{"gene":"OTUD5","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2007,"finding":"DUBA (OTUD5) binds TRAF3 and selectively cleaves K63-linked polyubiquitin chains from TRAF3, causing its dissociation from the downstream signaling complex containing TBK1, thereby negatively regulating type I interferon production. A discrete ubiquitin interaction motif (UIM) within DUBA was required for efficient deubiquitination of TRAF3.","method":"siRNA screen, Co-immunoprecipitation, in vitro deubiquitination assay, ectopic expression gain/loss-of-function","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, in vitro DUB assay, UIM mutagenesis, siRNA screen) in a single rigorous study; widely replicated by subsequent independent labs","pmids":["17991829"],"is_preprint":false},{"year":2012,"finding":"Phosphorylation of OTUD5 at a single residue, Ser177, is both necessary and sufficient to activate its deubiquitinase activity. Crystal structure of the ubiquitin aldehyde adduct of active DUBA reveals that phosphorylation and ubiquitin C-terminal tail binding cooperate to fold DUBA around its substrate, explaining the phospho-dependence of catalytic activity.","method":"Crystal structure of ubiquitin aldehyde adduct, phosphomimetic/phospho-dead mutagenesis, in vitro DUB activity assays","journal":"Nature Structural & Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro activity assays in a single rigorous study","pmids":["22245969"],"is_preprint":false},{"year":2014,"finding":"DUBA (OTUD5) interacts with the E3 ubiquitin ligase UBR5; in naive T cells UBR5 suppresses DUBA abundance, while in activated T cells DUBA accumulates and stabilizes UBR5, which then ubiquitylates RORγt in response to TGF-β signaling. DUBA thus acts as a negative regulator of IL-17A production.","method":"Co-immunoprecipitation, T cell-specific conditional knockout mouse, cytokine measurement, western blot","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, conditional KO mouse model with defined phenotype, multiple orthogonal methods; published in high-impact journal","pmids":["25470037"],"is_preprint":false},{"year":2013,"finding":"OTUD5 directly interacts with and deubiquitinates p53, stabilizing it and enabling rapid p53-dependent transcription and apoptosis in response to DNA damage stress.","method":"Co-immunoprecipitation, in vitro deubiquitination assay, overexpression/knockdown with apoptosis readouts","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and deubiquitination assay with functional readout, single lab","pmids":["24143256"],"is_preprint":false},{"year":2014,"finding":"OTUD5 binds PDCD5 in response to genotoxic stress (etoposide treatment) and deubiquitinates PDCD5 at Lys-97/98, stabilizing it. PDCD5 stabilization by OTUD5 is required upstream for sequential p53 activation; PDCD5 defective for OTUD5 interaction (E94D mutant) could not rescue p53 activation, placing OTUD5 upstream of PDCD5 in the genotoxic stress apoptosis cascade.","method":"Co-immunoprecipitation, in vitro deubiquitination assay, knockdown/rescue with point mutants, p53 activation readouts","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, deubiquitination assay, epistasis via mutant rescue, single lab","pmids":["25499082"],"is_preprint":false},{"year":2019,"finding":"OTUD5 localizes to DNA double-strand breaks (DSBs), interacts with UBR5 and SPT16 (FACT component) through two distinct regions, stabilizes UBR5, and represses RNA Pol II elongation and RNA synthesis at damaged chromatin. Both its catalytic activity (via UBR5 stabilization) and scaffolding activity (via FACT binding) are required for Pol II arrest at lesions. A cancer-associated UIM missense mutation abrogates FACT association and Pol II arrest.","method":"DUB RNAi screen, Co-immunoprecipitation, localization by imaging, RNA synthesis assays, domain mapping, cancer mutation analysis","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNAi screen, Co-IP, imaging, functional RNA synthesis assay), single lab","pmids":["30508113"],"is_preprint":false},{"year":2019,"finding":"OTUD5 deubiquitinates and stabilizes Ku80, promoting NHEJ repair of DNA DSBs. OTUD5 depletion impaired NHEJ, caused excess end resection, and facilitated HR repair during S/G2 phase.","method":"Co-immunoprecipitation, ubiquitination assay, NHEJ/HR reporter assays, knockdown with DSB repair readouts","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and functional DNA repair assays, single lab","pmids":["30980112"],"is_preprint":false},{"year":2020,"finding":"OTUD5 interacts with STING, cleaves its K48-linked polyubiquitin chains, and promotes STING stability, thereby supporting type I IFN signaling after cytosolic DNA stimulation. Myeloid-specific OTUD5 knockout mice showed faster STING turnover and were more susceptible to HSV-1 and melanoma.","method":"Co-immunoprecipitation, K48-ubiquitin-specific deubiquitination assay, conditional knockout mouse models (Lyz2-Cre and CD11c-Cre), western blot, IFN measurement","journal":"Cellular & Molecular Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, linkage-specific DUB assay, two independent conditional KO mouse models with defined in vivo phenotypes","pmids":["32879469"],"is_preprint":false},{"year":2020,"finding":"OTUD5 deubiquitinates TRIM25, reducing its ubiquitination level and decreasing TRIM25-driven transcriptional activity, leading to elevated PML expression and tumor suppression. OTUD5 knockdown enhances TRIM25 transcriptional activity and accelerates tumor growth in nude mice.","method":"RNAi screen, Co-immunoprecipitation, ubiquitination assay, nude mouse xenograft, western blot","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi screen, Co-IP, ubiquitination assay, in vivo xenograft, single lab","pmids":["32826889"],"is_preprint":false},{"year":2020,"finding":"OTUD5 stabilizes βTrCP1 via its deubiquitinase activity, leading to degradation of DEPTOR (an mTORC1/2 inhibitor), thereby acting as a positive regulator of mTOR complex 1 and 2 signaling. mTOR directly phosphorylates OTUD5 and activates its DUB activity, forming a positive feedback loop.","method":"Co-immunoprecipitation, DUB activity assays, RNA-seq, cell size/autophagy phenotyping, Drosophila genetic rescue (RNAi of duba suppresses dRheb-induced wing phenotype), knockdown in mTOR-mutant cancer lines","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional assays, Drosophila in vivo genetics, single lab","pmids":["33110214"],"is_preprint":false},{"year":2021,"finding":"OTUD5 interacts with and deubiquitinates YAP in macrophages, stabilizing YAP and promoting M2 macrophage polarization, which in turn favors triple-negative breast cancer metastasis via the MCP-1/CCR2 pathway.","method":"Co-immunoprecipitation, ubiquitination assay, macrophage polarization assays, in vivo tumor models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional polarization and tumor assays, single lab","pmids":["33587979"],"is_preprint":false},{"year":2021,"finding":"OTUD5 is a K48/K63 linkage-specific deubiquitylase that controls neuroectodermal differentiation by cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators including ARID1A/B, HDAC2, and HCF1. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Pathogenic hemizygous variants in OTUD5 cause a new disorder (LINKED syndrome).","method":"Patient variant identification, biochemical ubiquitin linkage specificity assays, chromatin accessibility (ATAC-seq), gene expression analysis, structure-function via patient mutations","journal":"Science Advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — linkage-specific biochemical assays, ATAC-seq, patient variant epistasis, multiple orthogonal methods","pmids":["33523931"],"is_preprint":false},{"year":2022,"finding":"OTUD5 deubiquitinates and stabilizes RNF186 (a RING-type E3 ligase), and the stabilized RNF186 promotes degradation of sestrin2 (an mTOR inhibitor), thereby activating mTOR signaling and promoting bladder cancer progression (OTUD5-RNF186-sestrin2-mTOR axis).","method":"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, western blot, in vivo tumor models","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional cancer progression assays, single lab","pmids":["36085200"],"is_preprint":false},{"year":2022,"finding":"OTUD5 deubiquitinates and stabilizes PTEN in non-small cell lung cancer cells, suppressing cell proliferation, invasion, and migration. miR-652-3p targets and inhibits OTUD5 expression, thereby promoting NSCLC progression through reduced PTEN stability.","method":"Co-immunoprecipitation, ubiquitination assay, dual-luciferase assay for miRNA targeting, knockdown/overexpression with functional readouts","journal":"Bosnian Journal of Basic Medical Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, dual-luciferase validation, single lab","pmids":["35765958"],"is_preprint":false},{"year":2023,"finding":"OTUD5 binds GPX4 and stabilizes it by removing ubiquitin chains, conferring ferroptosis resistance. During ischemia-reperfusion, mTORC1-mediated autophagy degrades OTUD5, leading to subsequent GPX4 decay and ferroptosis in renal tubular cells. AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal recovery.","method":"Co-immunoprecipitation, ubiquitination assay, OTUD5 knockout/AAV overexpression, spatial transcriptomics, in vivo I/R injury model","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assay, genetic KO, AAV rescue, in vivo models with multiple orthogonal methods","pmids":["38110369"],"is_preprint":false},{"year":2023,"finding":"DUBA (OTUD5) deubiquitinates SLC7A11, stabilizing it and promoting resistance to ferroptosis in differentiated cancer cells. DUBA also promotes stemness via SLC7A11 stabilization; SLC7A11 then increases c-Myc expression through cysteine, defining a DUBA-SLC7A11-c-Myc axis critical for cancer stem cell ferroptosis resistance.