Affinage

OTUD4

OTU domain-containing protein 4 · UniProt Q01804

Length
1114 aa
Mass
124.0 kDa
Annotated
2026-06-10
35 papers in source corpus 32 papers cited in narrative 31 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

OTUD4 is an OTU-family deubiquitinase that controls protein stability and inflammatory signaling through three distinct modes of action: linkage-specific catalysis, regulated activation of a latent activity, and catalysis-independent scaffolding (PMID:25944111, PMID:29395066). In its scaffolding mode, OTUD4 catalytic activity is dispensable; instead it recruits the deubiquitinases USP7 and USP9X to stabilize substrates such as the alkylation-repair demethylases ALKBH2/ALKBH3, and recruits USP7 to the KSHV transcription factor K-RTA to promote herpesvirus lytic reactivation (PMID:25944111, PMID:38215174, PMID:40208866). As a catalytic enzyme, OTUD4 nominally cleaves K48-linked polyubiquitin to protect substrates from proteasomal degradation, including the antiviral signaling adaptor MAVS (PMID:30410068) and the histone methyltransferase SETDB1, where stabilization drives H3K9me3, E-cadherin repression, and EMT (PMID:37739210). A separate, phosphorylation-gated mechanism converts OTUD4 into a K63-specific deubiquitinase that, together with an adjacent ubiquitin-interacting motif and a histidine-centered catalytic loop conferring linkage specificity, removes K63 chains from innate-immune signaling components MyD88, TRAF6, and the TAK1/TAB3 signalosome to suppress TLR/TNF-driven NF-κB activation (PMID:29395066, PMID:31964525, PMID:41062071); in Paneth cells this restrains antimicrobial peptide expression and intestinal inflammation (PMID:37193092). Independently of ubiquitin catalysis, OTUD4 is an RNA-binding protein that localizes to neuronal RNA transport granules and is recruited to stress granules, where it is required for granule assembly and cell survival under stress (PMID:31138677). A tumor-associated H148Y variant in the catalytic His loop abolishes both K63 and K48 deubiquitinase activity while retaining substrate binding (PMID:41062071).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2015 High

    Established that OTUD4 can function entirely without its own catalytic activity, redefining it as a scaffold that recruits other DUBs to its substrates.

    Evidence Co-IP, catalytic-mutant analysis, in vitro reconstitution, and cellular alkylation-sensitivity assays linking OTUD4 to USP7/USP9X and ALKBH2/3

    PMID:25944111

    Open questions at the time
    • Structural basis of USP7/USP9X recruitment unresolved
    • Generality of the scaffold mode to other substrates untested at the time
  2. 2018 High

    Showed OTUD4 acts as a K48-linkage deubiquitinase that stabilizes a defined signaling substrate (MAVS) and is transcriptionally induced by infection, placing it in antiviral signaling.

    Evidence Conditional KO mice, reciprocal Co-IP, in vivo VSV challenge, and MAVS reconstitution rescue

    PMID:30410068

    Open questions at the time
    • Direct enzymology of K48 cleavage on MAVS not reconstituted in vitro
    • Relationship to its later-described K63 activity unaddressed
  3. 2018 High

    Resolved how a single OTU domain achieves two opposite outputs by demonstrating that phosphorylation plus a UIM activates a latent K63-specific activity targeting MyD88 to dampen TLR-NF-κB signaling.

    Evidence In vitro DUB assays, phospho- and UIM-mutant analysis, Otud4-/- macrophage TLR stimulation, mass spectrometry

    PMID:29395066

    Open questions at the time
    • Kinase responsible for the activating phosphorylation not identified
    • How K48 vs K63 modes are partitioned in vivo unclear
  4. 2020 Medium

    Extended OTUD4's K63-directed anti-inflammatory role to TRAF6 and to ischemia-reperfusion injury, broadening its NF-κB-suppressing substrate set.

