Affinage

OTUD1

OTU domain-containing protein 1 · UniProt Q5VV17

Length
481 aa
Mass
51.1 kDa
Annotated
2026-06-10
61 papers in source corpus 46 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OTUD1 is an OTU-family deubiquitinase that acts as a pleiotropic, context-dependent regulator of inflammation, innate immunity, cell death, and cardiac/metabolic homeostasis by editing ubiquitin chains on a diverse set of signaling substrates (PMID:29235476, PMID:29734366, PMID:35941131). Its catalytic activity depends on the active-site cysteine C320, and its C-terminal ubiquitin-interacting motif (UIM) enhances enzymatic activity and confers a strong preference for K63-linked substrates, although it also processes K48, K33, and atypical K6 linkages in vitro (PMID:37589489, PMID:37153745, PMID:39118286). In innate antiviral and antimicrobial immunity OTUD1 is induced downstream of NF-κB and FOXO3 and restrains type I interferon and inflammatory output: it stabilizes the E3 ligase Smurf1 to drive degradation of the MAVS/TRAF3/TRAF6 signalosome and removes K63- and K6-linked chains from IRF3 to block its nuclear function and DNA binding, while in fungal and bacterial contexts it edits CARD9 and RIPK1 to tune NF-κB and MAPK signaling (PMID:29734366, PMID:30100102, PMID:32075857, PMID:34876703, PMID:33789983, PMID:39118286). Through its catalytic activity it also stabilizes or destabilizes substrates controlling other pathways—SMAD7 in TGF-β signaling, YAP in Hippo output, IREB2 to promote ferroptosis, and NRF2 to drive antioxidant responses—and its N-terminal intrinsically disordered region binds KEAP1 via an ETGE motif and inhibits Akt independently of catalysis (PMID:29235476, PMID:29891922, PMID:31225491, PMID:33393230, PMID:35941131, PMID:36640312, PMID:39079388). A distinct branch of its biology centers on cardiac and metabolic disease, where OTUD1 acts on STAT3, PDE5A, AMPKα2, and other substrates to promote fibrosis, hypertrophy, and heart failure (PMID:37153745, PMID:38185350, PMID:40683882). Loss-of-function and disease-associated OTUD1 mutations (including a UC-associated G430V variant) impair its immunosuppressive activity and are linked to autoimmune and inflammatory disease (PMID:30100102, PMID:34876703).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2017 High

    Established OTUD1 as a deubiquitinase with a defined substrate and a clear physiological output, showing it removes K33 chains from SMAD7 to suppress TGF-β pro-metastatic signaling.

    Evidence Loss-of-function screen in mice with co-IP, linkage-specific deubiquitination assays, and in vivo xenograft/orthotopic models

    PMID:29235476

    Open questions at the time
    • Did not define structural basis of linkage selectivity
    • Other substrates and pathways unexplored at this stage
  2. 2018 High

    Extended OTUD1 substrate scope to growth and immune signaling, showing it edits K63 chains on YAP to restrain Hippo/YAP output and stabilizes Smurf1 to dismantle the MAVS/TRAF3/TRAF6 signalosome and suppress type I IFN.

    Evidence DUB library screens, co-IP, linkage-specific ubiquitination assays, fractionation, and OTUD1-deficient mice with viral infection models

    PMID:29734366 PMID:29891922 PMID:31225491

    Open questions at the time
    • Whether YAP and antiviral roles operate in the same cell types unclear
    • Did not resolve how OTUD1 is targeted to distinct substrates
  3. 2018 High

    Showed OTUD1 directly controls IRF3 and that disease-associated loss-of-function mutations impair this suppression, linking OTUD1 to autoimmune disease and establishing FOXO3-dependent induction.

    Evidence Co-IP, site-specific (K98) ubiquitination mapping, mutant analysis, and OTUD1-deficient cells and mice

    PMID:30100102

    Open questions at the time
    • Did not reconcile IRF3 K63 (K98) editing with later K6-chain mechanism
    • Structural basis of mutation-induced activity loss not determined
  4. 2020 High

    Refined the IRF3 mechanism by showing OTUD1 cleaves atypical K6-linked chains required specifically for IRF3 promoter binding, decoupling its action from IRF3 stability, dimerization, and translocation.

    Evidence Linkage-specific in vitro deubiquitination, ChIP for promoter binding, and Otud1-/- mice with viral challenge

    PMID:32075857

    Open questions at the time
    • Identity of the K6-chain ligase not established
    • Relationship between K6 and earlier K63/K98 IRF3 findings unresolved
  5. 2021 High

    Defined OTUD1 as a regulator of cell death and metabolic stress through multiple substrates—stabilizing IREB2 to drive iron-dependent ferroptosis, editing AIF and degrading MCL1 to control apoptosis, and stabilizing MCL1 to modulate BH3-mimetic sensitivity.