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, in vitro ferroptosis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional ferroptosis assays, single lab","pmids":["37537342"],"is_preprint":false},{"year":2023,"finding":"OTUD5 assembles a complex containing FACT, HDAC1, and HDAC2 at replication forks through its C-terminal disordered tail. OTUD5 recruits and stabilizes HDAC1/2, decreasing H4K16 acetylation and limiting FACT loading, R-loop formation, and replication fork stress. Disruption of OTUD5-FACT interaction activates the Fanconi Anemia pathway for survival.","method":"RNAi depletion, iPOND (replication fork proteomics), FACT-interaction domain mapping, R-loop assays, H4K16ac ChIP, engineered cell lines uncoupling FACT-OTUD5 interaction","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, Co-IP, ChIP, R-loop assay, engineered cell lines), single lab","pmids":["37713620"],"is_preprint":false},{"year":2023,"finding":"OTUD5 interacts with VDAC2 and cleaves K48-linked polyubiquitin chains from VDAC2, inhibiting its proteasomal degradation. OTUD5-mediated VDAC2 stabilization is required for mitochondrial homeostasis protection against hepatic steatosis in MASH.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, hepatocyte-specific Otud5 knockout mouse, metabolomics","journal":"Cellular and Molecular Gastroenterology and Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, MS substrate identification, K48-specific DUB assay, hepatocyte-specific KO mouse, single lab","pmids":["38036082"],"is_preprint":false},{"year":2024,"finding":"OTUD5 deubiquitinates K63-linked ubiquitin chains on TAK1 at K158 via its active site C224, preventing TAK1 phosphorylation and reducing downstream NF-κB/MAPK inflammatory responses in podocytes. Podocyte-specific Otud5 KO exacerbates DKD and AAV9-OTUD5 overexpression is protective.","method":"Mass spectrometry substrate identification, Co-immunoprecipitation, K63-specific deubiquitination assay, active-site mutagenesis (C224), podocyte-specific KO mouse, AAV9 overexpression","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — MS substrate identification, Co-IP, K63-specific DUB assay with active site mutagenesis, conditional KO and AAV rescue in vivo, multiple orthogonal methods","pmids":["38937512"],"is_preprint":false},{"year":2024,"finding":"OTUD5 promotes end-joining of deprotected telomeres by stabilizing UBR5, which is required for DNA damage-induced ATM activity. OTUD5 facilitates ATM-dependent phosphorylation of KAP1 at S824, enabling heterochromatin-associated DNA repair. Loss of OTUD5 impairs KAP1S824 phosphorylation and suppresses end-joining at deprotected telomeres and heterochromatin DSBs.","method":"Functional genetic screen, Co-immunoprecipitation, phosphorylation assays, OTUD5 KO cell lines, telomere dysfunction assays","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen, Co-IP, phosphorylation readouts, KO cells with defined phenotype, single lab","pmids":["39420004"],"is_preprint":false},{"year":2024,"finding":"OTUD5 deubiquitinates SLC7A11, cleaving K48-linked polyubiquitin chains and enhancing SLC7A11 stability, thereby promoting TNBC progression and paclitaxel resistance by modulating ferroptosis.","method":"Co-immunoprecipitation, K48-specific ubiquitination assay, knockdown/overexpression, ferroptosis assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K48-specific DUB assay, functional ferroptosis assays, single lab","pmids":["39276913"],"is_preprint":false},{"year":2024,"finding":"OTUD5 deubiquitinates and stabilizes SLC38A1 by preventing ubiquitin-mediated proteasomal degradation, thereby promoting HCC cell proliferation.","method":"Mass spectrometry, Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, in vivo tumor model","journal":"Biology Direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS substrate identification, Co-IP, ubiquitination assay, in vivo xenograft, single lab","pmids":["38658981"],"is_preprint":false},{"year":2024,"finding":"OTUD5 promotes K63-linked polyubiquitination of α-synuclein (independent of its DUB catalytic activity) and mediates its endolysosomal degradation by recruiting the E3 ligase NEDD4. OTUD5 conditional KO in dopaminergic neurons worsens α-synuclein pathology after preformed fibril injection.","method":"Co-immunoprecipitation, ubiquitination assay, catalytic mutant analysis, conditional KO mouse model with α-Syn PFF injection, lysosomal degradation assays","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, catalytic mutant, conditional KO with disease model, single lab","pmids":["39721018"],"is_preprint":false},{"year":2024,"finding":"USP11 deubiquitinates OTUD5 (increasing its protein levels), and the USP11-OTUD5 axis activates STING-dependent inflammatory signaling in endothelial cells to exacerbate radiation-induced pneumonitis.","method":"Proteomics/ubiquitinomics after USP11 overexpression, Co-immunoprecipitation, Usp11-KO mouse model, AAV-OTUD5 overexpression in lung, western blot","journal":"International Journal of Radiation Oncology, Biology, Physics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteome/ubiquitinome profiling, Co-IP, KO mouse, AAV rescue, single lab","pmids":["38364946"],"is_preprint":false},{"year":2024,"finding":"CacyBP interacts with OTUD5, enhances its ubiquitination, and promotes its proteasomal degradation, thereby reducing OTUD5 protein levels and driving lung adenocarcinoma tumorigenesis.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, cancer cell functional assays","journal":"Carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, limited mechanistic depth","pmids":["38558058"],"is_preprint":false},{"year":2025,"finding":"DUBA (OTUD5) undergoes self-deubiquitination in activated microglia, stabilizing itself. Stabilized DUBA then deubiquitinates IRAK1 (removing K48-linked chains), preventing IRAK1 degradation and enhancing NF-κB and MAPK signaling to promote neuroinflammation. Microglial-specific DUBA ablation mitigates LPS-induced depression-like behavior and ischemic stroke injury.","method":"Co-immunoprecipitation, K48-specific DUB assay, microglial-specific KO mouse, LPS and stroke in vivo models","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K48-specific DUB assay, microglial-specific KO mouse with defined in vivo phenotypes, single lab","pmids":["40755418"],"is_preprint":false},{"year":2025,"finding":"DUBA (OTUD5) interacts with NOD2 and RIPK2, removing K48-linked polyubiquitin chains from both proteins through its enzymatic activity, thereby preventing their proteasomal degradation and sustaining NOD2-mediated innate immune signaling in macrophages.","method":"Co-immunoprecipitation, K48-specific ubiquitination assay, macrophage-specific KO mouse, cytokine measurement, MDP stimulation","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific DUB assay, macrophage-specific KO mouse with defined in vivo phenotypes, single lab","pmids":["40240520"],"is_preprint":false},{"year":2025,"finding":"OTUD5 directly interacts with and deubiquitinates TIF1γ. The stabilized TIF1γ attenuates TGF-β-induced SMAD3/4 complex formation, blocking TGF-β-induced EMT and NSCLC metastasis. TGF-β stimulation represses OTUD5 transcription via SMAD3/4, forming an OTUD5-TIF1γ-SMAD3/4 positive feedback loop.