiquitination assay, oxLDL uptake assay, siRNA knockdown, rescue experiment","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay with rescue, single lab, single study","pmids":["40294697"],"is_preprint":false},{"year":2024,"finding":"OTUD7B suppresses cone photoreceptor degeneration in retinal degenerative disease models by downregulating NF-κB activity. Otud7b knockout mice showed increased cone degeneration under light-induced damage, dry AMD, and RP models; inhibition of NF-κB attenuated this degeneration.","method":"Otud7b knockout mouse models, RNA-sequencing, luciferase reporter (NF-κB activity), NF-κB inhibitor treatment, light-induced damage and RP disease models","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout models, luciferase reporter, NF-κB inhibitor rescue, single lab","pmids":["38510130"],"is_preprint":false}],"current_model":"OTUD7B/Cezanne is a Lys11-linkage-preferring OTU family deubiquitinase that regulates multiple signaling pathways by deubiquitinating a diverse set of substrates—including RIP1, TRAF3, TRAF6, TRAF2, GβL, Zap70, LSD1, ERα, HIF-1α, E2F1, EGFR, IGF-1R, SQSTM1/p62, IRF3, β-catenin, HNF4α, SERCA2a, BRCA1, GFAP, p53, and others—using a catalytic cysteine that can be inactivated by ROS oxidation, with substrate recruitment mediated by a UBA domain that binds Lys63-linked chains and is regulated by oxygen-dependent FIH1-mediated asparagine hydroxylation; through these activities OTUD7B controls canonical and non-canonical NF-κB signaling, mTORC2 assembly and AKT activation, TCR signaling, APC/C-dependent mitotic progression, DNA damage response, antiviral innate immunity, HIF-dependent hypoxia responses, and Wnt/cell cycle signaling."},"narrative":{"mechanistic_narrative":"OTUD7B (Cezanne) is an OTU-family deubiquitinase that serves as a master rheostat for ubiquitin-dependent signaling, acting both as a Lys11-linkage-preferring catalytic eraser and as a Lys63-chain reader [PMID:20622874, PMID:27732584, PMID:31699778]. Structural and biochemical analyses establish its defining biochemistry: it was the first DUB shown to preferentially cleave Lys11-linked chains, and crystal structures with mono- and Lys11-diubiquitin reveal that ubiquitin-assisted conformational changes activate the enzyme while only Lys11 chains engage productively across the active site to drive turnover [PMID:20622874, PMID:27732584]. Its activity is gated by oxygen and redox state: FIH1 hydroxylates Asn35 in the N-terminal UBA-like domain to inhibit ubiquitin binding, and ROS oxidation of the catalytic cysteine reversibly inactivates the enzyme [PMID:31937588, PMID:31072419]. In inflammatory signaling, OTUD7B restrains both NF-κB arms—deubiquitinating RIP1 and TRAF6 to suppress canonical NF-κB, and stabilizing TRAF3 to prevent aberrant non-canonical NF-κB activation [PMID:18178551, PMID:23564640, PMID:23334419, PMID:33198776]. Recruitment to the activated TNFR complex depends on its UBA domain binding Lys63 chains via Leu9/Ser10 [PMID:28817177]. Beyond inflammation, OTUD7B controls mTORC2 assembly and AKT activation by removing K63 chains from GβL, facilitates TCR signaling by deubiquitinating Zap70, and antagonizes APC/C-mediated K11 ubiquitination of mitotic substrates to safeguard faithful mitosis [PMID:28489822, PMID:26903241, PMID:29973362]. It functions in the DNA damage response as both a Lys63 reader and Lys11 eraser to promote Rap80/BRCA1-A recruitment, and counteracts APC/C-Cdh1/Ube2S-driven K11 ubiquitination of BRCA1 to maintain genome stability and PARP-inhibitor resistance [PMID:31699778, PMID:41359628]. Through substrate deubiquitination it further stabilizes a broad set of regulators including HIF-1α, E2F1, ERα, LSD1, β-catenin, HNF4α, SERCA2a, and p53, linking it to hypoxia responses, transcriptional control, Wnt signaling, cardiac remodeling, and p53-dependent apoptosis [PMID:25355043, PMID:26148512, PMID:34050636, PMID:34035221, PMID:33599243, PMID:39990225, PMID:40158182, PMID:41695487].","teleology":[{"year":2008,"claim":"Established OTUD7B's first signaling role: whether a DUB could negatively feed back on TNF-induced NF-κB was unknown, and Cezanne was shown to deubiquitinate RIP1 to dampen canonical NF-κB in a catalytic-cysteine-dependent manner.","evidence":"siRNA knockdown, NF-κB reporter, catalytic mutant (C209) rescue, RIP1 ubiquitination assay","pmids":["18178551"],"confidence":"High","gaps":["Did not define the chain linkage removed from RIP1","Recruitment mechanism to the TNFR complex unresolved at this stage"]},{"year":2010,"claim":"Defined the enzyme's core biochemical identity: the linkage specificity of OTU DUBs was poorly mapped, and Cezanne was identified as the first DUB with preferential Lys11-chain activity.","evidence":"In vitro DUB assays, X-ray crystallography and NMR of Lys11-diubiquitin","pmids":["20622874"],"confidence":"High","gaps":["Did not yet explain structurally how Lys11 selectivity is achieved at the active site","Physiological Lys11 substrates not identified"]},{"year":2010,"claim":"Identified the first endogenous regulator of Cezanne activity: DJ-1 (Park7) was shown to bind and inhibit Cezanne DUB activity, thereby enhancing NF-κB and cell survival.","evidence":"Mass spectrometry, endogenous Co-IP, DUB activity assay, Park7-/- primary cells","pmids":["21097510"],"confidence":"Medium","gaps":["Structural basis of inhibition undefined","Single lab without reciprocal biochemical reconstitution"]},{"year":2013,"claim":"Extended Cezanne to receptor signaling control: it was unknown how EGFR ubiquitination is reversed, and Cezanne was found to oppose CBL-mediated EGFR ubiquitination and degradation, requiring both catalytic and ubiquitin-binding domains.","evidence":"RNAi screen, Co-IP, ubiquitination assay, domain mutagenesis, EGFR degradation assay","pmids":["22179831"],"confidence":"High","gaps":["Chain linkage removed from EGFR not defined","Functional consequence of EGFR-mediated transphosphorylation of Cezanne unclear"]},{"year":2013,"claim":"Established OTUD7B as a non-redundant brake on the non-canonical NF-κB pathway, distinguishing it from canonical regulation, by stabilizing TRAF3 against proteolysis.","evidence":"Otud7b knockout mice, Co-IP, ubiquitination assay, NF-κB readouts, genetic epistasis","pmids":["23334419"],"confidence":"High","gaps":["Stimulus-dependent recruitment to TRAF3 not detailed","Chain linkage on TRAF3 not specified here"]},{"year":2013,"claim":"Connected Cezanne to hypoxic and inflammatory responses: hypoxia induces Cezanne via p38 MAPK, and it deubiquitinates TRAF6 (K63 removal) to suppress NF-κB, protecting against renal ischemia-reperfusion injury.","evidence":"siRNA, Otud7b knockout mice, TRAF6 ubiquitination assay, NF-κB assay, IR injury model","pmids":["23564640"],"confidence":"High","gaps":["Direct TRAF6 binding interface not mapped","Relative contribution of transcriptional vs post-transcriptional induction unresolved"]},{"year":2014,"claim":"Linked Cezanne to HIF biology: it regulates HIF-1α stability through a proteasome-independent, pVHL-dependent route, with hydroxylase activity dispensable.","evidence":"siRNA, HIF-1α stability assays, proteasome/hydroxylase inhibitors, target gene expression","pmids":["25355043"],"confidence":"Medium","gaps":["No direct biochemical reconstitution of a Cezanne–HIF-1α interaction","Chaperone-mediated autophagy route inferred, not directly demonstrated"]},{"year":2015,"claim":"Refined the HIF connection to a transcriptional mechanism: Cezanne controls HIF2α expression indirectly by stabilizing E2F1, which drives the EPAS1 promoter.","evidence":"siRNA, exogenous E2F1 rescue, qRT-PCR, promoter reporter, protein stability assay","pmids":["26148512"],"confidence":"Medium","gaps":["Direct deubiquitination of E2F1 not biochemically resolved","Single-lab study"]},{"year":2016,"claim":"Solved the structural basis of Lys11 selectivity: how a single OTU domain discriminates chain linkage was unknown, and structures with mono- and Lys11-diubiquitin showed all chains bind the S1 site but only Lys11 engages productively across the active site.","evidence":"Multiple crystal structures, HDX-MS, in vitro DUB assays","pmids":["27732584"],"confidence":"High","gaps":["Did not connect structural mechanism to specific cellular Lys11 substrates","Allosteric activation in cells not tested"]},{"year":2016,"claim":"Placed Otud7b in adaptive immunity: it positively regulates TCR signaling by deubiquitinating