Affinage

OTUD5

OTU domain-containing protein 5 · UniProt Q96G74

Length
571 aa
Mass
60.6 kDa
Annotated
2026-06-10
52 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2007 High

    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

    PMID:17991829

    Open questions at the time
    • Did not explain how DUB activity itself is regulated
    • Linkage specificity beyond K63 not yet defined
  2. 2010 Medium

    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

    PMID:21115691

    Open questions at the time
    • Mechanism controlling DUBA upregulation not resolved
  3. 2012 High

    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

    PMID:22245969

    Open questions at the time
    • Identity of the activating kinase(s) in vivo not established here
    • Whether all substrate engagements require Ser177 phosphorylation unknown
  4. 2013 Medium

    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

    PMID:24143256

    Open questions at the time
    • Single lab
    • Linkage type on p53 not defined
  5. 2014 High

    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)

    PMID:25470037 PMID:25499082

    Open questions at the time
    • How DUBA abundance is set by UBR5 versus stabilizing UBR5 across cell types not fully reconciled
  6. 2016 Medium

    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

    PMID:27518434

    Open questions at the time
    • Mammalian caspase substrate not demonstrated
    • Single ortholog system
  7. 2019 Medium

    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

    PMID:30508113 PMID:30980112

    Open questions at the time
    • Recruitment mechanism to lesions not fully mapped
    • Single lab for each arm
  8. 2020 High

    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

    PMID:32826889 PMID:32879469 PMID:33110214

    Open questions at the time
    • How linkage selectivity (K48 vs K63) is determined per substrate unresolved
    • Feedback with mTOR phosphorylation of OTUD5 not structurally defined
  9. 2021 High

    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

    PMID:33523931 PMID:33587979

    Open questions at the time
    • Full set of developmentally relevant substrates not enumerated
    • Mechanism connecting variants to specific enhancer defects incomplete
  10. 2023 High

    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

    PMID:37537342 PMID:37713620 PMID:38036082 PMID:38110369

    Open questions at the time
    • Whether these substrate sets are regulated by the same activation cue is unclear
    • Tissue-specific selectivity mechanisms unknown
  11. 2024 High

    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

    PMID:38658981 PMID:38937512 PMID:39420004 PMID:39721018

    Open questions at the time
    • How OTUD5 switches between catalytic and ligase-recruiting modes is undefined
    • ATM/KAP1 axis mechanism single lab
  12. 2025 Medium

    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

    PMID:38364946 PMID:38558058 PMID:40070026 PMID:40240520 PMID:40513425 PMID:40755418 PMID:42185242

    Open questions at the time
    • Several axes rest on single-lab evidence
    • Some studies (TRAF4, CacyBP) lack linkage-specificity detail
  13. 2026 Medium