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, TGF-β signaling readouts (SMAD3/4 complex), NSCLC in vitro/in vivo metastasis assays","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis via siRNA rescue, in vivo metastasis model, single lab","pmids":["42185242"],"is_preprint":false},{"year":2025,"finding":"OTUD5 deubiquitinates GPX4 and stabilizes it; p53 activation (e.g., by nutlin-3a) suppresses OTUD5 transcription, leading to GPX4 degradation and sensitization of gastric cancer cells to ferroptosis. Only wild-type p53 (not mutant) suppresses OTUD5 transcription.","method":"Co-immunoprecipitation, ubiquitination assay, CRISPR-Cas9 Otud5 KO, subcutaneous tumor model, immunofluorescence, flow cytometry","journal":"Clinical and Translational Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, CRISPR KO, in vivo model, multiple methods, single lab","pmids":["40070026"],"is_preprint":false},{"year":2025,"finding":"OTUD5 stabilizes TRAF4 by removing ubiquitin chains, and stabilized TRAF4 activates the p38/JNK signaling pathway to promote apoptosis and oxidative stress in hyperoxia-induced lung injury.","method":"Co-immunoprecipitation, dual immunofluorescence, AAV9-siOTUD5 in vivo silencing, TUNEL/cleaved caspase-3 apoptosis assays, western blot","journal":"Tissue & Cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and in vivo silencing, single lab, limited mechanistic depth on DUB linkage specificity","pmids":["40513425"],"is_preprint":false},{"year":2026,"finding":"OTUD5 stabilizes GSK3β by removing K48-linked ubiquitin chains; a pathogenic variant (p.Val233Met) in the OTU domain reduces this DUB activity, accelerating GSK3β degradation (shortening half-life by ~40%), causing aberrant NPC proliferation and impaired neuronal differentiation.","method":"iPSC-derived NPCs, CRISPR-corrected isogenic controls, Co-IP/mass spectrometry substrate identification, ubiquitination assay, cycloheximide chase, Ki67/Tuj1 immunofluorescence, flow cytometry","journal":"Stem Cell Research & Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS substrate ID, Co-IP, ubiquitination assay, CHX chase, isogenic iPSC model, single lab","pmids":["41851816"],"is_preprint":false},{"year":2016,"finding":"Drosophila DUBA (ortholog of OTUD5) physically interacts with the initiator caspase Dronc and deubiquitylates it, contributing to efficient apoptosis. DUBA-null Drosophila are male sterile with defects in spermatid individualisation and reduced caspase activity; genetic rescue experiments demonstrate that DUBA phosphorylation and catalytic activity are required in vivo for spermatogenesis.","method":"Co-immunoprecipitation (Drosophila), genetic null mutant, genetic rescue with phosphomimetic/catalytic mutants, caspase activity assays","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genetic null, in vivo rescue with catalytic and phospho-mutants, single lab (Drosophila ortholog)","pmids":["27518434"],"is_preprint":false},{"year":2010,"finding":"IL-1R1 signaling is required for TLR9-dependent K63-linked ubiquitination of TRAF3; in the absence of IL-1R1, DUBA (OTUD5) expression is upregulated and cleaves K63-linked ubiquitin from TRAF3, impairing type I IFN and IL-10 production. DUBA siRNA augmented TLR9-dependent IFN response.","method":"siRNA knockdown, Il1r1-/- mice, K63-ubiquitin-specific pulldown, cytokine measurement","journal":"Journal of Experimental Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse KO, K63-ubiquitin assay, siRNA, multiple readouts; independent replication of TRAF3 K63-deubiquitination finding","pmids":["21115691"],"is_preprint":false},{"year":2025,"finding":"OTUD5 physically interacts with IRF7 and inhibits its K63-linked ubiquitination, thereby suppressing IRF7 transcriptional activation and reducing type I IFN production. OTUD5 was identified as a negative regulator of IRF7 in a DUB-targeted siRNA genetic screen.","method":"DUB-targeted siRNA genetic screen, Co-immunoprecipitation, K63-ubiquitination assay, IFN reporter assays","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 2 / Weak — Co-IP and K63-specific ubiquitination assay, siRNA screen, single lab, preprint only","pmids":["bio_10.1101_2025.09.09.675186"],"is_preprint":true},{"year":2025,"finding":"A focused CRISPR screen identified OTUD5 as a regulator of KAT2A stability when the SAGA CORE is disrupted; OTUD5 (together with UBR5) functions in orphan quality-control of unassembled KAT2A.","method":"CRISPR screen, western blot validation","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 4 / Weak — CRISPR screen hit only, no direct biochemical characterization of OTUD5-KAT2A interaction, preprint","pmids":["bio_10.1101_2025.07.24.666361"],"is_preprint":true}],"current_model":"OTUD5 (DUBA) is a phosphorylation-activated cysteine deubiquitinase (activated by Ser177 phosphorylation) that cleaves K48- and/or K63-linked polyubiquitin chains from a broad range of substrates—including TRAF3 (K63), STING (K48), TAK1 (K63), p53, PDCD5, GPX4, Ku80, IRAK1, NEDD4-recruited α-synuclein, YAP, SLC7A11, βTrCP1, VDAC2, PTEN, TRIM25, RNF186, and chromatin regulators (ARID1A/B, HDAC2, HCF1)—to regulate innate immunity, DNA damage responses, ferroptosis, mTOR signaling, replication fork integrity, and neuroectodermal development; a UIM domain is required for efficient substrate deubiquitination and an OTUD5-UBR5 complex mediates transcription regulation at damaged chromatin."},"narrative":{"mechanistic_narrative":"OTUD5 (DUBA) is a phosphorylation-activated cysteine deubiquitinase that cleaves both K48- and K63-linked polyubiquitin chains to control substrate stability and signaling across innate immunity, DNA damage responses, ferroptosis, and development [PMID:17991829, PMID:33523931]. Its catalytic activity is switched on by phosphorylation of a single residue, Ser177, which together with ubiquitin C-terminal tail binding folds the enzyme around its substrate—the structural basis for its phospho-dependent activation [PMID:22245969], and an internal ubiquitin interaction motif (UIM) is required for efficient substrate deubiquitination [PMID:17991829]. In innate immunity OTUD5 acts bidirectionally: it removes K63 chains from TRAF3 to dissociate it from the TBK1 complex and dampen type I interferon [PMID:17991829], yet stabilizes STING by cleaving its K48 chains to support interferon signaling after cytosolic DNA sensing [PMID:32879469], and stabilizes NOD2/RIPK2 to sustain innate signaling in macrophages [PMID:40240520]. At damaged chromatin and replication forks OTUD5 has both catalytic and scaffolding roles, stabilizing UBR5 and binding the FACT component SPT16 to arrest RNA Pol II elongation [PMID:30508113], stabilizing Ku80 to promote NHEJ [PMID:30980112], and assembling an HDAC1/2-FACT complex through its C-terminal disordered tail to limit R-loop formation and replication stress [PMID:37713620]. A recurring theme is stabilization of metabolic and survival factors—GPX4 and SLC7A11 to confer ferroptosis resistance [PMID:38110369, PMID:37537342], βTrCP1 and RNF186 to activate mTOR signaling [PMID:33110214, PMID:36085200], and p53 via PDCD5 to enable genotoxic-stress apoptosis [PMID:24143256, PMID:25499082]. Hemizygous pathogenic OTUD5 variants cause LINKED syndrome, a neuroectodermal developmental disorder, reflecting its role in deubiquitinating chromatin regulators (ARID1A/B, HDAC2, HCF1) to maintain enhancer accessibility during differentiation [PMID:33523931].","teleology":[{"year":2007,"claim":"Established OTUD5/DUBA as a deubiquitinase with a defined substrate and immune function, answering whether it acts on a specific signaling node.","evidence":"siRNA screen, Co-IP, and in vitro DUB assay showing K63-chain removal from TRAF3 and UIM requirement","pmids":["17991829"],"confidence":"High","gaps":["Did not explain how DUB activity itself is regulated","Linkage specificity beyond K63 not yet defined"]},{"year":2010,"claim":"Confirmed the TRAF3 K63-deubiquitination model in an independent immune context and tied DUBA expression to IL-1R1 status.","evidence":"siRNA, Il1r1-/- mice, and K63-ubiquitin-specific pulldown with cytokine readouts","pmids":["21115691"],"confidence":"Medium","gaps":["Mechanism controlling DUBA upregulation not resolved"]},{"year":2012,"claim":"Solved how the enzyme is switched on, showing phosphorylation at Ser177 is necessary and sufficient for catalysis—a structural basis for conditional activation.","evidence":"Crystal structure of ubiquitin aldehyde adduct plus phosphomimetic/phospho-dead mutagenesis and in vitro activity","pmids":["22245969"],"confidence":"High","gaps":["Identity of the activating kinase(s) in vivo not established here","Whether all substrate engagements require Ser177 phosphorylation unknown"]},{"year":2013,"claim":"Extended substrate range to the DNA damage axis by showing direct p53 deubiquitination and stabilization.","evidence":"Co-IP, in vitro DUB assay, and apoptosis readouts with