Zap70, blocking recruitment of inhibitory Sts1/Sts2 phosphatases.","evidence":"Knockout mice, Co-IP, ubiquitination assay, T cell activation and autoimmune models","pmids":["26903241"],"confidence":"High","gaps":["Chain linkage on Zap70 not specified","Direct vs indirect blocking of Sts1/2 association not fully dissected"]},{"year":2017,"claim":"Connected OTUD7B to growth-factor/metabolic signaling: it dictates mTORC2 vs mTORC1 balance by removing K63 chains from GβL, promoting GβL–SIN1 interaction, AKT activation, and Kras-driven tumorigenesis.","evidence":"Co-IP, ubiquitination assay, GβL K305R/K313R mutagenesis, knockout mice, in vivo tumor model","pmids":["28489822"],"confidence":"High","gaps":["Stimulus that triggers GβL deubiquitination not defined","Interplay with TRAF2 ligase in cells partially characterized"]},{"year":2018,"claim":"Defined a cell-cycle role: OTUD7B antagonizes APC/C-generated K11 ubiquitination of mitotic substrates, and its loss accelerates substrate degradation and causes mitotic errors.","evidence":"siRNA, K11-specific ubiquitination assays, Co-IP with APC/C substrates, cell cycle and micronuclei microscopy","pmids":["29973362"],"confidence":"High","gaps":["How Cezanne is restricted to specific APC/C substrates not resolved","Temporal coordination with APC/C activity incompletely mapped"]},{"year":2019,"claim":"Revealed dual reader/eraser function in the DNA damage response: Cezanne reads K63 chains via its UBA domain and erases K11 chains via DUB activity to promote Rap80/BRCA1-A recruitment.","evidence":"Ubiquitin-binding domain array, Co-IP, ubiquitination assay, IR sensitivity, DNA repair assays","pmids":["31699778"],"confidence":"Medium","gaps":["The K11-ubiquitinated DDR substrate(s) not fully identified","Single-lab study"]},{"year":2019,"claim":"Established redox gating of activity: ROS reversibly inactivate Cezanne by oxidizing its catalytic cysteine, prolonging NF-κB signaling.","evidence":"Activity-based probes (HA-UbVME, DCP-Bio1), DTT reactivation, NF-κB reporter","pmids":["31072419"],"confidence":"Medium","gaps":["Physiological ROS thresholds for inactivation not quantified","Single-lab study"]},{"year":2020,"claim":"Mapped the UBA-domain recruitment mechanism: Leu9/Ser10 mediate Lys63-chain binding required to bring Cezanne to the activated TNFR complex and suppress RIP1 ubiquitination.","evidence":"UBA truncation and point mutagenesis, Co-IP, ubiquitin-binding assay, NF-κB reporter","pmids":["28817177"],"confidence":"Medium","gaps":["Structural validation of the binding surface not provided","Single-lab study"]},{"year":2020,"claim":"Defined oxygen-sensing control of substrate recruitment: FIH1 hydroxylates Asn35 in the UBA-like domain to inhibit its noncanonical ubiquitin binding, linking O2 levels to Cezanne function.","evidence":"MS identification of hydroxylation, in vitro ubiquitin-binding reconstitution, mutagenesis, FIH1 assay","pmids":["31937588"],"confidence":"High","gaps":["Cellular consequences of Asn35 hydroxylation on specific substrates not tested","Crosstalk with redox cysteine gating unresolved"]},{"year":2020,"claim":"Extended substrate range into vascular biology and Wnt: OTUD7B deubiquitinates and stabilizes KLF4, regulating VSMC phenotype.","evidence":"Co-IP, ubiquitination assay, ChIP, carotid artery ligation model","pmids":["32685020"],"confidence":"Medium","gaps":["Chain linkage on KLF4 not specified","Single-lab study"]},{"year":2021,"claim":"Identified epigenetic and hormonal substrates: OTUD7B deubiquitinates LSD1 (K63 at K226/K277) controlling complex specificity and metastasis, and stabilizes ERα to support ER-positive breast cancer proliferation.","evidence":"Site-specific ubiquitination mutants, Co-IP, ChIP-seq, invasion/proliferation assays, xenografts","pmids":["34050636","34035221"],"confidence":"Medium","gaps":["Whether ERα and LSD1 regulation are coordinated in the same cells unknown","Single-lab studies"]},{"year":2022,"claim":"Connected OTUD7B to antiviral immunity and vascular proliferation: it promotes IRF3 selective autophagic degradation via deubiquitinating SQSTM1/p62 at K7, and drives β-catenin/CCN1-dependent VSMC proliferation.","evidence":"Co-IP, site-specific (K7) and catalytic-mutant (C209S) ubiquitination assays, autophagy flux, knockout mice, arterial injury model","pmids":["35100065","33599243"],"confidence":"Medium","gaps":["Chain linkage on β-catenin not specified in this context","Whether IRF3 itself is a direct DUB substrate not established"]},{"year":2023,"claim":"Expanded the K48-deubiquitination repertoire and innate immune/Wnt roles: OTUD7B stabilizes TRAF2 (K48 removal) to sustain dendritic-cell survival and CD8+ priming, deubiquitinates VPS34/PIK3C3 to promote autophagy and drug resistance, stabilizes YAP1, and promotes nuclear LEF1–β-catenin to activate Wnt targets.","evidence":"DC-specific knockout, K48-ubiquitination assays, Co-IP with domain mutants, autophagy/drug resistance assays, fractionation, infection and xenograft models","pmids":["37516734","37596251","37429790","37371581"],"confidence":"High","gaps":["YAP1 and LEF1 findings rest on single low-confidence studies","How OTUD7B switches between K48, K63, and K11 substrates not mechanistically unified"]},{"year":2024,"claim":"Added tumor and tissue-protective substrates: OTUD7B stabilizes FOXM1 (breast cancer stemness) and VEGFA (vascular mimicry), and protects cone photoreceptors by downregulating NF-κB.","evidence":"Co-IP, ubiquitination/rescue assays, sphere assays, Otud7b knockout mice with retinal degeneration models, NF-κB inhibitor rescue","pmids":["38298430","39376029","38510130"],"confidence":"Medium","gaps":["FOXM1 and VEGFA links are single low-confidence studies","Substrate(s) deubiquitinated to control retinal NF-κB not identified"]},{"year":2025,"claim":"Consolidated OTUD7B as a stability regulator of major tumor-suppressor and physiological substrates: it deubiquitinates p53 (stabilization, mitochondrial apoptosis, mutual feedback), counteracts APC/C-Cdh1/Ube2S K11 ubiquitination of BRCA1, sequentially K63/K48-deubiquitinates RIPK1 and stabilizes GFAP in astrocytes, stabilizes HNF4α and β-catenin in metabolic disease, and regulates SERCA2a (K63 at K628) in cardiac hypertrophy.","evidence":"MS pulldown, CRISPR knockout, Co-IP, linkage- and site-specific ubiquitination assays, ChIP, ubiquitinome analysis, tissue-specific knockout mice (astrocyte, cardiomyocyte), TAC/Ang II and EAE models, xenografts","pmids":["39990225","41359628","41115891","40158182","39520879","41695487"],"confidence":"High","gaps":["Whether a unifying logic governs linkage choice across these substrates is unresolved","Tissue-specific determinants of substrate selection not defined"]},{"year":2025,"claim":"Showed metabolic PTMs reprogram OTUD7B activity: β-hydroxybutyrylation at K511 impairs DUB activity toward APC/C substrates, blunting cytoplasmic dsDNA accumulation and cGAS-STING activation in therapy-resistant prostate cancer; Lox-1 was also identified as a stabilized substrate in macrophage lipid uptake.","evidence":"PTM site identification, APC/C substrate degradation and cGAS-STING readouts, Co-IP, oxLDL uptake/rescue assays, in vivo models","pmids":["40393641","40294697"],"confidence":"Medium","gaps":["Lox-1 link is a single low-confidence study","How K511 hydroxybutyrylation mechanistically alters catalysis not reconstituted"]},{"year":null,"claim":"It remains unknown what governs OTUD7B's selection among Lys11, Lys48, and Lys63 substrates in a given cell, and how its redox (catalytic cysteine), oxygen (FIH1/Asn35), and metabolic (K511 hydroxybutyrylation) gating mechanisms are integrated to direct activity to specific substrates.