    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

    PMID:41851816

    Open questions at the time
    • Single iPSC system
    • Relationship to LINKED-syndrome chromatin substrates not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unifying model for substrate selection
  • Activating kinases per pathway largely unidentified
  • Catalytic versus scaffolding/ligase-recruiting mode switching uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016787 hydrolase activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-73894 DNA Repair 3 R-HSA-1266738 Developmental Biology 2 R-HSA-4839726 Chromatin organization 2
Partners
GPX4KU80SLC7A11STING1TAK1TRAF3UBR5VDAC2
Complex memberships
OTUD5-FACT-HDAC1/2 complexOTUD5-UBR5 complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 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. siRNA screen, Co-immunoprecipitation, in vitro deubiquitination assay, ectopic expression gain/loss-of-function Science High 17991829
2012 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. Crystal structure of ubiquitin aldehyde adduct, phosphomimetic/phospho-dead mutagenesis, in vitro DUB activity assays Nature Structural & Molecular Biology High 22245969
2014 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. Co-immunoprecipitation, T cell-specific conditional knockout mouse, cytokine measurement, western blot Nature High 25470037
2013 OTUD5 directly interacts with and deubiquitinates p53, stabilizing it and enabling rapid p53-dependent transcription and apoptosis in response to DNA damage stress. Co-immunoprecipitation, in vitro deubiquitination assay, overexpression/knockdown with apoptosis readouts PloS one Medium 24143256
2014 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. Co-immunoprecipitation, in vitro deubiquitination assay, knockdown/rescue with point mutants, p53 activation readouts Cancer letters Medium 25499082
2019 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. DUB RNAi screen, Co-immunoprecipitation, localization by imaging, RNA synthesis assays, domain mapping, cancer mutation analysis Nucleic Acids Research Medium 30508113
2019 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. Co-immunoprecipitation, ubiquitination assay, NHEJ/HR reporter assays, knockdown with DSB repair readouts Cellular and Molecular Life Sciences Medium 30980112
2020 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. Co-immunoprecipitation, K48-ubiquitin-specific deubiquitination assay, conditional knockout mouse models (Lyz2-Cre and CD11c-Cre), western blot, IFN measurement Cellular & Molecular Immunology High 32879469
2020 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. RNAi screen, Co-immunoprecipitation, ubiquitination assay, nude mouse xenograft, western blot Nature Communications Medium 32826889
2020 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. 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 Cell Death and Differentiation Medium 33110214
2021 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. Co-immunoprecipitation, ubiquitination assay, macrophage polarization assays, in vivo tumor models Cancer letters Medium 33587979
2021 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). Patient variant identification, biochemical ubiquitin linkage specificity assays, chromatin accessibility (ATAC-seq), gene expression analysis, structure-function via patient mutations Science Advances High 33523931
2022 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). Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, western blot, in vivo tumor models Cell Death & Disease Medium 36085200
2022 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. Co-immunoprecipitation, ubiquitination assay, dual-luciferase assay for miRNA targeting, knockdown/overexpression with functional readouts Bosnian Journal of Basic Medical Sciences Medium 35765958
2023 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. Co-immunoprecipitation, ubiquitination assay, OTUD5 knockout/AAV overexpression, spatial transcriptomics, in vivo I/R injury model Nature Communications High 38110369
2023 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. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, in vitro ferroptosis assays Oncogene Medium 37537342
2023 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. RNAi depletion, iPOND (replication fork proteomics), FACT-interaction domain mapping, R-loop assays, H4K16ac ChIP, engineered cell lines uncoupling FACT-OTUD5 interaction Nucleic Acids Research Medium 37713620
2023 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. Co-immunoprecipitation, mass spectrometry, ubiquitination assay, hepatocyte-specific Otud5 knockout mouse, metabolomics Cellular and Molecular Gastroenterology and Hepatology Medium 38036082
2024 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. Mass spectrometry substrate identification, Co-immunoprecipitation, K63-specific deubiquitination assay, active-site mutagenesis (C224), podocyte-specific KO mouse, AAV9 overexpression Nature Communications High 38937512
2024 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. Functional genetic screen, Co-immunoprecipitation, phosphorylation assays, OTUD5 KO cell lines, telomere dysfunction assays Nature Communications Medium 39420004
2024 OTUD5 deubiquitinates SLC7A11, cleaving K48-linked polyubiquitin chains and enhancing SLC7A11 stability, thereby promoting TNBC progression and paclitaxel resistance by modulating ferroptosis. Co-immunoprecipitation, K48-specific ubiquitination assay, knockdown/overexpression, ferroptosis assays Cancer letters Medium 39276913
2024 OTUD5 deubiquitinates and stabilizes SLC38A1 by preventing ubiquitin-mediated proteasomal degradation, thereby promoting HCC cell proliferation. Mass spectrometry, Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, in vivo tumor model Biology Direct Medium 38658981
2024 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. Co-immunoprecipitation, ubiquitination assay, catalytic mutant analysis, conditional KO mouse model with α-Syn PFF injection, lysosomal degradation assays Advanced Science Medium 39721018
2024 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. Proteomics/ubiquitinomics after USP11 overexpression, Co-immunoprecipitation, Usp11-KO mouse model, AAV-OTUD5 overexpression in lung, western blot International Journal of Radiation Oncology, Biology, Physics Medium 38364946
2024 CacyBP interacts with OTUD5, enhances its ubiquitination, and promotes its proteasomal degradation, thereby reducing OTUD5 protein levels and driving lung adenocarcinoma tumorigenesis. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, cancer cell functional assays Carcinogenesis Low 38558058
2025 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. Co-immunoprecipitation, K48-specific DUB assay, microglial-specific KO mouse, LPS and stroke in vivo models Advanced Science Medium 40755418
2025 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. Co-immunoprecipitation, K48-specific ubiquitination assay, macrophage-specific KO mouse, cytokine measurement, MDP stimulation Cell Death and Differentiation Medium 40240520
2025 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. Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, TGF-β signaling readouts (SMAD3/4 complex), NSCLC in vitro/in vivo metastasis assays Cell Death & Disease Medium 42185242
2025 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. Co-immunoprecipitation, ubiquitination assay, CRISPR-Cas9 Otud5 KO, subcutaneous tumor model, immunofluorescence, flow cytometry Clinical and Translational Medicine Medium 40070026
2025 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. Co-immunoprecipitation, dual immunofluorescence, AAV9-siOTUD5 in vivo silencing, TUNEL/cleaved caspase-3 apoptosis assays, western blot Tissue & Cell Low 40513425
2026 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. iPSC-derived NPCs, CRISPR-corrected isogenic controls, Co-IP/mass spectrometry substrate identification, ubiquitination assay, cycloheximide chase, Ki67/Tuj1 immunofluorescence, flow cytometry Stem Cell Research & Therapy Medium 41851816
2016 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. Co-immunoprecipitation (Drosophila), genetic null mutant, genetic rescue with phosphomimetic/catalytic mutants, caspase activity assays Cell Death and Differentiation Medium 27518434
2010 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. siRNA knockdown, Il1r1-/- mice, K63-ubiquitin-specific pulldown, cytokine measurement Journal of Experimental Medicine Medium 21115691
2025 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. DUB-targeted siRNA genetic screen, Co-immunoprecipitation, K63-ubiquitination assay, IFN reporter assays bioRxiv (preprint)preprint Low bio_10.1101_2025.09.09.675186
2025 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. CRISPR screen, western blot validation bioRxiv (preprint)preprint Low bio_10.1101_2025.07.24.666361