knockdown/overexpression","pmids":["24143256"],"confidence":"Medium","gaps":["Single lab","Linkage type on p53 not defined"]},{"year":2014,"claim":"Placed OTUD5 within reciprocal stabilization circuits—with UBR5 in T cells and with PDCD5 upstream of p53—revealing context-dependent partner relationships.","evidence":"Reciprocal Co-IP, conditional KO mouse (UBR5/RORγt), and mutant-rescue epistasis (PDCD5 E94D)","pmids":["25470037","25499082"],"confidence":"High","gaps":["How DUBA abundance is set by UBR5 versus stabilizing UBR5 across cell types not fully reconciled"]},{"year":2016,"claim":"Demonstrated conserved in vivo requirement for both phosphorylation and catalysis using the Drosophila ortholog acting on caspase Dronc.","evidence":"Drosophila Co-IP, null mutant, and rescue with phosphomimetic/catalytic mutants with caspase assays","pmids":["27518434"],"confidence":"Medium","gaps":["Mammalian caspase substrate not demonstrated","Single ortholog system"]},{"year":2019,"claim":"Defined dual catalytic and scaffolding functions at DNA double-strand breaks, coupling UBR5 stabilization and FACT binding to transcriptional silencing and NHEJ.","evidence":"RNAi screen, Co-IP, imaging, RNA synthesis assays, domain mapping, plus Ku80 stabilization and NHEJ/HR reporter assays","pmids":["30508113","30980112"],"confidence":"Medium","gaps":["Recruitment mechanism to lesions not fully mapped","Single lab for each arm"]},{"year":2020,"claim":"Broadened the substrate landscape to STING (K48), TRIM25, and the mTOR axis via βTrCP1/DEPTOR, showing OTUD5 can stabilize either immune-positive or growth-promoting nodes.","evidence":"Conditional KO mice, K48-specific DUB assays, Co-IP, xenografts, and Drosophila genetic rescue of dRheb phenotype","pmids":["32879469","32826889","33110214"],"confidence":"High","gaps":["How linkage selectivity (K48 vs K63) is determined per substrate unresolved","Feedback with mTOR phosphorylation of OTUD5 not structurally defined"]},{"year":2021,"claim":"Linked OTUD5 to human disease and chromatin control, establishing that K48-cleavage of chromatin regulators maintains enhancer accessibility during neuroectodermal differentiation.","evidence":"Patient variant identification, linkage-specific biochemistry, ATAC-seq, and structure-function via patient mutations; YAP deubiquitination in macrophages","pmids":["33523931","33587979"],"confidence":"High","gaps":["Full set of developmentally relevant substrates not enumerated","Mechanism connecting variants to specific enhancer defects incomplete"]},{"year":2023,"claim":"Consolidated OTUD5 as a ferroptosis and metabolic-homeostasis regulator by stabilizing GPX4, SLC7A11, and VDAC2, and added a replication-fork chromatin complex with HDAC1/2-FACT.","evidence":"Co-IP, K48-specific ubiquitination assays, genetic KO/AAV rescue in vivo, iPOND, ChIP, and R-loop assays","pmids":["38110369","37537342","38036082","37713620"],"confidence":"High","gaps":["Whether these substrate sets are regulated by the same activation cue is unclear","Tissue-specific selectivity mechanisms unknown"]},{"year":2024,"claim":"Resolved active-site-dependent K63 cleavage of TAK1 and added catalysis-independent substrate handling, showing OTUD5 can also recruit an E3 ligase (NEDD4) to promote α-synuclein degradation.","evidence":"MS substrate ID, K63-specific DUB assay with C224 active-site mutagenesis, conditional KO/AAV in vivo, and catalytic-mutant analysis for α-synuclein","pmids":["38937512","39721018","39420004","38658981"],"confidence":"High","gaps":["How OTUD5 switches between catalytic and ligase-recruiting modes is undefined","ATM/KAP1 axis mechanism single lab"]},{"year":2025,"claim":"Expanded the regulatory network—self-deubiquitination stabilizing OTUD5, IRAK1/NOD2/RIPK2 control in inflammation, TIF1γ/TGF-β feedback, and upstream regulators USP11 and CacyBP—mapping how OTUD5 levels themselves are tuned.","evidence":"Cell-type-specific KO mice, K48-specific DUB assays, Co-IP, ubiquitinomics, and in vivo disease models","pmids":["40755418","40240520","42185242","38364946","38558058","40070026","40513425"],"confidence":"Medium","gaps":["Several axes rest on single-lab evidence","Some studies (TRAF4, CacyBP) lack linkage-specificity detail"]},{"year":2026,"claim":"Connected a specific pathogenic OTU-domain variant to reduced DUB activity and a developmental phenotype via GSK3β destabilization, tying biochemical loss-of-function to neural progenitor defects.","evidence":"Isogenic iPSC-derived NPCs, CRISPR correction, MS substrate ID, ubiquitination and CHX-chase assays","pmids":["41851816"],"confidence":"Medium","gaps":["Single iPSC system","Relationship to LINKED-syndrome chromatin substrates not integrated"]},{"year":null,"claim":"How OTUD5 achieves substrate- and linkage-selective deubiquitination (K48 vs K63) across its very broad substrate set, and which upstream kinases gate Ser177-dependent activation in each context, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for substrate selection","Activating kinases per pathway largely unidentified","Catalytic versus scaffolding/ligase-recruiting mode switching uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,7,11,18]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,18]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,16]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[5,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,7,26]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5,6,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,14,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,12,27]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[11,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,30]}],"complexes":["OTUD5-UBR5 complex","OTUD5-FACT-HDAC1/2 complex"],"partners":["UBR5","TRAF3","STING1","TAK1","KU80","GPX4","SLC7A11","VDAC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96G74","full_name":"OTU domain-containing protein 5","aliases":["Deubiquitinating enzyme A","DUBA"],"length_aa":571,"mass_kda":60.6,"function":"Deubiquitinating enzyme that functions as a negative regulator of the innate immune system (PubMed:17991829, PubMed:22245969, PubMed:23827681, PubMed:33523931). Has peptidase activity towards 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains (PubMed:22245969). Can also cleave 'Lys-11'-linked ubiquitin chains (in vitro) (PubMed:22245969). Acts via TRAF3 deubiquitination and subsequent suppression of type I interferon (IFN) production (PubMed:17991829). Controls neuroectodermal differentiation through cleaving 'Lys-48'-linked ubiquitin chains to counteract degradation of select chromatin regulators such as ARID1A, HDAC2 and HCF1 (PubMed:33523931). Acts as a positive regulator of mTORC1 and mTORC2 signaling following phosphorylation by MTOR: acts by mediating deubiquitination of BTRC, leading to its stability (PubMed:33110214)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96G74/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OTUD5","classification":"Not Classified","n_dependent_lines":343,"n_total_lines":1208,"dependency_fraction":0.28394039735099336},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OTUD5","total_profiled":1310},"omim":[{"mim_id":"603149","title":"INTERLEUKIN 17A; IL17A","url":"https://www.omim.org/entry/603149"},{"mim_id":"301056","title":"MULTIPLE CONGENITAL ANOMALIES-NEURODEVELOPMENTAL SYNDROME, X-LINKED; MCAND","url":"https://www.omim.org/entry/301056"},{"mim_id":"300713","title":"OTU DOMAIN-CONTAINING PROTEIN 5; OTUD5","url":"https://www.omim.org/entry/300713"},{"mim_id":"300116","title":"MATURE T-CELL PROLIFERATION 1; MTCP1","url":"https://www.omim.org/entry/300116"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OTUD5"},"hgnc":{"alias_symbol":["DKFZp761A052","DUBA"],"prev_symbol":[]},"alphafold":{"accession":"Q96G74","domains":[{"cath_id":"3.90.70.80","chopping":"180-352","consensus_level":"high","plddt":90.0997,"start":180,"end":352},{"cath_id":"1.10.287","chopping":"358-410","consensus_level":"medium","plddt":86.7266,"start":358,"end":410}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96G74","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96G74-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96G74-F1-predicted_aligned_error_v6.png","plddt_mean":63.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OTUD5","jax_strain_url":"https://www.jax.org/strain/search?query=OTUD5"},"sequence":{"accession":"Q96G74","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96G74.