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking PTM gating to substrate choice","Most substrate identifications are single-lab and not cross-validated","Structural basis for K48/K63 cleavage versus the established K11 preference not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,4,10]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[13,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16,26]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4,9,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10,28]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[11,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,15,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,4,22,25,30]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[15,24]}],"complexes":[],"partners":["TRAF3","RIPK1","MLST8","ZAP70","EGFR","TRAF2","TRAF6","PARK7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6GQQ9","full_name":"OTU domain-containing protein 7B","aliases":["Cellular zinc finger anti-NF-kappa-B protein","Cezanne","Zinc finger A20 domain-containing protein 1","Zinc finger protein Cezanne"],"length_aa":843,"mass_kda":92.5,"function":"Negative regulator of the non-canonical NF-kappa-B pathway that acts by mediating deubiquitination of TRAF3, an inhibitor of the NF-kappa-B pathway, thereby acting as a negative regulator of B-cell responses (PubMed:18178551). In response to non-canonical NF-kappa-B stimuli, deubiquitinates 'Lys-48'-linked polyubiquitin chains of TRAF3, preventing TRAF3 proteolysis and over-activation of non-canonical NF-kappa-B (By similarity). Negatively regulates mucosal immunity against infections (By similarity). Deubiquitinates ZAP70, and thereby regulates T cell receptor (TCR) signaling that leads to the activation of NF-kappa-B (PubMed:26903241). Plays a role in T cell homeostasis and is required for normal T cell responses, including production of IFNG and IL2 (By similarity). Mediates deubiquitination of EGFR (PubMed:22179831). Has deubiquitinating activity toward 'Lys-11', 'Lys-48' and 'Lys-63'-linked polyubiquitin chains (PubMed:11463333, PubMed:20622874, PubMed:23827681, PubMed:27732584). Has a much higher catalytic rate with 'Lys-11'-linked polyubiquitin chains (in vitro); however the physiological significance of these data are unsure (PubMed:27732584). Hydrolyzes both linear and branched forms of polyubiquitin (PubMed:12682062). Acts as a regulator of mTORC1 and mTORC2 assembly by mediating 'Lys-63'-linked deubiquitination of MLST8, thereby promoting assembly of the mTORC2 complex, while inhibiting formation of the mTORC1 complex (PubMed:28489822)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6GQQ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OTUD7B","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OTUD7B","total_profiled":1310},"omim":[{"mim_id":"612190","title":"MTOR-ASSOCIATED PROTEIN LST8; MLST8","url":"https://www.omim.org/entry/612190"},{"mim_id":"611749","title":"ZINC FINGER RANBP2-TYPE DOMAIN-CONTAINING PROTEIN 1; ZRANB1","url":"https://www.omim.org/entry/611749"},{"mim_id":"611748","title":"OTU DOMAIN-CONTAINING PROTEIN 7B; OTUD7B","url":"https://www.omim.org/entry/611748"},{"mim_id":"601896","title":"TNF RECEPTOR-ASSOCIATED FACTOR 3; TRAF3","url":"https://www.omim.org/entry/601896"},{"mim_id":"601895","title":"TNF RECEPTOR-ASSOCIATED FACTOR 2; TRAF2","url":"https://www.omim.org/entry/601895"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Microtubules","reliability":"Uncertain"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OTUD7B"},"hgnc":{"alias_symbol":["CEZANNE"],"prev_symbol":["ZA20D1"]},"alphafold":{"accession":"Q6GQQ9","domains":[{"cath_id":"1.10.8.10","chopping":"6-47","consensus_level":"high","plddt":89.5314,"start":6,"end":47},{"cath_id":"3.90.70.80","chopping":"104-268_292-439_613-627","consensus_level":"high","plddt":89.1898,"start":104,"end":627},{"cath_id":"-","chopping":"802-836","consensus_level":"medium","plddt":82.8243,"start":802,"end":836}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6GQQ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6GQQ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6GQQ9-F1-predicted_aligned_error_v6.png","plddt_mean":66.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OTUD7B","jax_strain_url":"https://www.jax.org/strain/search?query=OTUD7B"},"sequence":{"accession":"Q6GQQ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6GQQ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6GQQ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6GQQ9"}},"corpus_meta":[{"pmid":"20622874","id":"PMC_20622874","title":"Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne.","date":"2010","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20622874","citation_count":275,"is_preprint":false},{"pmid":"23334419","id":"PMC_23334419","title":"OTUD7B controls non-canonical NF-κB activation through deubiquitination of TRAF3.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23334419","citation_count":196,"is_preprint":false},{"pmid":"18178551","id":"PMC_18178551","title":"NF-kappaB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18178551","citation_count":183,"is_preprint":false},{"pmid":"28489822","id":"PMC_28489822","title":"TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 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is a cell cycle-regulated deubiquitinase that antagonizes the degradation of APC/C substrates.","date":"2018","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/29973362","citation_count":79,"is_preprint":false},{"pmid":"25355043","id":"PMC_25355043","title":"Cezanne (OTUD7B) regulates HIF-1α homeostasis in a proteasome-independent manner.","date":"2014","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/25355043","citation_count":79,"is_preprint":false},{"pmid":"31747939","id":"PMC_31747939","title":"Long noncoding RNA 00976 promotes pancreatic cancer progression through OTUD7B by sponging miR-137 involving EGFR/MAPK pathway.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31747939","citation_count":65,"is_preprint":false},{"pmid":"26148512","id":"PMC_26148512","title":"Cezanne regulates E2F1-dependent HIF2α expression.","date":"2015","source":"Journal of cell 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CR","url":"https://pubmed.ncbi.nlm.nih.gov/33198776","citation_count":37,"is_preprint":false},{"pmid":"31572671","id":"PMC_31572671","title":"Upregulation of OTUD7B (Cezanne) Promotes Tumor Progression via AKT/VEGF Pathway in Lung Squamous Carcinoma and Adenocarcinoma.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31572671","citation_count":37,"is_preprint":false},{"pmid":"28880268","id":"PMC_28880268","title":"Cezanne predicts progression and adjuvant TACE response in hepatocellular carcinoma.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28880268","citation_count":36,"is_preprint":false},{"pmid":"32685020","id":"PMC_32685020","title":"Salvia miltiorrhiza-derived miRNAs suppress vascular remodeling through regulating OTUD7B/KLF4/NMHC IIA 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Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/30874463","citation_count":24,"is_preprint":false},{"pmid":"36351890","id":"PMC_36351890","title":"RHBDL2 promotes the proliferation, migration, and invasion of pancreatic cancer by stabilizing the N1ICD via the OTUD7B and activating the Notch signaling pathway.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36351890","citation_count":24,"is_preprint":false},{"pmid":"34324860","id":"PMC_34324860","title":"Transcranial direct-current stimulation protects against cerebral ischemia-reperfusion injury through regulating Cezanne-dependent signaling.","date":"2021","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34324860","citation_count":23,"is_preprint":false},{"pmid":"29416635","id":"PMC_29416635","title":"OTUD7B upregulation predicts a poor response to paclitaxel in patients with triple-negative breast 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Crystallographic and NMR analyses of Lys11-linked diubiquitin revealed compact conformations with exposed Ile44, and in vitro assays demonstrated Cezanne's Lys11-linkage preference.\",\n      \"method\": \"In vitro DUB activity assay, X-ray crystallography, NMR spectroscopy\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus NMR plus in vitro biochemical assay, replicated across multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"20622874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structures of Cezanne alone, in complex with monoubiquitin, and in complex with Lys11-linked diubiquitin reveal the molecular basis of Lys11-linkage specificity: ubiquitin-assisted conformational changes activate the enzyme, all chain types interact with the S1 site, but only Lys11-linked chains can bind productively across the active site to stimulate catalytic turnover.