Source papers

Stage 0 corpus · 52 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 DUBA: a deubiquitinase that regulates type I interferon production. Science (New York, N.Y.) 391 17991829
2014 Deubiquitinase DUBA is a post-translational brake on interleukin-17 production in T cells. Nature 117 25470037
2012 Phosphorylation-dependent activity of the deubiquitinase DUBA. Nature structural & molecular biology 103 22245969
2020 OTUD5 promotes innate antiviral and antitumor immunity through deubiquitinating and stabilizing STING. Cellular & molecular immunology 86 32879469
2021 OTUD5-mediated deubiquitination of YAP in macrophage promotes M2 phenotype polarization and favors triple-negative breast cancer progression. Cancer letters 71 33587979
2023 Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury. Nature communications 64 38110369
2019 The OTUD5-UBR5 complex regulates FACT-mediated transcription at damaged chromatin. Nucleic acids research 62 30508113
2010 Interleukin 1 receptor signaling regulates DUBA expression and facilitates Toll-like receptor 9-driven antiinflammatory cytokine production. The Journal of experimental medicine 61 21115691
2013 OTUD5 regulates p53 stability by deubiquitinating p53. PloS one 47 24143256
2020 OTUD5 cooperates with TRIM25 in transcriptional regulation and tumor progression via deubiquitination activity. Nature communications 46 32826889
2024 Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury. Nature communications 41 38937512
2014 Deubiquitinase OTUD5 mediates the sequential activation of PDCD5 and p53 in response to genotoxic stress. Cancer letters 39 25499082
2021 Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation. Science advances 37 33523931
2023 The DUBA-SLC7A11-c-Myc axis is critical for stemness and ferroptosis. Oncogene 36 37537342
2022 Deubiquitinase OTUD5 modulates mTORC1 signaling to promote bladder cancer progression. Cell death & disease 31 36085200
2019 The deubiquitinase OTUD5 regulates Ku80 stability and non-homologous end joining. Cellular and molecular life sciences : CMLS 29 30980112
2020 Deubiquitinase OTUD5 is a positive regulator of mTORC1 and mTORC2 signaling pathways. Cell death and differentiation 28 33110214
2024 The deubiquitinase OTUD5 stabilizes SLC7A11 to promote progression and reduce paclitaxel sensitivity in triple-negative breast cancer. Cancer letters 26 39276913
2024 OTUD5 promotes the growth of hepatocellular carcinoma by deubiquitinating and stabilizing SLC38A1. Biology direct 22 38658981
2022 The Deubiquitinating Enzyme OTUD5 Sustains Inflammatory Cytokine Response in Inflammatory Bowel Disease. Journal of Crohn's & colitis 22 34232309
2025 p53 inhibits OTUD5 transcription to promote GPX4 degradation and induce ferroptosis in gastric cancer. Clinical and translational medicine 20 40070026
2023 The Regulation and Double-Edged Roles of the Deubiquitinase OTUD5. Cells 20 37190070
2020 An X-linked syndrome with severe neurodevelopmental delay, hydrocephalus, and early lethality caused by a missense variation in the OTUD5 gene. Clinical genetics 19 33131077
2019 Effect of Deubiquitinase Ovarian Tumor Domain-Containing Protein 5 (OTUD5) on Radiosensitivity of Cervical Cancer by Regulating the Ubiquitination of Akt and its Mechanism. Medical science monitor : international medical journal of experimental and clinical research 17 31075090
2024 USP11 Exacerbates Radiation-Induced Pneumonitis by Activating Endothelial Cell Inflammatory Response via OTUD5-STING Signaling. International journal of radiation oncology, biology, physics 16 38364946
2016 The de-ubiquitylating enzyme DUBA is essential for spermatogenesis in Drosophila. Cell death and differentiation 15 27518434
2022 Mechanism of OTUD5 in non-small cell lung cancer cell proliferation, invasion, and migration. Bosnian journal of basic medical sciences 13 35765958
2024 Dapagliflozin suppressed gastric cancer growth via regulating OTUD5 mediated YAP1 deubiquitination. European journal of pharmacology 11 39293571