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96G74/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96G74"}},"corpus_meta":[{"pmid":"17991829","id":"PMC_17991829","title":"DUBA: 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macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41937022","citation_count":0,"is_preprint":false},{"pmid":"41687749","id":"PMC_41687749","title":"Saquinavir induces pyroptosis through the OTUD5-JAK1-GSDME axis in hepatocellular carcinoma.","date":"2026","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41687749","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.09.675186","title":"A genetic screen to identify deubiquitinases as regulators of IRF7","date":"2025-09-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.09.675186","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.05.674562","title":"Genotoxic antibody-drug conjugates combined with Bcl-xL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer","date":"2025-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.05.674562","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.24.666361","title":"Disruption of the SAGA CORE triggers collateral degradation of KAT2A","date":"2025-07-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.24.666361","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":29347,"output_tokens":8673,"usd":0.109068,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18439,"output_tokens":4540,"usd":0.102847,"stage2_stop_reason":"end_turn"},"total_usd":0.211915,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"DUBA (OTUD5) binds TRAF3 and selectively cleaves K63-linked polyubiquitin chains from TRAF3, causing its dissociation from the downstream signaling complex containing TBK1, thereby negatively regulating type I interferon production. A discrete ubiquitin interaction motif (UIM) within DUBA was required for efficient deubiquitination of TRAF3.\",\n      \"method\": \"siRNA screen, Co-immunoprecipitation, in vitro deubiquitination assay, ectopic expression gain/loss-of-function\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, in vitro DUB assay, UIM mutagenesis, siRNA screen) in a single rigorous study; widely replicated by subsequent independent labs\",\n      \"pmids\": [\"17991829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Phosphorylation of OTUD5 at a single residue, Ser177, is both necessary and sufficient to activate its deubiquitinase activity. Crystal structure of the ubiquitin aldehyde adduct of active DUBA reveals that phosphorylation and ubiquitin C-terminal tail binding cooperate to fold DUBA around its substrate, explaining the phospho-dependence of catalytic activity.\",\n      \"method\": \"Crystal structure of ubiquitin aldehyde adduct, phosphomimetic/phospho-dead mutagenesis, in vitro DUB activity assays\",\n      \"journal\": \"Nature Structural & Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro activity assays in a single rigorous study\",\n      \"pmids\": [\"22245969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DUBA (OTUD5) interacts with the E3 ubiquitin ligase UBR5; in naive T cells UBR5 suppresses DUBA abundance, while in activated T cells DUBA accumulates and stabilizes UBR5, which then ubiquitylates RORγt in response to TGF-β signaling. DUBA thus acts as a negative regulator of IL-17A production.\",\n      \"method\": \"Co-immunoprecipitation, T cell-specific conditional knockout mouse, cytokine measurement, western blot\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, conditional KO mouse model with defined phenotype, multiple orthogonal methods; published in high-impact journal\",\n      \"pmids\": [\"25470037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"OTUD5 directly interacts with and deubiquitinates p53, stabilizing it and enabling rapid p53-dependent transcription and apoptosis in response to DNA damage stress.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay, overexpression/knockdown with apoptosis readouts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and deubiquitination assay with functional readout, single lab\",\n      \"pmids\": [\"24143256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OTUD5 binds PDCD5 in response to genotoxic stress (etoposide treatment) and deubiquitinates PDCD5 at Lys-97/98, stabilizing it. PDCD5 stabilization by OTUD5 is required upstream for sequential p53 activation; PDCD5 defective for OTUD5 interaction (E94D mutant) could not rescue p53 activation, placing OTUD5 upstream of PDCD5 in the genotoxic stress apoptosis cascade.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay, knockdown/rescue with point mutants, p53 activation readouts\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, deubiquitination assay, epistasis via mutant rescue, single lab\",\n      \"pmids\": [\"25499082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OTUD5 localizes to DNA double-strand breaks (DSBs), interacts with UBR5 and SPT16 (FACT component) through two distinct regions, stabilizes UBR5, and represses RNA Pol II elongation and RNA synthesis at damaged chromatin. Both its catalytic activity (via UBR5 stabilization) and scaffolding activity (via FACT binding) are required for Pol II arrest at lesions. A cancer-associated UIM missense mutation abrogates FACT association and Pol II arrest.\",\n      \"method\": \"DUB RNAi screen, Co-immunoprecipitation, localization by imaging, RNA synthesis assays, domain mapping, cancer mutation analysis\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNAi screen, Co-IP, imaging, functional RNA synthesis assay), single lab\",\n      \"pmids\": [\"30508113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OTUD5 deubiquitinates and stabilizes Ku80, promoting NHEJ repair of DNA DSBs. OTUD5 depletion impaired NHEJ, caused excess end resection, and facilitated HR repair during S/G2 phase.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, NHEJ/HR reporter assays, knockdown with DSB repair readouts\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and functional DNA repair assays, single lab\",\n      \"pmids\": [\"30980112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OTUD5 interacts with STING, cleaves its K48-linked polyubiquitin chains, and promotes STING stability, thereby supporting type I IFN signaling after cytosolic DNA stimulation. Myeloid-specific OTUD5 knockout mice showed faster STING turnover and were more susceptible to HSV-1 and melanoma.\",\n      \"method\": \"Co-immunoprecipitation, K48-ubiquitin-specific deubiquitination assay, conditional knockout mouse models (Lyz2-Cre and CD11c-Cre), western blot, IFN measurement\",\n      \"journal\": \"Cellular & Molecular Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, linkage-specific DUB assay, two independent conditional KO mouse models with defined in vivo phenotypes\",\n      \"pmids\": [\"32879469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OTUD5 deubiquitinates TRIM25, reducing its ubiquitination level and decreasing TRIM25-driven transcriptional activity, leading to elevated PML expression and tumor suppression. OTUD5 knockdown enhances TRIM25 transcriptional activity and accelerates tumor growth in nude mice.\",\n      \"method\": \"RNAi screen, Co-immunoprecipitation, ubiquitination assay, nude mouse xenograft, western blot\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi screen, Co-IP, ubiquitination assay, in vivo xenograft, single lab\",\n      \"pmids\": [\"32826889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OTUD5 stabilizes βTrCP1 via its deubiquitinase activity, leading to degradation of DEPTOR (an mTORC1/2 inhibitor), thereby acting as a positive regulator of mTOR complex 1 and 2 signaling. mTOR directly phosphorylates OTUD5 and activates its DUB activity, forming a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, DUB activity assays, RNA-seq, cell size/autophagy phenotyping, Drosophila genetic rescue (RNAi of duba suppresses dRheb-induced wing phenotype), knockdown in mTOR-mutant cancer lines\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional assays, Drosophila in vivo genetics, single lab\",\n      \"pmids\": [\"33110214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OTUD5 interacts with and deubiquitinates YAP in macrophages, stabilizing YAP and promoting M2 macrophage polarization, which in turn favors triple-negative breast cancer metastasis via the MCP-1/CCR2 pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, macrophage polarization assays, in vivo tumor models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional polarization and tumor assays, single lab\",\n      \"pmids\": [\"33587979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OTUD5 is a K48/K63 linkage-specific deubiquitylase that controls neuroectodermal differentiation by cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators including ARID1A/B, HDAC2, and HCF1. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Pathogenic hemizygous variants in OTUD5 cause a new disorder (LINKED syndrome).\",\n      \"method\": \"Patient variant identification, biochemical ubiquitin linkage specificity assays, chromatin accessibility (ATAC-seq), gene expression analysis, structure-function via patient mutations\",\n      \"journal\": \"Science Advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — linkage-specific biochemical assays, ATAC-seq, patient variant epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"33523931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OTUD5 deubiquitinates and stabilizes RNF186 (a RING-type E3 ligase), and the stabilized RNF186 promotes degradation of sestrin2 (an mTOR inhibitor), thereby activating mTOR signaling and promoting bladder cancer progression (OTUD5-RNF186-sestrin2-mTOR axis).\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, western blot, in vivo tumor models\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional cancer progression assays, single lab\",\n      \"pmids\": [\"36085200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OTUD5 deubiquitinates and stabilizes PTEN in non-small cell lung cancer cells, suppressing cell proliferation, invasion, and migration. miR-652-3p targets and inhibits OTUD5 expression, thereby promoting NSCLC progression through reduced PTEN stability.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, dual-luciferase assay for miRNA targeting, knockdown/overexpression with functional readouts\",\n      \"journal\": \"Bosnian Journal of Basic Medical Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, dual-luciferase validation, single lab\",\n      \"pmids\": [\"35765958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OTUD5 binds GPX4 and stabilizes it by removing ubiquitin chains, conferring ferroptosis resistance. During ischemia-reperfusion, mTORC1-mediated autophagy degrades OTUD5, leading to subsequent GPX4 decay and ferroptosis in renal tubular cells. AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal recovery.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, OTUD5 knockout/AAV overexpression, spatial transcriptomics, in vivo I/R injury model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assay, genetic KO, AAV rescue, in vivo models with multiple orthogonal methods\",\n      \"pmids\": [\"38110369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DUBA (OTUD5) deubiquitinates SLC7A11, stabilizing it and promoting resistance to ferroptosis in differentiated cancer cells. DUBA also promotes stemness via SLC7A11 stabilization; SLC7A11 then increases c-Myc expression through cysteine, defining a DUBA-SLC7A11-c-Myc axis critical for cancer stem cell ferroptosis resistance.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, in vitro ferroptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional ferroptosis assays, single lab\",\n      \"pmids\": [\"37537342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OTUD5 assembles a complex containing FACT, HDAC1, and HDAC2 at replication forks through its C-terminal disordered tail. OTUD5 recruits and stabilizes HDAC1/2, decreasing H4K16 acetylation and limiting FACT loading, R-loop formation, and replication fork stress. Disruption of OTUD5-FACT interaction activates the Fanconi Anemia pathway for survival.\",\n      \"method\": \"RNAi depletion, iPOND (replication fork proteomics), FACT-interaction domain mapping, R-loop assays, H4K16ac ChIP, engineered cell lines uncoupling FACT-OTUD5 interaction\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, Co-IP, ChIP, R-loop assay, engineered cell lines), single lab\",\n      \"pmids\": [\"37713620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OTUD5 interacts with VDAC2 and cleaves K48-linked polyubiquitin chains from VDAC2, inhibiting its proteasomal degradation. OTUD5-mediated VDAC2 stabilization is required for mitochondrial homeostasis protection against hepatic steatosis in MASH.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, hepatocyte-specific Otud5 knockout mouse, metabolomics\",\n      \"journal\": \"Cellular and Molecular Gastroenterology and Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, MS substrate identification, K48-specific DUB assay, hepatocyte-specific KO mouse, single lab\",\n      \"pmids\": [\"38036082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD5 deubiquitinates K63-linked ubiquitin chains on TAK1 at K158 via its active site C224, preventing TAK1 phosphorylation and reducing downstream NF-κB/MAPK inflammatory responses in podocytes. Podocyte-specific Otud5 KO exacerbates DKD and AAV9-OTUD5 overexpression is protective.\",\n      \"method\": \"Mass spectrometry substrate identification, Co-immunoprecipitation, K63-specific deubiquitination assay, active-site mutagenesis (C224), podocyte-specific KO mouse, AAV9 overexpression\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — MS substrate identification, Co-IP, K63-specific DUB assay with active site mutagenesis, conditional KO and AAV rescue in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"38937512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD5 promotes end-joining of deprotected telomeres by stabilizing UBR5, which is required for DNA damage-induced ATM activity. OTUD5 facilitates ATM-dependent phosphorylation of KAP1 at S824, enabling heterochromatin-associated DNA repair. Loss of OTUD5 impairs KAP1S824 phosphorylation and suppresses end-joining at deprotected telomeres and heterochromatin DSBs.\",\n      \"method\": \"Functional genetic screen, Co-immunoprecipitation, phosphorylation assays, OTUD5 KO cell lines, telomere dysfunction assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen, Co-IP, phosphorylation readouts, KO cells with defined phenotype, single lab\",\n      \"pmids\": [\"39420004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD5 deubiquitinates SLC7A11, cleaving K48-linked polyubiquitin chains and enhancing SLC7A11 stability, thereby promoting TNBC progression and paclitaxel resistance by modulating ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation, K48-specific ubiquitination assay, knockdown/overexpression, ferroptosis assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K48-specific DUB assay, functional ferroptosis assays, single lab\",\n      \"pmids\": [\"39276913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD5 deubiquitinates and stabilizes SLC38A1 by preventing ubiquitin-mediated proteasomal degradation, thereby promoting HCC cell proliferation.\",\n      \"method\": \"Mass spectrometry, Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, in vivo tumor model\",\n      \"journal\": \"Biology Direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS substrate identification, Co-IP, ubiquitination assay, in vivo xenograft, single lab\",\n      \"pmids\": [\"38658981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD5 promotes K63-linked polyubiquitination of α-synuclein (independent of its DUB catalytic activity) and mediates its endolysosomal degradation by recruiting the E3 ligase NEDD4. OTUD5 conditional KO in dopaminergic neurons worsens α-synuclein pathology after preformed fibril injection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, catalytic mutant analysis, conditional KO mouse model with α-Syn PFF injection, lysosomal degradation assays\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, catalytic mutant, conditional KO with disease model, single lab\",\n      \"pmids\": [\"39721018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP11 deubiquitinates OTUD5 (increasing its protein levels), and the USP11-OTUD5 axis activates STING-dependent inflammatory signaling in endothelial cells to exacerbate radiation-induced pneumonitis.\",\n      \"method\": \"Proteomics/ubiquitinomics after USP11 overexpression, Co-immunoprecipitation, Usp11-KO mouse model, AAV-OTUD5 overexpression in lung, western blot\",\n      \"journal\": \"International Journal of Radiation Oncology, Biology, Physics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteome/ubiquitinome profiling, Co-IP, KO mouse, AAV rescue, single lab\",\n      \"pmids\": [\"38364946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CacyBP interacts with OTUD5, enhances its ubiquitination, and promotes its proteasomal degradation, thereby reducing OTUD5 protein levels and driving lung adenocarcinoma tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, cancer cell functional assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay, single lab, limited mechanistic depth\",\n      \"pmids\": [\"38558058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DUBA (OTUD5) undergoes self-deubiquitination in activated microglia, stabilizing itself. Stabilized DUBA then deubiquitinates IRAK1 (removing K48-linked chains), preventing IRAK1 degradation and enhancing NF-κB and MAPK signaling to promote neuroinflammation. Microglial-specific DUBA ablation mitigates LPS-induced depression-like behavior and ischemic stroke injury.