    Evidence Co-IP and overexpression in hypoxia/reoxygenation and hepatic IR mouse models

    PMID:31964525

    Open questions at the time
    • No endogenous loss-of-function validation
    • Linkage-specificity of TRAF6 cleavage not enzymatically confirmed
  5. 2019 Medium

    Identified an entirely non-ubiquitin function: OTUD4 is an RNA-binding protein component of stress/transport granule networks required for granule assembly and survival.

    Evidence Pulldown/MS from brain lysate, RNA-binding assays, immunofluorescence in neurons/HeLa, siRNA knockdown phenotype

    PMID:31138677

    Open questions at the time
    • RNA targets not defined
    • Whether catalytic or scaffold activity contributes to granule function unknown
  6. 2020 Medium

    Showed OTUD4 enhances TGFβ signaling through both catalytic and non-catalytic mechanisms and is itself a TGFβ target, defining a feed-forward loop.

    Evidence Catalytic-mutant analysis, receptor trafficking assays, Co-IP, knockdown/overexpression

    PMID:32973272

    Open questions at the time
    • Direct deubiquitination of SMURF2/TGFβRI not enzymatically dissected
    • Single-lab finding
  7. 2023 High

    Cemented the MyD88 K63 mechanism in a physiological epithelial context, showing OTUD4 in Paneth cells limits antimicrobial peptide output and shapes mucosal immunity.

    Evidence Two-lineage conditional KO mice, organoids, ubiquitination assays, DSS colitis and Salmonella infection models

    PMID:37193092

    Open questions at the time
    • Trigger for OTUD4 activation in Paneth cells unclear
    • Tissue-specific regulation of K48 vs K63 modes not addressed
  8. 2023 Medium

    Expanded OTUD4's K48-substrate repertoire into oncogenic chromatin and EMT regulation by stabilizing SETDB1 (recruited via IRTKS) with site-specific deubiquitination.

    Evidence Co-IP, site-specific ubiquitination mapping (K182/K1050), chromatin accessibility analysis in cancer cells

    PMID:37739210

    Open questions at the time
    • IRTKS-OTUD4 recruitment mechanism not structurally defined
    • Single-lab study
  9. 2022 Medium

    Connected OTUD4 substrate stabilization to cell-death programs by showing it stabilizes GSDME to enhance pyroptosis and radiosensitivity.

    Evidence Co-IP/MS substrate identification, in vitro and in vivo irradiation assays in nasopharyngeal carcinoma

    PMID:36411454

    Open questions at the time
    • Linkage specificity of GSDME deubiquitination not defined
    • Single tumor context
  10. 2024 Medium

    Demonstrated OTUD4 reads and removes non-canonical ubiquitin linkages (K11/K29/K33 on CDK1; K6/K27 on FGFR1), broadening its biochemical linkage repertoire beyond K48/K63.

    Evidence Co-IP, linkage-specific ubiquitination assays, proliferation/invasion and xenograft assays in GBM

    PMID:38429268

    Open questions at the time
    • Direct catalysis on each linkage type not reconstituted in vitro
    • Single-lab finding
  11. 2024 High

    Established OTUD4 as a druggable node in tumor immune evasion by stabilizing CD73 downstream of TGFβ, with a small molecule disrupting the interaction sensitizing to anti-PD-L1.

    Evidence Multiomics, reciprocal Co-IP, ST80 inhibitor studies, preclinical TNBC models, spatial transcriptomics

    PMID:38530357

    Open questions at the time
    • Whether CD73 stabilization is catalytic or scaffold-based not fully dissected
    • Generalizability beyond TNBC unknown
  12. 2024 High

    Confirmed the catalysis-independent scaffold/USP7 mode in a viral setting, stabilizing K-RTA to drive KSHV reactivation and validating peptide disruption in vivo.