\",\n      \"method\": \"X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, in vitro DUB activity assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures combined with HDX-MS and enzymatic assays, rigorous mechanistic dissection in one study\",\n      \"pmids\": [\"27732584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cezanne/OTUD7B suppresses canonical NF-κB activation downstream of TNF receptor signaling by deubiquitinating RIP1, reducing polyubiquitinated RIP1 at activated TNFRs. The catalytic cysteine (Cys209) is essential for this activity, as the C209 mutant loses NF-κB suppression. Cezanne is induced by TNFα, forming a negative feedback loop.\",\n      \"method\": \"siRNA knockdown, NF-κB luciferase reporter, overexpression with catalytic mutant, Co-IP, RIP1 ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, catalytic-mutant rescue, reporter assay, and loss-of-function in one study\",\n      \"pmids\": [\"18178551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"OTUD7B is a pivotal regulator of the non-canonical NF-κB pathway. In response to non-canonical NF-κB stimuli, OTUD7B binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant non-canonical NF-κB activation. OTUD7B deficiency in mice causes hyperactivation of non-canonical NF-κB without affecting canonical NF-κB.\",\n      \"method\": \"Mouse knockout, Co-IP, ubiquitination assay, NF-κB signaling readouts, genetic epistasis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout mouse model plus Co-IP plus ubiquitination assay, multiple orthogonal methods\",\n      \"pmids\": [\"23334419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OTUD7B removes K63-linked polyubiquitin chains from GβL (MLST8), preventing GβL interaction with SIN1 that would disrupt mTORC2 assembly. TRAF2 E3 ligase promotes K63-linked polyubiquitination of GβL to favor mTORC1, while OTUD7B deubiquitinates GβL to promote GβL–SIN1 interaction and mTORC2 formation. Genetic deletion of Otud7b in mice suppresses AKT activation and Kras-driven lung tumorigenesis.\",\n      \"method\": \"Co-IP, ubiquitination assay, mouse genetic knockout, in vivo tumorigenesis model, site-directed mutagenesis (GβL K305R/K313R)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo mouse models, mutagenesis, multiple orthogonal methods replicated across human and mouse\",\n      \"pmids\": [\"28489822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Otud7b facilitates TCR signaling by deubiquitinating Zap70 upon TCR ligation, preventing association of Zap70 with negative-regulatory phosphatases Sts1 and Sts2. Otud7b deficiency attenuates Zap70 activation and downstream pathways, impairing T cell activation and rendering mice refractory to T cell-mediated autoimmune responses.\",\n      \"method\": \"Mouse knockout, Co-IP, ubiquitination assay, T cell activation assays, autoimmune disease model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout, Co-IP, ubiquitination assay, and disease phenotype with mechanistic pathway placement\",\n      \"pmids\": [\"26903241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cezanne-1/OTUD7B deubiquitinates EGFR, opposing CBL-mediated receptor ubiquitination and degradation, thereby enhancing EGFR signaling. Physical interaction between Cezanne-1 and EGFR was demonstrated, and EGFR transphosphorylates Cezanne-1. Both the catalytic and ubiquitin-binding domains of Cezanne-1 are required for these functions.\",\n      \"method\": \"RNA interference screen, Co-IP, ubiquitination assay, domain deletion/mutation analysis, EGFR degradation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, domain mutagenesis, ubiquitination assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22179831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cezanne/OTUD7B regulates HIF-1α protein stability in a proteasome-independent manner dependent on the tumor suppressor pVHL, with hydroxylase activity dispensable. Loss of Cezanne decreases HIF-1α protein levels and target gene expression; data suggest chaperone-mediated autophagy as the degradation route when Cezanne is absent.\",\n      \"method\": \"siRNA knockdown, HIF-1α protein stability assay, inhibitor treatment (proteasome, hydroxylase), HIF-1α target gene expression\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, loss-of-function with mechanistic pathway exclusion, but no direct biochemical reconstitution of the Cezanne–HIF-1α interaction\",\n      \"pmids\": [\"25355043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cezanne/OTUD7B regulates HIF2α expression in an E2F1-dependent transcriptional manner: Cezanne controls the stability of the transcription factor E2F1, which directly drives HIF2α (EPAS1) promoter activity. Exogenous E2F1 rescues HIF2α transcript and protein when Cezanne is depleted.\",\n      \"method\": \"siRNA knockdown, rescue experiment with exogenous E2F1, qRT-PCR, promoter reporter assay, protein stability assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus rescue plus promoter assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26148512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cezanne/OTUD7B is induced in endothelial cells by hypoxia via p38 MAPK-dependent transcriptional and post-transcriptional mechanisms, and it suppresses NF-κB activation by deubiquitinating TRAF6 (removing Lys63-linked polyubiquitin). Genetic deletion of Cezanne in mice enhances renal inflammation and injury after ischemia-reperfusion.\",\n      \"method\": \"siRNA knockdown, mouse genetic knockout, TRAF6 ubiquitination assay, NF-κB activation assay, ischemia-reperfusion model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout mouse model, TRAF6 ubiquitination assay, NF-κB readouts, multiple methods across in vitro and in vivo\",\n      \"pmids\": [\"23564640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cezanne/OTUD7B is a cell cycle-regulated DUB that antagonizes APC/C-mediated ubiquitination of mitotic substrates. Cezanne is specifically active against K11-linked ubiquitin chains formed by APC/C, binds APC/C substrates, and reverses their ubiquitination. Cezanne depletion accelerates APC/C substrate degradation and causes mitotic errors and micronuclei formation.\",\n      \"method\": \"siRNA depletion, ubiquitination assays, Co-IP with APC/C substrates, cell cycle analysis, microscopy for micronuclei\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple APC/C substrate interactions confirmed by Co-IP, K11-chain specificity assay, loss-of-function with defined mitotic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"29973362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cezanne/OTUD7B promotes recruitment of the Rap80/BRCA1-A complex to DNA damage sites by acting as a 'reader' of Lys63-linked polyubiquitin (via its UBA domain) and an 'eraser' of Lys11-linked ubiquitination (via its DUB activity). Its UBA domain selectively binds Lys63-linked chains; loss of Cezanne DUB activity increases Lys11 ubiquitination and impairs Rap80/BRCA1-A recruitment, Rad18, and 53BP1 recruitment.\",\n      \"method\": \"Ubiquitin-binding domain protein array screen, Co-IP, ubiquitination assay, ionizing radiation sensitivity assay, DNA repair assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitin-binding domain array plus Co-IP plus functional DNA repair assays, single lab\",\n      \"pmids\": [\"31699778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The N-terminal UBA domain of Cezanne/OTUD7B binds Lys63-linked polyubiquitin chains via Leu9 and Ser10 residues, and this binding is required for recruitment of Cezanne to the activated TNFR complex to suppress RIP1 polyubiquitination and NF-κB activation. Mutations at these UBA residues disrupt TNFR complex recruitment and dramatically reduce NF-κB inhibition.\",\n      \"method\": \"UBA domain truncation and point mutagenesis, Co-IP, ubiquitin-binding assay, NF-κB reporter assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with defined binding residues plus Co-IP plus reporter, single lab\",\n      \"pmids\": [\"28817177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FIH1 (factor inhibiting HIF1) hydroxylates Asn35 within the N-terminal UBA-like domain of Cezanne in an oxygen-dependent manner, and this hydroxylation inhibits ubiquitin binding by UBACez. The UBACez domain binds Lys11-, Lys48-, Lys63-, and Met1-linked ubiquitin chains in vitro via a noncanonical surface, linking oxygen sensing to Cezanne substrate recruitment.