\",\n      \"method\": \"Co-immunoprecipitation, K48-specific DUB assay, microglial-specific KO mouse, LPS and stroke in vivo models\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K48-specific DUB assay, microglial-specific KO mouse with defined in vivo phenotypes, single lab\",\n      \"pmids\": [\"40755418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DUBA (OTUD5) interacts with NOD2 and RIPK2, removing K48-linked polyubiquitin chains from both proteins through its enzymatic activity, thereby preventing their proteasomal degradation and sustaining NOD2-mediated innate immune signaling in macrophages.\",\n      \"method\": \"Co-immunoprecipitation, K48-specific ubiquitination assay, macrophage-specific KO mouse, cytokine measurement, MDP stimulation\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific DUB assay, macrophage-specific KO mouse with defined in vivo phenotypes, single lab\",\n      \"pmids\": [\"40240520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD5 directly interacts with and deubiquitinates TIF1γ. The stabilized TIF1γ attenuates TGF-β-induced SMAD3/4 complex formation, blocking TGF-β-induced EMT and NSCLC metastasis. TGF-β stimulation represses OTUD5 transcription via SMAD3/4, forming an OTUD5-TIF1γ-SMAD3/4 positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, TGF-β signaling readouts (SMAD3/4 complex), NSCLC in vitro/in vivo metastasis assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis via siRNA rescue, in vivo metastasis model, single lab\",\n      \"pmids\": [\"42185242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD5 deubiquitinates GPX4 and stabilizes it; p53 activation (e.g., by nutlin-3a) suppresses OTUD5 transcription, leading to GPX4 degradation and sensitization of gastric cancer cells to ferroptosis. Only wild-type p53 (not mutant) suppresses OTUD5 transcription.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, CRISPR-Cas9 Otud5 KO, subcutaneous tumor model, immunofluorescence, flow cytometry\",\n      \"journal\": \"Clinical and Translational Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, CRISPR KO, in vivo model, multiple methods, single lab\",\n      \"pmids\": [\"40070026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD5 stabilizes TRAF4 by removing ubiquitin chains, and stabilized TRAF4 activates the p38/JNK signaling pathway to promote apoptosis and oxidative stress in hyperoxia-induced lung injury.\",\n      \"method\": \"Co-immunoprecipitation, dual immunofluorescence, AAV9-siOTUD5 in vivo silencing, TUNEL/cleaved caspase-3 apoptosis assays, western blot\",\n      \"journal\": \"Tissue & Cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and in vivo silencing, single lab, limited mechanistic depth on DUB linkage specificity\",\n      \"pmids\": [\"40513425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OTUD5 stabilizes GSK3β by removing K48-linked ubiquitin chains; a pathogenic variant (p.Val233Met) in the OTU domain reduces this DUB activity, accelerating GSK3β degradation (shortening half-life by ~40%), causing aberrant NPC proliferation and impaired neuronal differentiation.\",\n      \"method\": \"iPSC-derived NPCs, CRISPR-corrected isogenic controls, Co-IP/mass spectrometry substrate identification, ubiquitination assay, cycloheximide chase, Ki67/Tuj1 immunofluorescence, flow cytometry\",\n      \"journal\": \"Stem Cell Research & Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS substrate ID, Co-IP, ubiquitination assay, CHX chase, isogenic iPSC model, single lab\",\n      \"pmids\": [\"41851816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Drosophila DUBA (ortholog of OTUD5) physically interacts with the initiator caspase Dronc and deubiquitylates it, contributing to efficient apoptosis. DUBA-null Drosophila are male sterile with defects in spermatid individualisation and reduced caspase activity; genetic rescue experiments demonstrate that DUBA phosphorylation and catalytic activity are required in vivo for spermatogenesis.\",\n      \"method\": \"Co-immunoprecipitation (Drosophila), genetic null mutant, genetic rescue with phosphomimetic/catalytic mutants, caspase activity assays\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genetic null, in vivo rescue with catalytic and phospho-mutants, single lab (Drosophila ortholog)\",\n      \"pmids\": [\"27518434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-1R1 signaling is required for TLR9-dependent K63-linked ubiquitination of TRAF3; in the absence of IL-1R1, DUBA (OTUD5) expression is upregulated and cleaves K63-linked ubiquitin from TRAF3, impairing type I IFN and IL-10 production. DUBA siRNA augmented TLR9-dependent IFN response.\",\n      \"method\": \"siRNA knockdown, Il1r1-/- mice, K63-ubiquitin-specific pulldown, cytokine measurement\",\n      \"journal\": \"Journal of Experimental Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse KO, K63-ubiquitin assay, siRNA, multiple readouts; independent replication of TRAF3 K63-deubiquitination finding\",\n      \"pmids\": [\"21115691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OTUD5 physically interacts with IRF7 and inhibits its K63-linked ubiquitination, thereby suppressing IRF7 transcriptional activation and reducing type I IFN production. OTUD5 was identified as a negative regulator of IRF7 in a DUB-targeted siRNA genetic screen.\",\n      \"method\": \"DUB-targeted siRNA genetic screen, Co-immunoprecipitation, K63-ubiquitination assay, IFN reporter assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and K63-specific ubiquitination assay, siRNA screen, single lab, preprint only\",\n      \"pmids\": [\"bio_10.1101_2025.09.09.675186\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A focused CRISPR screen identified OTUD5 as a regulator of KAT2A stability when the SAGA CORE is disrupted; OTUD5 (together with UBR5) functions in orphan quality-control of unassembled KAT2A.\",\n      \"method\": \"CRISPR screen, western blot validation\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — CRISPR screen hit only, no direct biochemical characterization of OTUD5-KAT2A interaction, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.07.24.666361\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"OTUD5 (DUBA) is a phosphorylation-activated cysteine deubiquitinase (activated by Ser177 phosphorylation) that cleaves K48- and/or K63-linked polyubiquitin chains from a broad range of substrates—including TRAF3 (K63), STING (K48), TAK1 (K63), p53, PDCD5, GPX4, Ku80, IRAK1, NEDD4-recruited α-synuclein, YAP, SLC7A11, βTrCP1, VDAC2, PTEN, TRIM25, RNF186, and chromatin regulators (ARID1A/B, HDAC2, HCF1)—to regulate innate immunity, DNA damage responses, ferroptosis, mTOR signaling, replication fork integrity, and neuroectodermal development; a UIM domain is required for efficient substrate deubiquitination and an OTUD5-UBR5 complex mediates transcription regulation at damaged chromatin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OTUD5 (DUBA) is a phosphorylation-activated cysteine deubiquitinase that cleaves both K48- and K63-linked polyubiquitin chains to control substrate stability and signaling across innate immunity, DNA damage responses, ferroptosis, and development [#0, #11]. Its catalytic activity is switched on by phosphorylation of a single residue, Ser177, which together with ubiquitin C-terminal tail binding folds the enzyme around its substrate—the structural basis for its phospho-dependent activation [#1], and an internal ubiquitin interaction motif (UIM) is required for efficient substrate deubiquitination [#0]. In innate immunity OTUD5 acts bidirectionally: it removes K63 chains from TRAF3 to dissociate it from the TBK1 complex and dampen type I interferon [#0], yet stabilizes STING by cleaving its K48 chains to support interferon signaling after cytosolic DNA sensing [#7], and stabilizes NOD2/RIPK2 to sustain innate signaling in macrophages [#26]. At damaged chromatin and replication forks OTUD5 has both catalytic and scaffolding roles, stabilizing UBR5 and binding the FACT component SPT16 to arrest RNA Pol II elongation [#5], stabilizing Ku80 to promote NHEJ [#6], and assembling an HDAC1/2-FACT complex through its C-terminal disordered tail to limit R-loop formation and replication stress [#16]. A recurring theme is stabilization of metabolic and survival factors—GPX4 and SLC7A11 to confer ferroptosis resistance [#14, #15], βTrCP1 and RNF186 to activate mTOR signaling [#9, #12], and p53 via PDCD5 to enable genotoxic-stress apoptosis [#3, #4]. Hemizygous pathogenic OTUD5 variants cause LINKED syndrome, a neuroectodermal developmental disorder, reflecting its role in deubiquitinating chromatin regulators (ARID1A/B, HDAC2, HCF1) to maintain enhancer accessibility during differentiation [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established OTUD5/DUBA as a deubiquitinase with a defined substrate and immune function, answering whether it acts on a specific signaling node.