    Evidence Co-IP, catalytic-mutant analysis, viral reactivation assays, in vivo murine herpesvirus model with p8 peptide

    PMID:38215174 PMID:40208866

    Open questions at the time
    • Structure of the OTUD4-USP7-K-RTA complex not solved
    • Host triggers of scaffold engagement unclear
  13. 2024 Medium

    Multiple studies extended OTUD4 K48-type substrate stabilization across metabolism, ferroptosis, and tumor biology (PFKFB3, RBM47, GPX4), linking it to glycolysis, ferroptosis suppression, and autophagy.

    Evidence Co-IP, ubiquitination assays, CRISPR KO, autophagy flux and ferroptosis sensitivity assays, in vivo tumor/fibrosis models

    PMID:37162556 PMID:38553613 PMID:40338740

    Open questions at the time
    • Direct enzymology and linkage specificity vary in rigor across substrates
    • Most are single-lab, single-context studies
  14. 2025 High

    Mapped a histidine-centered catalytic loop as the determinant of K63 linkage specificity and showed a tumor-associated H148Y variant abolishes both K48 and K63 activity while retaining binding, linking structure, function, and disease.

    Evidence Co-IP, in vitro DUB assays, His-loop mutagenesis, disease-variant functional analysis, NF-κB assays on TAK1/TAB1/TAB3

    PMID:41062071

    Open questions at the time
    • No crystal/cryo-EM structure of the His loop reported
    • Phenotypic consequences of H148Y in vivo not established
  15. 2025 Medium

    Revealed competitive regulation of OTUD4 substrate access, with SPARC displacing MyD88 to derepress NF-κB signaling in intestinal barrier disruption.

    Evidence Co-IP, SPARC-deficient mice, p65 nuclear translocation assays in a Crohn's disease model

    PMID:39888301

    Open questions at the time
    • Structural basis of competitive binding undefined
    • Single-lab finding
  16. 2026 Low

    Demonstrated context-dependent, even opposing, effects of OTUD4 on the same substrate (YAP), highlighting unresolved control of its linkage output and directionality.

    Evidence Co-IP and ubiquitination assays in ovarian (K63 stabilization model) versus pancreatic (K48 degradation model) cancer cells

    PMID:39778277 PMID:41687501

    Open questions at the time
    • Contradictory K63-stabilizing vs K48-degrading reports not reconciled
    • No shared system or reciprocal validation comparing the two contexts

Open questions

Synthesis pass · forward-looking unresolved questions
  • How OTUD4 switches between K48, K63, non-canonical-linkage catalysis, scaffold function, and RNA-binding within a given cell, and what upstream signals select each mode, remains unresolved.
  • No structural model integrating the OTU domain, His loop, UIM, and RNA-binding regions
  • Kinase(s) and signals governing mode-switching unidentified
  • Contradictory substrate-direction reports (e.g. YAP) unresolved

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 GO:0098772 molecular function regulator activity 2 GO:0140098 catalytic activity, acting on RNA 2 GO:0003723 RNA binding 1
Localization
GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1 R-HSA-8953854 Metabolism of RNA 1
Partners
EGFRGPX4MAVSMYD88TAK1TRAF6USP7USP9X
Complex memberships
TAK1 signalosome (TAK1/TAB1/TAB3)stress granule / neuronal RNA transport granule network