\",\n      \"method\": \"Mass spectrometry identification of hydroxylation, in vitro ubiquitin-binding assay, mutagenesis, oxygen-dependent FIH1 assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct identification of PTM site, in vitro ubiquitin-binding reconstitution, mutagenesis, and FIH1 hydroxylation assay in one study\",\n      \"pmids\": [\"31937588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DJ-1 (Park7) physically interacts with Cezanne/OTUD7B and inhibits its deubiquitinating activity. The interaction maps to the N-terminal 70 residues of DJ-1 and leads to enhanced NF-κB activation and increased cell survival, opposing Cezanne's negative regulatory role on NF-κB.\",\n      \"method\": \"Mass spectrometry, Co-IP of endogenous proteins, DUB activity assay, NF-κB nuclear translocation assay, mouse Park7-/- primary cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous Co-IP, DUB activity assay, genetic validation in knockout cells, single lab\",\n      \"pmids\": [\"21097510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OTUD7B acts as a negative regulator of antiviral innate immunity by promoting IRF3 selective autophagic degradation. Mechanistically, OTUD7B interacts with IRF3 and deubiquitinates SQSTM1/p62 at K7 (removing K63-linked chains), enhancing SQSTM1 oligomerization to function as a cargo receptor for IRF3 autophagic degradation.\",\n      \"method\": \"Co-IP, ubiquitination assay (K63-chain removal), autophagy flux assay, siRNA knockdown, viral infection model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific ubiquitination (K7) identification, loss-of-function, single lab with multiple methods\",\n      \"pmids\": [\"35100065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OTUD7B deubiquitinates LSD1 at K226/K277 residues (K63-linked ubiquitin chains), controlling LSD1 binding partner specificity and stability. OTUD7B deficiency increases K63-linked ubiquitination of LSD1, disrupting the LSD1/CoREST complex and targeting LSD1 for p62-mediated proteolysis, impairing genome-wide LSD1 occupancy and promoting H3K4/H3K9 methylation changes that abrogate breast cancer metastasis.\",\n      \"method\": \"Co-IP, K63-ubiquitination assay with site-specific mutants (K226R/K277R), chromatin immunoprecipitation, ChIP-seq, cell invasion assay, xenograft\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific ubiquitination identification, Co-IP, ChIP-seq, in vivo model, single lab\",\n      \"pmids\": [\"34050636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OTUD7B interacts with, deubiquitinates, and stabilizes estrogen receptor α (ERα) in a catalytic-activity-dependent manner, preventing ERα degradation. OTUD7B depletion decreases ERα protein level, ERα target gene expression, and ERα-positive breast cancer cell proliferation; overexpression of ERα rescues the OTUD7B-depletion phenotype.\",\n      \"method\": \"Co-IP, ubiquitination assay, rescue experiment with ERα overexpression, cell proliferation assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, rescue experiment, single lab\",\n      \"pmids\": [\"34035221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OTUD7B directly binds to TRAF3 and deubiquitinates it via its OTU domain, inhibiting TRAF3 proteolysis and preventing NIK accumulation and non-canonical NF-κB pathway activation. A catalytic mutant (C194S/H358R) of OTUD7B fails to suppress LCL161-induced lung cancer cell invasion and migration, confirming that DUB activity is required.\",\n      \"method\": \"Co-IP, ubiquitination assay, luciferase reporter, shRNA silencing, overexpression of OTU catalytic mutant, in vivo metastasis model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, catalytic mutant validation, ubiquitination assay, in vivo model, single lab\",\n      \"pmids\": [\"33198776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Reactive oxygen species (ROS) inactivate Cezanne/OTUD7B by oxidizing its catalytic cysteine residue, as demonstrated using ubiquitin-derived thiol-reactive probes (HA-UbVME) and a biotin-tagged cysteine-reactive probe (DCP-Bio1). DTT reactivates Cezanne activity, linking ROS-mediated cysteine oxidation to prolonged NF-κB activation in hepatocellular carcinoma cells.\",\n      \"method\": \"Activity-based probe assay (HA-UbVME), DCP-Bio1 biotin-cysteine probe, DTT reactivation assay, NF-κB reporter\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — activity-based probe assay confirming catalytic cysteine oxidation, single lab, single study\",\n      \"pmids\": [\"31072419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OTUD7B interacts with and deubiquitinates YAP1, stabilizing it and promoting its transcriptional activity, including upregulation of NUAK2 and other YAP1 target genes, thereby accelerating gastric cancer progression.\",\n      \"method\": \"Co-IP, ubiquitination assay, xenograft model, qPCR of target genes\",\n      \"journal\": \"Digestive and liver disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"37429790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cezanne/OTUD7B drives vascular smooth muscle cell (VSMC) proliferation by deubiquitinating β-catenin, promoting β-catenin-dependent CCN1 expression. Wild-type but not catalytically inactive Cezanne (C209S mutant) increases VSMC proliferative ability and mobility. Global Cezanne deletion in mice reduced atherosclerotic plaque size but with reduced plaque stability.\",\n      \"method\": \"Overexpression of wild-type vs. C209S catalytic mutant, RNA-sequencing, Co-IP, mouse knockout, arterial injury model\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant comparison, RNA-seq, Co-IP, in vivo mouse model, single lab\",\n      \"pmids\": [\"33599243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OTUD7B stabilizes TRAF2 in dendritic cells by removing K48-linked ubiquitin chains from TRAF2, preventing its proteasomal degradation. TRAF2 in turn facilitates K63-linked polyubiquitination of RIPK1, activating NF-κB and MAP kinases, IL-12 production, and anti-apoptotic gene expression. DC-specific OTUD7B deficiency causes DC apoptosis and failure to prime CD8+ T cells in a malaria infection model.\",\n      \"method\": \"Co-IP, K48-ubiquitination assay, DC-specific knockout mouse, infection model, NF-κB/MAPK signaling assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — DC-specific knockout mouse, Co-IP, linkage-specific ubiquitination assay, in vivo infection model, multiple orthogonal methods\",\n      \"pmids\": [\"37516734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OTUD7B deubiquitinates KLF4, preventing its degradation and maintaining KLF4 protein levels in vascular smooth muscle cells. OTUD7B downregulation by plant-derived miRNAs (Sal-miR-1 and 3) reduces KLF4 deubiquitylation, leading to decreased KLF4 and increased NMHC IIA expression, promoting VSMC contractile phenotype and suppressing migration.\",\n      \"method\": \"Co-IP, ubiquitination assay, luciferase assay, ChIP, western blotting, carotid artery ligation model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP, in vivo vascular model, single lab\",\n      \"pmids\": [\"32685020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cezanne/OTUD7B stabilizes PIK3C3 (VPS34) by deubiquitinating K48-linked ubiquitination at Lysine 322, promoting autophagy. Additionally, Cezanne upregulates PIK3C2A transcription in a POLR2A-dependent manner as a compensatory PI3P-generating mechanism, and accelerates EGFR recycling, contributing to Osimertinib resistance in lung adenocarcinoma.\",\n      \"method\": \"Ubiquitination assay (K48, site-specific K322), Co-IP, POLR2A knockdown, autophagy flux assay, drug resistance assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific ubiquitination at K322 identified, Co-IP, functional autophagy assay, single lab\",\n      \"pmids\": [\"37596251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD7B deubiquitinates p53 (removing Mdm2-mediated and other K-linked polyubiquitin chains), stabilizing p53 and suppressing proteasomal degradation. OTUD7B overexpression suppresses HCC growth in cultures and xenografts through p53-dependent mitochondrial apoptosis (PUMA and BAX induction). OTUD7B expression is transcriptionally repressed via p53-dependent mechanisms, forming a mutual feedback loop.\",\n      \"method\": \"Mass spectrometry pulldown, Co-IP (endogenous, ectopic, mutant forms), ubiquitination assay, luciferase reporter, ChIP, shRNA knockdown, CRISPR-Cas9 knockout, xenograft\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including CRISPR knockout, Co-IP, ChIP, ubiquitination assay, and in vivo xenograft, single lab\",\n      \"pmids\": [\"39990225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OTUD7B interacts with LEF1 through its UBA domain (interacting with LEF1's HMG domain) and promotes nuclear localization of LEF1, increasing LEF1–β-catenin interaction in the nucleus and activating Wnt target gene transcription. OTUD7B overexpression upregulates ~75% of tested Wnt target genes.