\",\n      \"evidence\": \"siRNA screen, Co-IP, and in vitro DUB assay showing K63-chain removal from TRAF3 and UIM requirement\",\n      \"pmids\": [\"17991829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain how DUB activity itself is regulated\", \"Linkage specificity beyond K63 not yet defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Confirmed the TRAF3 K63-deubiquitination model in an independent immune context and tied DUBA expression to IL-1R1 status.\",\n      \"evidence\": \"siRNA, Il1r1-/- mice, and K63-ubiquitin-specific pulldown with cytokine readouts\",\n      \"pmids\": [\"21115691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism controlling DUBA upregulation not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Solved how the enzyme is switched on, showing phosphorylation at Ser177 is necessary and sufficient for catalysis—a structural basis for conditional activation.\",\n      \"evidence\": \"Crystal structure of ubiquitin aldehyde adduct plus phosphomimetic/phospho-dead mutagenesis and in vitro activity\",\n      \"pmids\": [\"22245969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the activating kinase(s) in vivo not established here\", \"Whether all substrate engagements require Ser177 phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended substrate range to the DNA damage axis by showing direct p53 deubiquitination and stabilization.\",\n      \"evidence\": \"Co-IP, in vitro DUB assay, and apoptosis readouts with knockdown/overexpression\",\n      \"pmids\": [\"24143256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Linkage type on p53 not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed OTUD5 within reciprocal stabilization circuits—with UBR5 in T cells and with PDCD5 upstream of p53—revealing context-dependent partner relationships.\",\n      \"evidence\": \"Reciprocal Co-IP, conditional KO mouse (UBR5/RORγt), and mutant-rescue epistasis (PDCD5 E94D)\",\n      \"pmids\": [\"25470037\", \"25499082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DUBA abundance is set by UBR5 versus stabilizing UBR5 across cell types not fully reconciled\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated conserved in vivo requirement for both phosphorylation and catalysis using the Drosophila ortholog acting on caspase Dronc.\",\n      \"evidence\": \"Drosophila Co-IP, null mutant, and rescue with phosphomimetic/catalytic mutants with caspase assays\",\n      \"pmids\": [\"27518434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian caspase substrate not demonstrated\", \"Single ortholog system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined dual catalytic and scaffolding functions at DNA double-strand breaks, coupling UBR5 stabilization and FACT binding to transcriptional silencing and NHEJ.\",\n      \"evidence\": \"RNAi screen, Co-IP, imaging, RNA synthesis assays, domain mapping, plus Ku80 stabilization and NHEJ/HR reporter assays\",\n      \"pmids\": [\"30508113\", \"30980112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recruitment mechanism to lesions not fully mapped\", \"Single lab for each arm\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadened the substrate landscape to STING (K48), TRIM25, and the mTOR axis via βTrCP1/DEPTOR, showing OTUD5 can stabilize either immune-positive or growth-promoting nodes.\",\n      \"evidence\": \"Conditional KO mice, K48-specific DUB assays, Co-IP, xenografts, and Drosophila genetic rescue of dRheb phenotype\",\n      \"pmids\": [\"32879469\", \"32826889\", \"33110214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How linkage selectivity (K48 vs K63) is determined per substrate unresolved\", \"Feedback with mTOR phosphorylation of OTUD5 not structurally defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked OTUD5 to human disease and chromatin control, establishing that K48-cleavage of chromatin regulators maintains enhancer accessibility during neuroectodermal differentiation.\",\n      \"evidence\": \"Patient variant identification, linkage-specific biochemistry, ATAC-seq, and structure-function via patient mutations; YAP deubiquitination in macrophages\",\n      \"pmids\": [\"33523931\", \"33587979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of developmentally relevant substrates not enumerated\", \"Mechanism connecting variants to specific enhancer defects incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Consolidated OTUD5 as a ferroptosis and metabolic-homeostasis regulator by stabilizing GPX4, SLC7A11, and VDAC2, and added a replication-fork chromatin complex with HDAC1/2-FACT.\",\n      \"evidence\": \"Co-IP, K48-specific ubiquitination assays, genetic KO/AAV rescue in vivo, iPOND, ChIP, and R-loop assays\",\n      \"pmids\": [\"38110369\", \"37537342\", \"38036082\", \"37713620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these substrate sets are regulated by the same activation cue is unclear\", \"Tissue-specific selectivity mechanisms unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved active-site-dependent K63 cleavage of TAK1 and added catalysis-independent substrate handling, showing OTUD5 can also recruit an E3 ligase (NEDD4) to promote α-synuclein degradation.\",\n      \"evidence\": \"MS substrate ID, K63-specific DUB assay with C224 active-site mutagenesis, conditional KO/AAV in vivo, and catalytic-mutant analysis for α-synuclein\",\n      \"pmids\": [\"38937512\", \"39721018\", \"39420004\", \"38658981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How OTUD5 switches between catalytic and ligase-recruiting modes is undefined\", \"ATM/KAP1 axis mechanism single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the regulatory network—self-deubiquitination stabilizing OTUD5, IRAK1/NOD2/RIPK2 control in inflammation, TIF1γ/TGF-β feedback, and upstream regulators USP11 and CacyBP—mapping how OTUD5 levels themselves are tuned.\",\n      \"evidence\": \"Cell-type-specific KO mice, K48-specific DUB assays, Co-IP, ubiquitinomics, and in vivo disease models\",\n      \"pmids\": [\"40755418\", \"40240520\", \"42185242\", \"38364946\", \"38558058\", \"40070026\", \"40513425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several axes rest on single-lab evidence\", \"Some studies (TRAF4, CacyBP) lack linkage-specificity detail\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected a specific pathogenic OTU-domain variant to reduced DUB activity and a developmental phenotype via GSK3β destabilization, tying biochemical loss-of-function to neural progenitor defects.\",\n      \"evidence\": \"Isogenic iPSC-derived NPCs, CRISPR correction, MS substrate ID, ubiquitination and CHX-chase assays\",\n      \"pmids\": [\"41851816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single iPSC system\", \"Relationship to LINKED-syndrome chromatin substrates not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OTUD5 achieves substrate- and linkage-selective deubiquitination (K48 vs K63) across its very broad substrate set, and which upstream kinases gate Ser177-dependent activation in each context, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for substrate selection\", \"Activating kinases per pathway largely unidentified\", \"Catalytic versus scaffolding/ligase-recruiting mode switching uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 7, 11, 18]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 18]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [5, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 7, 26]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5, 6, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 14, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 12, 27]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [11, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 30]}\n    ],\n    \"complexes\": [\"OTUD5-UBR5 complex\", \"OTUD5-FACT-HDAC1/2 complex\"],\n    \"partners\": [\"UBR5\", \"TRAF3\", \"STING1\", \"TAK1\", \"Ku80\", \"GPX4\", \"SLC7A11\", \"VDAC2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}