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 OTUD4 acts as a scaffold protein (in a catalytic-activity-independent manner) recruiting deubiquitinases USP7 and USP9X to stabilize the DNA demethylases ALKBH2 and ALKBH3, promoting repair of alkylation DNA damage. OTUD4 catalytic activity is completely dispensable for this scaffolding function. Co-immunoprecipitation, knockdown/knockout with cellular sensitivity assays, in vitro reconstitution, catalytic mutant analysis The EMBO journal High 25944111
2018 OTUD4 deubiquitinates MAVS by removing K48-linked polyubiquitin chains, stabilizing MAVS and promoting innate antiviral (IRF3/NF-κB) signaling. OTUD4 expression is upregulated by viral infection in an IRF3/7-dependent manner. Knockout mice (Cre-ER Otud4fl/fl, Lyz2-Cre Otud4fl/fl), co-immunoprecipitation, in vivo VSV challenge, reconstitution of MAVS in OTUD4-deficient cells Cell research High 30410068
2018 Phosphorylation of OTUD4 near its catalytic domain activates a latent K63-specific deubiquitinase activity (distinct from its nominal K48-specificity). This K63 activity also requires an adjacent ubiquitin-interacting motif (UIM) that increases affinity for K63-linked chains. The activated OTUD4 targets MyD88 for K63 deubiquitination, negatively regulating TLR-mediated NF-κB activation. In vitro deubiquitinase assays, phospho-mutant analysis, UIM mutants, Otud4-/- macrophages with TLR stimulation assays, mass spectrometry Molecular cell High 29395066
2020 OTUD4 interacts with TRAF6 and removes K63-linked auto-polyubiquitin chains from TRAF6, impairing NF-κB activation and reducing inflammatory cytokine levels in hepatic ischemia-reperfusion injury models. Co-immunoprecipitation, overexpression in hypoxia/reoxygenation and hepatic IR mouse models, Western blotting Biochemical and biophysical research communications Medium 31964525
2019 OTUD4 is an RNA-binding protein that is part of a complex network with core stress granule factors (FMRP/FMR1, SMN1, G3BP1, TIA1). OTUD4 localizes to neuronal RNA transport granules under physiological conditions and is recruited to cytoplasmic stress granules upon cellular stress. Knockdown of OTUD4 impairs stress granule formation and leads to apoptotic cell death. Pulldown and mass spectrometry on mouse brain lysates, RNA-binding assays, immunofluorescence in rat hippocampal neurons and HeLa cells, siRNA knockdown Journal of cell science Medium 31138677
2020 OTUD4 enhances TGFβ signaling through both catalytically dependent and independent mechanisms: it promotes membrane presence of TGFβ receptor I and inactivates the TGFβ negative regulator SMURF2. OTUD4 is itself a transcriptional target of TGFβ, forming a positive feedback loop. Catalytic mutant analysis, receptor trafficking assays, co-immunoprecipitation, knockdown/overexpression Scientific reports Medium 32973272
2022 OTUD4 deubiquitinates and stabilizes GSDME (gasdermin E), enhancing irradiation-induced pyroptosis in nasopharyngeal carcinoma cells and increasing radiosensitivity. Immunoprecipitation, mass spectrometry, in vitro and in vivo irradiation assays, Western blotting Journal of experimental & clinical cancer research : CR Medium 36411454