\",\n      \"method\": \"DUB library screen, Co-IP with domain mutants, nuclear/cytoplasmic fractionation, qPCR array\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with domain mapping and fractionation, single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"37371581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD7B interacts with FOXM1 and reduces its polyubiquitylation, stabilizing FOXM1 protein in breast cancer cells. OTUD7B knockdown decreases FOXM1 protein and FOXM1 overexpression rescues the inhibitory effects of OTUD7B knockdown on breast cancer cell proliferation and stemness.\",\n      \"method\": \"Co-IP, ubiquitination assay, rescue experiment with FOXM1 overexpression, cell proliferation/sphere assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay, rescue experiment, single lab, single study\",\n      \"pmids\": [\"38298430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BRCA1 protein stability is regulated in a cell cycle-dependent manner through K11-linked ubiquitination by APC/C (with Cdh1 recognizing a BRCA1 degron) and the E2 Ube2S, while Cezanne/OTUD7B counteracts this by removing K11-linked ubiquitin from BRCA1. Cezanne deficiency leads to increased BRCA1 K11-ubiquitination, decreased BRCA1 protein level, and increased cellular sensitivity to PARP inhibitors.\",\n      \"method\": \"Ubiquitination assay (K11-linkage specific), cell cycle analysis, PARP inhibitor sensitivity assay, genetic depletion of Cezanne/Ube2S/APC/C components\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — linkage-specific ubiquitination assay, genetic epistasis with APC/C-Cdh1 and Ube2S, functional drug sensitivity readout, single study\",\n      \"pmids\": [\"41359628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD7B interacts with and deubiquitinates VEGFA, stabilizing it and promoting vascular mimicry in non-small cell lung cancer. OTUD7B knockdown increases VEGFA ubiquitination and reduces VEGFA protein levels, suppressing vascular mimicry.\",\n      \"method\": \"Co-IP, ubiquitination assay, tube formation/vascular mimicry assay, luciferase reporter (miR-491-5p target site), xenograft\",\n      \"journal\": \"The journal of gene medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, functional context established but mechanistic depth limited\",\n      \"pmids\": [\"39376029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD7B stabilizes HNF4α by removing K48-linked ubiquitin chains, preventing its proteasomal degradation. OTUD7B-HNF4α interaction regulates fatty acid oxidation-related gene expression and suppresses ferroptosis and cardiac hypertrophy in response to pressure overload.\",\n      \"method\": \"Co-IP, K48-ubiquitination assay, transcriptome analysis, cardiomyocyte-specific knockout/overexpression, TAC mouse model\",\n      \"journal\": \"Biomarker research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K48-linkage-specific ubiquitination assay, in vivo cardiomyocyte-specific models, single lab\",\n      \"pmids\": [\"40158182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD7B deubiquitinates β-catenin by removing K48-linked ubiquitin chains, preventing its proteasomal degradation and activating β-catenin/Wnt signaling in hepatocytes. OTUD7B overexpression reduces hepatic lipid deposition and inflammation in NAFLD mouse models, with NR4A2 identified as a transcriptional regulator of OTUD7B.\",\n      \"method\": \"Co-IP, K48-ubiquitination assay, TopFlash reporter, adenoviral overexpression in NAFLD mouse model, ChIP-seq data analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination assay, reporter assay, in vivo model, single lab\",\n      \"pmids\": [\"39520879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD7B restricts TNF-induced NF-κB and MAPK activation in astrocytes through sequential K63- and K48-deubiquitination of RIPK1. Additionally, OTUD7B prevents proteasomal degradation of GFAP through K48-deubiquitination of GFAP. In EAE (MS model), astrocytic OTUD7B deficiency increases chemokine expression and CD4+ T cell recruitment to inflammatory lesions.\",\n      \"method\": \"RNA-sequencing of isolated astrocytes, spatial transcriptomics, Co-IP, K63/K48-ubiquitination assays, astrocyte-specific knockout mouse, EAE model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — astrocyte-specific knockout, linkage-specific ubiquitination assays for two distinct substrates, spatial transcriptomics, multiple orthogonal methods, in vivo disease model\",\n      \"pmids\": [\"41115891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD7B deubiquitinates SERCA2a by removing K63-linked ubiquitin at K628 through its catalytic site C194, promoting SERCA2a–phospholamban (PLN) interaction and restricting SERCA2a activity in Ca2+ handling, thereby driving hypertrophic response in cardiomyocytes. Cardiomyocyte-specific OTUD7B deletion mitigated, while overexpression exacerbated, cardiac hypertrophy in Ang II and TAC models.\",\n      \"method\": \"Quantitative ubiquitinome analysis, site-directed mutagenesis (K628, C194), Co-IP, cardiomyocyte-specific knockout and overexpression mouse models, TAC/Ang II models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — quantitative ubiquitinome, site-directed mutagenesis identifying catalytic site and substrate ubiquitination site, Co-IP, in vivo cardiomyocyte-specific models, multiple orthogonal methods\",\n      \"pmids\": [\"41695487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"β-hydroxybutyrylation of OTUD7B at lysine 511 impairs its DUB activity toward APC/C substrates, resulting in impaired APC/C substrate degradation, reduced cytoplasmic double-stranded DNA accumulation, and attenuated cGAS-STING activation, contributing to immune suppression in enzalutamide-resistant prostate cancer.\",\n      \"method\": \"β-hydroxybutyrylation identification (mass spectrometry implied), APC/C substrate degradation assay, cGAS-STING pathway readout, cell line and in vivo models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — site-specific PTM identification (K511), functional DUB activity readout, single lab, limited mechanistic reconstitution detail in abstract\",\n      \"pmids\": [\"40393641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD7B deubiquitinates Lox-1, preventing its ubiquitin-mediated degradation and stabilizing Lox-1 protein in macrophages (THP-1 and U937 cells). OTUD7B knockdown reduces Lox-1 levels and impairs oxLDL uptake; Lox-1 overexpression rescues oxLDL uptake in OTUD7B-deficient cells.\",\n      \"method\": \"Co-IP, ubiquitination assay, oxLDL uptake assay, siRNA knockdown, rescue experiment\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay with rescue, single lab, single study\",\n      \"pmids\": [\"40294697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD7B suppresses cone photoreceptor degeneration in retinal degenerative disease models by downregulating NF-κB activity. Otud7b knockout mice showed increased cone degeneration under light-induced damage, dry AMD, and RP models; inhibition of NF-κB attenuated this degeneration.