2023 Hepatocyte Deubiquitinating Enzyme OTUD5 Deficiency is a Key Aggravator for Metabolic Dysfunction-Associated Steatohepatitis by Disturbing Mitochondrial Homeostasis. Cellular and molecular gastroenterology and hepatology 11 38036082
2021 OTUD5 Variants Associated With X-Linked Intellectual Disability and Congenital Malformation. Frontiers in cell and developmental biology 10 33748114
2018 microRNA-210 participates in regulating RIG-I signaling pathway via targeting DUBA in miiuy croaker after poly(I:C) stimulation. Fish & shellfish immunology 10 29408541
2024 DuBA.flow─A Low-Cost, Long-Read Amplicon Sequencing Workflow for the Validation of Synthetic DNA Constructs. ACS synthetic biology 9 38295293
2023 Deubiquitinase OTUD5 promotes hepatitis B virus replication by removing K48-linked ubiquitination of HBV core/precore and upregulates HNF4ɑ expressions by inhibiting the ERK1/2/mitogen-activated protein kinase pathway. Cellular and molecular life sciences : CMLS 9 37897511
2024 OTUD5 Protects Dopaminergic Neurons by Promoting the Degradation of α-Synuclein in Parkinson's Disease Model. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 8 39721018
2023 OTUD5 limits replication fork instability by organizing chromatin remodelers. Nucleic acids research 8 37713620
2024 OTUD5 promotes end-joining of deprotected telomeres by promoting ATM-dependent phosphorylation of KAP1S824. Nature communications 6 39420004
2025 Regulation of Neuroinflammation by Microglial DUBA-IRAK1-IKKβ Signaling Loop. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 5 40755418
2023 A novel missense variant in OTUD5 causes X-linked multiple congenital anomalies-neurodevelopmental syndrome. Molecular genetics & genomic medicine 4 38037881
2025 DUBA sustains the stability of NOD2 and RIPK2 to enhance innate immune responses. Cell death and differentiation 2 40240520
2025 Overexpression of OTUD5 in IPSCs-derived extracellular vesicles promotes angiogenesis after myocardial infarction by inhibiting endothelial cell ferroptosis. Nutrition, metabolism, and cardiovascular diseases : NMCD 2 41076333
2025 Entrectinib binds to HMGB1 and activates cardiomyocyte autophagy by inhibiting OTUD5-MTORC1 signaling to induce cardiotoxicity. Autophagy 2 41115073
2025 Roles of Deubiquitinases OTUD3 and OTUD5 in Inflammatory Bowel Diseases. International journal of molecular sciences 1 41155222
2024 CacyBP promotes the development of lung adenocarcinoma by regulating OTUD5. Carcinogenesis 1 38558058
2015 DUBA-UBR5 axis: other than transactivation. Cell research 1 25633593
2026 A multifaceted analysis of OTUD5 integrated MAVS in innate immunity of Primary Biliary Cholangitis. PloS one 0 41650163
2026 Saquinavir induces pyroptosis through the OTUD5-JAK1-GSDME axis in hepatocellular carcinoma. Free radical biology & medicine 0 41687749
2026 A novel OTUD5 variant disrupts neural progenitor cell homeostasis: mechanistic insights from HEK293T cell-based analyses. Stem cell research & therapy 0 41851816
2026 Grouper deubiquitinating enzyme ovarian tumor domain-containing protein 5 (OTUD5) stabilizes stimulator of interferon genes (STING) via the autophagy-lysosomal pathway to modulate antiviral innate immunity in fish. International journal of biological macromolecules 0 41937022
2026 OTUD5-TIF1γ-SMAD3/4 positive feedback loop inhibits TGF-β-induced EMT and metastasis in NSCLC. Cell death & disease 0 42185242
2025 OTUD5 enhances activation of multiple cell death pathways and hyperoxia-induced lung injury by stabilizing TRAF4 and activating the p38/JNK pathway. Tissue & cell 0 40513425
2025 Deubiquitinase OTUD5 facilitates stiffness-induced hepatic stellate cell activation by stabilizing YAP. Molecular and cellular biochemistry 0 41324862
2024 Rainbow trout DUBA inhibits type I interferon signaling by deubiquitinating TRAF3. Fish & shellfish immunology 0 38670412

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