2023 OTUD4 in Paneth cells restricts expression of antimicrobial peptides (AMPs) by maintaining low K63-linked ubiquitination of MyD88, thereby limiting NF-κB and MAPK activation. Knockout of OTUD4 leads to hyper-K63-ubiquitination of MyD88, increased AMP expression, and resistance to DSS-induced colitis and Salmonella infection. Intestinal organoids, Vil-Cre;Otud4fl/fl and Def-Cre;Otud4fl/fl conditional KO mice, ubiquitination assays, LPS/PGN stimulation Cell insight High 37193092
2023 OTUD4 is recruited by IRTKS to remove K48-linked polyubiquitin chains at K182/K1050 of the histone methyltransferase SETDB1, blocking its proteasomal degradation. Stabilized SETDB1 increases H3K9me3, reduces chromatin accessibility at the CDH1 locus, suppresses E-cadherin, and promotes EMT and tumor metastasis. Co-immunoprecipitation, ubiquitination assays, chromatin accessibility analysis, knockdown/overexpression in cancer cells Cancer letters Medium 37739210
2023 OTUD4 deubiquitinates and stabilizes PFKFB3 (a glycolysis activator), blocking its degradation via the ubiquitin-proteasome pathway. TGF-β1 blunts ubiquitination-mediated PFKFB3 degradation through OTUD4, promoting glycolysis and cardiac fibroblast activation in post-MI cardiac fibrosis. Co-immunoprecipitation, ubiquitination assays, pharmacological and genetic inhibition of PFKFB3, in vitro and in vivo cardiac fibrosis models Journal of molecular medicine (Berlin, Germany) Medium 37162556
2023 OTUD4 deubiquitinates and stabilizes Snail1, a key EMT transcription factor, promoting metastasis of triple-negative breast cancer. Reconstitution of Snail1 in OTUD4-deficient cells rescues the metastatic phenotype. Knockdown/knockout, reconstitution assays, co-immunoprecipitation, in vivo metastasis models Experimental cell research Medium 38040050
2023 OTUD4 interacts with PAI-1 (plasminogen activator inhibitor-1) and prevents its ubiquitin-mediated degradation, protecting against cigarette smoke extract-induced lung epithelial cell apoptosis. Protein profile screening, co-immunoprecipitation, knockdown/overexpression in vitro and in vivo (mouse model) Cell death & disease Low 37726265
2024 OTUD4 interacts with CDK1 directly and removes K11-, K29-, and K33-linked polyubiquitin from CDK1, stabilizing it. OTUD4 also binds FGFR1 and reduces its K6- and K27-linked polyubiquitination, indirectly stabilizing CDK1. Both axes activate downstream MAPK signaling to promote GBM progression. Co-immunoprecipitation, ubiquitination assays, in vitro and in vivo proliferation/invasion assays in GBM cells Cell death & disease Medium 38429268
2024 OTUD4 deubiquitinates CD73 (counteracting TRIM21-mediated ubiquitination), stabilizing CD73 and suppressing antitumor immune responses in TNBC. TGF-β signaling orchestrates this OTUD4/CD73 proteolytic axis. A small-molecule inhibitor (ST80) disrupts the OTUD4-CD73 interaction and sensitizes tumors to anti-PD-L1 therapy. Multiomic analyses, co-immunoprecipitation, small-molecule inhibitor studies, preclinical TNBC mouse models, spatial transcriptomics The Journal of clinical investigation High 38530357
2024 OTUD4 interacts with RBM47 and promotes RBM47 stability via deubiquitination, which in turn regulates ATF3 mRNA stability and promotes ATF3-mediated ferroptosis, suppressing ccRCC progression. Co-immunoprecipitation, knockdown/overexpression, in vitro/in vivo tumor assays, ferroptosis sensitivity assays Apoptosis : an international journal on programmed cell death Medium 38553613