\",\n      \"method\": \"Otud7b knockout mouse models, RNA-sequencing, luciferase reporter (NF-κB activity), NF-κB inhibitor treatment, light-induced damage and RP disease models\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout models, luciferase reporter, NF-κB inhibitor rescue, single lab\",\n      \"pmids\": [\"38510130\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OTUD7B/Cezanne is a Lys11-linkage-preferring OTU family deubiquitinase that regulates multiple signaling pathways by deubiquitinating a diverse set of substrates—including RIP1, TRAF3, TRAF6, TRAF2, GβL, Zap70, LSD1, ERα, HIF-1α, E2F1, EGFR, IGF-1R, SQSTM1/p62, IRF3, β-catenin, HNF4α, SERCA2a, BRCA1, GFAP, p53, and others—using a catalytic cysteine that can be inactivated by ROS oxidation, with substrate recruitment mediated by a UBA domain that binds Lys63-linked chains and is regulated by oxygen-dependent FIH1-mediated asparagine hydroxylation; through these activities OTUD7B controls canonical and non-canonical NF-κB signaling, mTORC2 assembly and AKT activation, TCR signaling, APC/C-dependent mitotic progression, DNA damage response, antiviral innate immunity, HIF-dependent hypoxia responses, and Wnt/cell cycle signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OTUD7B (Cezanne) is an OTU-family deubiquitinase that serves as a master rheostat for ubiquitin-dependent signaling, acting both as a Lys11-linkage-preferring catalytic eraser and as a Lys63-chain reader [#0, #1, #11]. Structural and biochemical analyses establish its defining biochemistry: it was the first DUB shown to preferentially cleave Lys11-linked chains, and crystal structures with mono- and Lys11-diubiquitin reveal that ubiquitin-assisted conformational changes activate the enzyme while only Lys11 chains engage productively across the active site to drive turnover [#0, #1]. Its activity is gated by oxygen and redox state: FIH1 hydroxylates Asn35 in the N-terminal UBA-like domain to inhibit ubiquitin binding, and ROS oxidation of the catalytic cysteine reversibly inactivates the enzyme [#13, #19]. In inflammatory signaling, OTUD7B restrains both NF-\\u03baB arms\\u2014deubiquitinating RIP1 and TRAF6 to suppress canonical NF-\\u03baB, and stabilizing TRAF3 to prevent aberrant non-canonical NF-\\u03baB activation [#2, #9, #3, #18]. Recruitment to the activated TNFR complex depends on its UBA domain binding Lys63 chains via Leu9/Ser10 [#12]. Beyond inflammation, OTUD7B controls mTORC2 assembly and AKT activation by removing K63 chains from G\\u03b2L, facilitates TCR signaling by deubiquitinating Zap70, and antagonizes APC/C-mediated K11 ubiquitination of mitotic substrates to safeguard faithful mitosis [#4, #5, #10]. It functions in the DNA damage response as both a Lys63 reader and Lys11 eraser to promote Rap80/BRCA1-A recruitment, and counteracts APC/C-Cdh1/Ube2S-driven K11 ubiquitination of BRCA1 to maintain genome stability and PARP-inhibitor resistance [#11, #28]. Through substrate deubiquitination it further stabilizes a broad set of regulators including HIF-1\\u03b1, E2F1, ER\\u03b1, LSD1, \\u03b2-catenin, HNF4\\u03b1, SERCA2a, and p53, linking it to hypoxia responses, transcriptional control, Wnt signaling, cardiac remodeling, and p53-dependent apoptosis [#7, #8, #16, #17, #21, #25, #30, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established OTUD7B's first signaling role: whether a DUB could negatively feed back on TNF-induced NF-\\u03baB was unknown, and Cezanne was shown to deubiquitinate RIP1 to dampen canonical NF-\\u03baB in a catalytic-cysteine-dependent manner.\",\n      \"evidence\": \"siRNA knockdown, NF-\\u03baB reporter, catalytic mutant (C209) rescue, RIP1 ubiquitination assay\",\n      \"pmids\": [\"18178551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the chain linkage removed from RIP1\", \"Recruitment mechanism to the TNFR complex unresolved at this stage\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the enzyme's core biochemical identity: the linkage specificity of OTU DUBs was poorly mapped, and Cezanne was identified as the first DUB with preferential Lys11-chain activity.\",\n      \"evidence\": \"In vitro DUB assays, X-ray crystallography and NMR of Lys11-diubiquitin\",\n      \"pmids\": [\"20622874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet explain structurally how Lys11 selectivity is achieved at the active site\", \"Physiological Lys11 substrates not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the first endogenous regulator of Cezanne activity: DJ-1 (Park7) was shown to bind and inhibit Cezanne DUB activity, thereby enhancing NF-\\u03baB and cell survival.\",\n      \"evidence\": \"Mass spectrometry, endogenous Co-IP, DUB activity assay, Park7-/- primary cells\",\n      \"pmids\": [\"21097510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of inhibition undefined\", \"Single lab without reciprocal biochemical reconstitution\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended Cezanne to receptor signaling control: it was unknown how EGFR ubiquitination is reversed, and Cezanne was found to oppose CBL-mediated EGFR ubiquitination and degradation, requiring both catalytic and ubiquitin-binding domains.\",\n      \"evidence\": \"RNAi screen, Co-IP, ubiquitination assay, domain mutagenesis, EGFR degradation assay\",\n      \"pmids\": [\"22179831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chain linkage removed from EGFR not defined\", \"Functional consequence of EGFR-mediated transphosphorylation of Cezanne unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established OTUD7B as a non-redundant brake on the non-canonical NF-\\u03baB pathway, distinguishing it from canonical regulation, by stabilizing TRAF3 against proteolysis.\",\n      \"evidence\": \"Otud7b knockout mice, Co-IP, ubiquitination assay, NF-\\u03baB readouts, genetic epistasis\",\n      \"pmids\": [\"23334419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimulus-dependent recruitment to TRAF3 not detailed\", \"Chain linkage on TRAF3 not specified here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected Cezanne to hypoxic and inflammatory responses: hypoxia induces Cezanne via p38 MAPK, and it deubiquitinates TRAF6 (K63 removal) to suppress NF-\\u03baB, protecting against renal ischemia-reperfusion injury.\",\n      \"evidence\": \"siRNA, Otud7b knockout mice, TRAF6 ubiquitination assay, NF-\\u03baB assay, IR injury model\",\n      \"pmids\": [\"23564640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TRAF6 binding interface not mapped\", \"Relative contribution of transcriptional vs post-transcriptional induction unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked Cezanne to HIF biology: it regulates HIF-1\\u03b1 stability through a proteasome-independent, pVHL-dependent route, with hydroxylase activity dispensable.\",\n      \"evidence\": \"siRNA, HIF-1\\u03b1 stability assays, proteasome/hydroxylase inhibitors, target gene expression\",\n      \"pmids\": [\"25355043\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical reconstitution of a Cezanne\\u2013HIF-1\\u03b1 interaction\", \"Chaperone-mediated autophagy route inferred, not directly demonstrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Refined the HIF connection to a transcriptional mechanism: Cezanne controls HIF2\\u03b1 expression indirectly by stabilizing E2F1, which drives the EPAS1 promoter.\",\n      \"evidence\": \"siRNA, exogenous E2F1 rescue, qRT-PCR, promoter reporter, protein stability assay\",\n      \"pmids\": [\"26148512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct deubiquitination of E2F1 not biochemically resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Solved the structural basis of Lys11 selectivity: how a single OTU domain discriminates chain linkage was unknown, and structures with mono- and Lys11-diubiquitin showed all chains bind the S1 site but only Lys11 engages productively across the active site.\",\n      \"evidence\": \"Multiple crystal structures, HDX-MS, in vitro DUB assays\",\n      \"pmids\": [\"27732584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect structural mechanism to specific cellular Lys11 substrates\", \"Allosteric activation in cells not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed Otud7b in adaptive immunity: it positively regulates TCR signaling by deubiquitinating Zap70, blocking recruitment of inhibitory Sts1/Sts2 phosphatases.\",\n      \"evidence\": \"Knockout mice, Co-IP, ubiquitination assay, T cell activation and autoimmune models\",\n      \"pmids\": [\"26903241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chain linkage on Zap70 not specified\", \"Direct vs indirect blocking of Sts1/2 association not fully dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected OTUD7B to growth-factor/metabolic signaling: it dictates mTORC2 vs mTORC1 balance by removing K63 chains from G\\u03b2L, promoting G\\u03b2L\\u2013SIN1 interaction, AKT activation, and Kras-driven tumorigenesis.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, G\\u03b2L K305R/K313R mutagenesis, knockout mice, in vivo tumor model\",\n      \"pmids\": [\"28489822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimulus that triggers G\\u03b2L deubiquitination not defined\", \"Interplay with TRAF2 ligase in cells partially characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a cell-cycle role: OTUD7B antagonizes APC/C-generated K11 ubiquitination of mitotic substrates, and its loss accelerates substrate degradation and causes mitotic errors.