2024 OTUD4 functions as a scaffold (non-catalytic) to recruit USP7 to the KSHV transcription factor K-RTA, leading to K-RTA deubiquitination and stabilization, thereby promoting KSHV lytic reactivation. Disrupting the OTUD4-USP7 interaction with a peptide (p8) suppresses herpesvirus replication in vivo. Co-immunoprecipitation, viral reactivation assays, catalytic mutant analysis, in vivo murine herpesvirus model with peptide inhibitor PLoS pathogens High 38215174 40208866
2024 NRF2 transcriptionally activates OTUD4 by binding its promoter; OTUD4 then deubiquitinates EGF protein, enhancing its stability in lung adenocarcinoma cells. NRF2 modulation, promoter binding analysis, ubiquitination assays, Western blotting in A549 cells Biochemical and biophysical research communications Low 38518721
2025 OTUD4 interacts with TAK1, TAB1, and TAB3 within the TAK1 signalosome and removes K63-linked polyubiquitin chains from TAK1 and TAB3, reducing TNF-induced NF-κB signaling. A histidine-centered loop (His loop) in the catalytic domain is required for K63 linkage specificity. A tumor-associated missense variant H148Y, located in this loop, retains TAK1 binding but abolishes deubiquitinase activity toward both K63- and K48-linked chains. Co-immunoprecipitation, in vitro deubiquitinase assays, catalytic His-loop mutagenesis (H148Y variant), NF-κB activation assays The Journal of biological chemistry High 41062071
2025 OTUD4 directly deubiquitinates GPX4, reducing its K48-linked polyubiquitination and stabilizing it from proteasomal degradation. In addition, OTUD4 inhibits RHEB-mediated autophagic degradation of GPX4, providing a second mechanism to prevent ferroptosis. OTUD4 KO cells are more sensitive to ferroptosis inducers and show reduced tumor growth. CRISPR-Cas9 KO cell lines, Co-immunoprecipitation, ubiquitination assays, autophagy flux analysis, in vivo tumor models combined with regorafenib Cell reports Medium 40338740
2025 SPARC competitively binds OTUD4 together with MyD88, displacing MyD88 from OTUD4 deubiquitinase regulation, facilitating p65 nuclear translocation and activation of the p65-MLCK/MLC2 pathway, leading to intestinal barrier disruption in Crohn's disease. Co-immunoprecipitation, SPARC-deficient mouse models, p65 nuclear translocation assays, METTL3-YTHDF1 axis analysis Advanced science Medium 39888301
2025 OTUD4 interacts with and deubiquitinates ZMYND8, stabilizing it from proteasomal degradation. The resulting OTUD4-ZMYND8-DDX3X axis activates WNT/β-catenin signaling, upregulates CSF1, and promotes M2 macrophage polarization to drive TNBC spinal metastasis. Co-immunoprecipitation, ubiquitination assays, transcriptomic profiling, in vivo metastasis models Neoplasia Medium 41297414
2025 OTUD4 interacts with UBAC1 and maintains UBAC1 stability via deubiquitination; loss of OTUD4 decreases UBAC1 expression, activates AKT/mTOR signaling, and restores autophagic flux in myocardial ischemia-reperfusion injury, protecting cardiomyocytes. CRISPR/Cas9 sgRNA screening, knockdown/overexpression in OGD-R cells, LAD artery ligation mouse model, co-immunoprecipitation, autophagic flux assays Journal of molecular medicine Medium 41107601
2025 OTUD4 directly interacts with and deubiquitinates p53, stabilizing it and enhancing its transcriptional activity. p53 knockdown abrogates OTUD4-mediated suppression of CRC malignant phenotypes, establishing the OTUD4-p53 axis. Co-immunoprecipitation, ubiquitination assays, p53 knockdown rescue experiments, cell proliferation/invasion assays Discover oncology Medium 41266709
2025 TRIM21 promotes K48-linked polyubiquitination of the hepatitis B small surface antigen (SHBs) at K122, leading to its proteasomal degradation, while OTUD4 counteracts TRIM21-induced polyubiquitination to stabilize SHBs. OTUD4 N-terminal amino acids 1–180 interact directly with SHBs, demonstrated by GST pull-down. Immunoprecipitation/mass spectrometry, co-immunoprecipitation, GST pull-down assays (in vitro and in vivo), ubiquitination assays Journal of virology Medium 40277358
2025 OTUD4 directly interacts with YAP1 and its downregulation enhances K63-linked ubiquitination and nuclear translocation of YAP1, increasing CCL2 transcription and macrophage recruitment in ovarian cancer. OTUD4 therefore suppresses M2 macrophage polarization through YAP1 regulation. Co-immunoprecipitation, ubiquitination assays, co-culture with THP-1 macrophages, ovarian tumor-bearing mouse model International immunopharmacology Medium 39778277
2025 WSB1 stabilizes ISOC2 by promoting its interaction with OTUD4, thereby preventing ISOC2 degradation via the ubiquitin-proteasome pathway. Silencing OTUD4 phenocopies tumor-suppressive effects of WSB1 ablation in prostate cancer, and disruption of the WSB1/OTUD4/ISOC2 axis upregulates P16INK4a. Mass spectrometry, co-immunoprecipitation, siRNA knockdown epistasis, in vitro and in vivo tumor assays American journal of cancer research Medium 41244113
2026 OTUD4 directly interacts with EGFR via its 568–1114 aa region binding EGFR residues 958–1210 aa, and cleaves K48-linked polyubiquitin chains from EGFR, stabilizing it. Additionally, NRP1 recruits OTUD4 to further deubiquitinate and stabilize EGFR, activating the PI3K/AKT pathway to promote TNBC invasiveness. Domain mapping co-immunoprecipitation, ubiquitination assays, knockdown/overexpression, in vitro invasion assays Cell death & disease Medium 41730840
2026 OTUD4 deubiquitinates and stabilizes SLC5A2 (SGLT2) in pancreatic cancer cells; interaction between OTUD4 and SLC5A2 prevents SLC5A2 proteasomal degradation and promotes glycolysis-mediated autophagy and cancer cell proliferation. Co-immunoprecipitation, ubiquitination assays, RNA-seq/GSEA, metabolomics, in vitro and in vivo tumor models FASEB journal Medium 40719816
2026 OTUD4 can interact with YAP in pancreatic cancer and promotes YAP K48-linked poly-ubiquitination and degradation (note: this finding is in tension with the ovarian cancer study above where OTUD4 downregulation increased K63-ubiquitination of YAP; the pancreatic cancer study reports OTUD4 promotes K48-ubiquitination and degradation of YAP, suggesting context-dependent effects). siRNA screening, GSEA, co-immunoprecipitation, ubiquitination assays in PAAD cells Neoplasia Low 41687501
2026 OTUD4 deubiquitinates MYH9 (myosin-9), preventing its degradation; stabilized MYH9 promotes cell adhesion molecule interactions that suppress prostate cancer growth. Protein mass spectrometry, co-immunoprecipitation, ubiquitination assays, xenograft models Oncology research Medium 41930143
2026 Fenofibrate-induced degradation of EZH2 is mediated via TRIM21 (E3 ubiquitin ligase) and OTUD4 (deubiquitinase), with TRIM21 and OTUD4 identified as key regulators of EZH2 protein stability in melanoma. The balance between these two enzymes determines EZH2 protein levels. Mass spectrometry, co-immunoprecipitation, pharmacological (fenofibrate) treatment, in vivo tumor models British journal of pharmacology Low 41652905