\",\n      \"evidence\": \"siRNA, K11-specific ubiquitination assays, Co-IP with APC/C substrates, cell cycle and micronuclei microscopy\",\n      \"pmids\": [\"29973362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Cezanne is restricted to specific APC/C substrates not resolved\", \"Temporal coordination with APC/C activity incompletely mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed dual reader/eraser function in the DNA damage response: Cezanne reads K63 chains via its UBA domain and erases K11 chains via DUB activity to promote Rap80/BRCA1-A recruitment.\",\n      \"evidence\": \"Ubiquitin-binding domain array, Co-IP, ubiquitination assay, IR sensitivity, DNA repair assays\",\n      \"pmids\": [\"31699778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The K11-ubiquitinated DDR substrate(s) not fully identified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established redox gating of activity: ROS reversibly inactivate Cezanne by oxidizing its catalytic cysteine, prolonging NF-\\u03baB signaling.\",\n      \"evidence\": \"Activity-based probes (HA-UbVME, DCP-Bio1), DTT reactivation, NF-\\u03baB reporter\",\n      \"pmids\": [\"31072419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological ROS thresholds for inactivation not quantified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped the UBA-domain recruitment mechanism: Leu9/Ser10 mediate Lys63-chain binding required to bring Cezanne to the activated TNFR complex and suppress RIP1 ubiquitination.\",\n      \"evidence\": \"UBA truncation and point mutagenesis, Co-IP, ubiquitin-binding assay, NF-\\u03baB reporter\",\n      \"pmids\": [\"28817177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural validation of the binding surface not provided\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined oxygen-sensing control of substrate recruitment: FIH1 hydroxylates Asn35 in the UBA-like domain to inhibit its noncanonical ubiquitin binding, linking O2 levels to Cezanne function.\",\n      \"evidence\": \"MS identification of hydroxylation, in vitro ubiquitin-binding reconstitution, mutagenesis, FIH1 assay\",\n      \"pmids\": [\"31937588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequences of Asn35 hydroxylation on specific substrates not tested\", \"Crosstalk with redox cysteine gating unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended substrate range into vascular biology and Wnt: OTUD7B deubiquitinates and stabilizes KLF4, regulating VSMC phenotype.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, ChIP, carotid artery ligation model\",\n      \"pmids\": [\"32685020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chain linkage on KLF4 not specified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified epigenetic and hormonal substrates: OTUD7B deubiquitinates LSD1 (K63 at K226/K277) controlling complex specificity and metastasis, and stabilizes ER\\u03b1 to support ER-positive breast cancer proliferation.\",\n      \"evidence\": \"Site-specific ubiquitination mutants, Co-IP, ChIP-seq, invasion/proliferation assays, xenografts\",\n      \"pmids\": [\"34050636\", \"34035221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ER\\u03b1 and LSD1 regulation are coordinated in the same cells unknown\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected OTUD7B to antiviral immunity and vascular proliferation: it promotes IRF3 selective autophagic degradation via deubiquitinating SQSTM1/p62 at K7, and drives \\u03b2-catenin/CCN1-dependent VSMC proliferation.\",\n      \"evidence\": \"Co-IP, site-specific (K7) and catalytic-mutant (C209S) ubiquitination assays, autophagy flux, knockout mice, arterial injury model\",\n      \"pmids\": [\"35100065\", \"33599243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chain linkage on \\u03b2-catenin not specified in this context\", \"Whether IRF3 itself is a direct DUB substrate not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded the K48-deubiquitination repertoire and innate immune/Wnt roles: OTUD7B stabilizes TRAF2 (K48 removal) to sustain dendritic-cell survival and CD8+ priming, deubiquitinates VPS34/PIK3C3 to promote autophagy and drug resistance, stabilizes YAP1, and promotes nuclear LEF1\\u2013\\u03b2-catenin to activate Wnt targets.\",\n      \"evidence\": \"DC-specific knockout, K48-ubiquitination assays, Co-IP with domain mutants, autophagy/drug resistance assays, fractionation, infection and xenograft models\",\n      \"pmids\": [\"37516734\", \"37596251\", \"37429790\", \"37371581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"YAP1 and LEF1 findings rest on single low-confidence studies\", \"How OTUD7B switches between K48, K63, and K11 substrates not mechanistically unified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added tumor and tissue-protective substrates: OTUD7B stabilizes FOXM1 (breast cancer stemness) and VEGFA (vascular mimicry), and protects cone photoreceptors by downregulating NF-\\u03baB.\",\n      \"evidence\": \"Co-IP, ubiquitination/rescue assays, sphere assays, Otud7b knockout mice with retinal degeneration models, NF-\\u03baB inhibitor rescue\",\n      \"pmids\": [\"38298430\", \"39376029\", \"38510130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FOXM1 and VEGFA links are single low-confidence studies\", \"Substrate(s) deubiquitinated to control retinal NF-\\u03baB not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated OTUD7B as a stability regulator of major tumor-suppressor and physiological substrates: it deubiquitinates p53 (stabilization, mitochondrial apoptosis, mutual feedback), counteracts APC/C-Cdh1/Ube2S K11 ubiquitination of BRCA1, sequentially K63/K48-deubiquitinates RIPK1 and stabilizes GFAP in astrocytes, stabilizes HNF4\\u03b1 and \\u03b2-catenin in metabolic disease, and regulates SERCA2a (K63 at K628) in cardiac hypertrophy.\",\n      \"evidence\": \"MS pulldown, CRISPR knockout, Co-IP, linkage- and site-specific ubiquitination assays, ChIP, ubiquitinome analysis, tissue-specific knockout mice (astrocyte, cardiomyocyte), TAC/Ang II and EAE models, xenografts\",\n      \"pmids\": [\"39990225\", \"41359628\", \"41115891\", \"40158182\", \"39520879\", \"41695487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether a unifying logic governs linkage choice across these substrates is unresolved\", \"Tissue-specific determinants of substrate selection not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed metabolic PTMs reprogram OTUD7B activity: \\u03b2-hydroxybutyrylation at K511 impairs DUB activity toward APC/C substrates, blunting cytoplasmic dsDNA accumulation and cGAS-STING activation in therapy-resistant prostate cancer; Lox-1 was also identified as a stabilized substrate in macrophage lipid uptake.\",\n      \"evidence\": \"PTM site identification, APC/C substrate degradation and cGAS-STING readouts, Co-IP, oxLDL uptake/rescue assays, in vivo models\",\n      \"pmids\": [\"40393641\", \"40294697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lox-1 link is a single low-confidence study\", \"How K511 hydroxybutyrylation mechanistically alters catalysis not reconstituted\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what governs OTUD7B's selection among Lys11, Lys48, and Lys63 substrates in a given cell, and how its redox (catalytic cysteine), oxygen (FIH1/Asn35), and metabolic (K511 hydroxybutyrylation) gating mechanisms are integrated to direct activity to specific substrates.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking PTM gating to substrate choice\", \"Most substrate identifications are single-lab and not cross-validated\", \"Structural basis for K48/K63 cleavage versus the established K11 preference not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 10]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [13, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16, 26]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4, 9, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10, 28]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [11, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 15, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 4, 22, 25, 30]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [15, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRAF3\", \"RIPK1\", \"MLST8\", \"ZAP70\", \"EGFR\", \"TRAF2\", \"TRAF6\", \"PARK7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}