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS. Cell research 98 30410068
2018 OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling. Molecular cell 95 29395066
2015 Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase. The EMBO journal 85 25944111
2022 OTUD4-mediated GSDME deubiquitination enhances radiosensitivity in nasopharyngeal carcinoma by inducing pyroptosis. Journal of experimental & clinical cancer research : CR 69 36411454
2024 OTUD4 promotes the progression of glioblastoma by deubiquitinating CDK1 and activating MAPK signaling pathway. Cell death & disease 31 38429268
2024 Pharmacological suppression of the OTUD4/CD73 proteolytic axis revives antitumor immunity against immune-suppressive breast cancers. The Journal of clinical investigation 28 38530357
2019 New roles for the de-ubiquitylating enzyme OTUD4 in an RNA-protein network and RNA granules. Journal of cell science 26 31138677
2020 OTUD4 alleviates hepatic ischemia-reperfusion injury by suppressing the K63-linked ubiquitination of TRAF6. Biochemical and biophysical research communications 22 31964525
2023 Upregulation of glycolytic enzyme PFKFB3 by deubiquitinase OTUD4 promotes cardiac fibrosis post myocardial infarction. Journal of molecular medicine (Berlin, Germany) 19 37162556
2013 Zebrafish transforming growth factor-β-stimulated clone 22 domain 3 (TSC22D3) plays critical roles in Bmp-dependent dorsoventral patterning via two deubiquitylating enzymes Usp15 and Otud4. Biochimica et biophysica acta 16 23665588
2023 Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes. Acta neuropathologica 14 37149835
2023 The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection. Cell insight 14 37193092
2023 Cooperation between IRTKS and deubiquitinase OTUD4 enhances the SETDB1-mediated H3K9 trimethylation that promotes tumor metastasis via suppressing E-cadherin expression. Cancer letters 14 37739210
2025 OTUD4 inhibits ferroptosis by stabilizing GPX4 and suppressing autophagic degradation to promote tumor progression. Cell reports 12 40338740
2020 OTUD4 enhances TGFβ signalling through regulation of the TGFβ receptor complex. Scientific reports 12 32973272
2025 Elevated SPARC Disrupts the Intestinal Barrier Integrity in Crohn's Disease by Interacting with OTUD4 and Activating the MYD88/NF-κB Pathway. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 11 39888301
2024 Deubiquitinating enzyme OTUD4 stabilizes RBM47 to induce ATF3 transcription: a novel mechanism underlying the restrained malignant properties of ccRCC cells. Apoptosis : an international journal on programmed cell death 11 38553613
2023 Deubiquitinating enzyme OTUD4 regulates metastasis in triple-negative breast cancer by stabilizing Snail1. Experimental cell research 10 38040050
2024 Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases. PLoS pathogens 8 38215174
2023 CSE reduces OTUD4 triggering lung epithelial cell apoptosis via PAI-1 degradation. Cell death & disease 8 37726265
2025 OTUD4-mediated inhibition of YAP1 signaling pathway in ovarian cancer: Implications for macrophage polarization and recruitment. International immunopharmacology 3 39778277
2025 Disrupting the OTUD4-USP7 deubiquitinase complex to suppress herpesvirus replication: a novel antiviral strategy. PLoS pathogens 3 40208866
2025 Ubiquitin-dependent proteasomal degradation of small hepatitis B virus surface antigen mediated by TRIM21 and antagonized by OTUD4. Journal of virology 3 40277358
2025 Deubiquitinase OTUD4 Stabilizes SLC5A2 to Promote Pancreatic Cancer Proliferation and Migration Through Enchaining Glycolysis-Mediated Autophagy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 40719816
2026 The ovarian tumor domain-containing protein 4 (OTUD4)-targeted ferroptosis inhibitor Maclekarpine E attenuates ulcerative colitis. Phytomedicine : international journal of phytotherapy and phytopharmacology 1 41759427
2025 The deubiquitinase OTUD4 suppresses TAK1 kinase-dependent NF-κB signaling and inflammation. The Journal of biological chemistry 1 41062071
2024 NRF2 regulates EGF stability through OTUD4 in lung adenocarcinoma. Biochemical and biophysical research communications 1 38518721
2026 Fenofibrate potentiates the therapeutic efficacy of EZH2 inhibitors on melanoma via TRIM21- and OTUD4-mediated EZH2 ubiquitination. British journal of pharmacology 0 41652905
2026 OTUD4 regulates pancreatic cancer progression via Hippo/YAP axis. Neoplasia (New York, N.Y.) 0 41687501
2026 OTUD4 deubiquitination stabilizes EGFR and activates the PI3K/AKT pathway to promote the invasiveness of triple-negative breast cancer. Cell death & disease 0 41730840
2026 OTUD4 Inhibits Prostate Cancer by Deubiquitinating MYH9. Oncology research 0 41930143
2025 Suppression of OTUD4 protects against myocardial ischemia-reperfusion injury by increasing autophagic flux and inhibiting apoptosis in cardiomyocytes. Journal of molecular medicine (Berlin, Germany) 0 41107601
2025 WSB1 promotes prostate cancer malignancy through OTUD4-mediated ISOC2 stabilization and P16INK4a suppression. American journal of cancer research 0 41244113
2025 OTUD4 suppresses colorectal cancer progression through deubiquitinating p53. Discover oncology 0 41266709
2025 OTUD4-ZMYND8-DDX3X Axis Drives Immunosuppressive Microenvironment in Spinal Metastases of Triple-Negative Breast Cancer. Neoplasia (New York, N.Y.) 0 41297414

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