    Evidence Co-IP, deubiquitination assays, site-specific AIF mutagenesis (K244/K255), iron/mitochondrial functional assays, and in vivo tumor models

    PMID:31467488 PMID:33393230 PMID:33898171

    Open questions at the time
    • Apparent opposing effects on apoptosis (MCL1 stabilization vs degradation) not reconciled
    • Context determining ferroptosis vs apoptosis output unclear
  6. 2021 High

    Established OTUD1 as a brake on NF-κB-driven inflammation across tissues by cleaving K63 chains from RIPK1 and editing CARD9, with a UC-associated G430V mutation abolishing the RIPK1 activity, tying OTUD1 to inflammatory bowel and antifungal immunity.

    Evidence Co-IP, linkage-specific deubiquitination, OTUD1-/- mice with DSS colitis and fungal infection, bone marrow transplantation, and mutant analysis

    PMID:33789983 PMID:34876703

    Open questions at the time
    • Opposing CARD9 outcomes across studies (suppressive vs activating) not yet integrated
    • How substrate choice between RIPK1 and CARD9 is determined unknown
  7. 2021 Medium

    Showed OTUD1 expression is transcriptionally controlled by upstream inputs (DDIT3/NF-κB during viral infection; Sp1 downstream of melatonin), placing OTUD1 within inducible regulatory circuits affecting antiviral defense and apoptosis.

    Evidence Overexpression/knockdown, co-IP, ubiquitination assays, DDIT3 knockout mice, and Sp1 inhibition with xenograft models

    PMID:33361422 PMID:34826170

    Open questions at the time
    • BVDV MAVS axis largely confirmatory of prior Smurf1 work
    • Bim K3 editing not independently validated
  8. 2022 High

    Identified non-catalytic functions of OTUD1's N-terminal intrinsically disordered region, showing it binds KEAP1 via an ETGE motif to couple OTUD1 to antioxidant/oxeiptosis responses and inhibits Akt by competing for PtdIns(3,4,5)P3 binding at the PH domain.

    Evidence DUB screen, mass spectrometry, ETGE mutagenesis, peptide binding and Akt localization assays, and OTUD1-/- disease models (IBD, hepatitis, sepsis)

    PMID:35941131 PMID:36640312

    Open questions at the time
    • Structural model of the IDR-KEAP1 and IDR-Akt interactions absent
    • How catalytic and non-catalytic functions are coordinated in cells unknown
  9. 2022 Medium

    Broadened OTUD1 substrate range into tumor suppression and translational control by stabilizing PTEN and KLF4 and by antagonizing ZNF598-mediated RPS10 ubiquitination to relieve ribosome stalling.

    Evidence Co-IP, BioID interactome, ubiquitination assays, polysome profiling, and cell proliferation/migration assays

    PMID:35098684 PMID:35280681 PMID:36445135

    Open questions at the time
    • Ribosome quality-control role rests on a single proximity-labeling study
    • PTEN/KLF4 effects characterized in limited cancer contexts
  10. 2023 High

    Provided the biochemical architecture of OTUD1, showing an N-terminal OTU catalytic domain plus a C-terminal UIM that enhances activity and confers K63 preference, and delivered ubiquitin-variant inhibitors with nanomolar potency.

    Evidence Phage-display UbV library screen, in vitro DUB assays with linkage-specific substrates, and cellular RIPK1 deubiquitination

    PMID:37589489

    Open questions at the time
    • No high-resolution structure of OTUD1 with substrate or inhibitor
    • How UIM and IDR jointly govern substrate selection unresolved
  11. 2023 Medium

    Defined a cardiac/renal disease axis in which OTUD1, via C320, edits STAT3, CDK9, and other substrates to amplify inflammatory and fibrotic signaling, while also regulating Notch2-ICD in T cells and SEC23B in the secretory pathway.

    Evidence LC-MS/MS, co-IP, C320 and site-specific mutagenesis, OTUD1 KO/OE mouse models (Ang II/TAC, aGVHD, periodontitis), and pharmacological rescue

    PMID:36574342 PMID:36929488 PMID:37153745 PMID:37639212 PMID:38012669 PMID:38110583

    Open questions at the time
    • Most cardiac substrate studies derive from single labs
    • Whether OTUD1 acts pro- or anti-inflammatory is highly context-dependent and not unified
  12. 2024 Medium

    Demonstrated convergent antioxidant and metabolic control, with OTUD1 stabilizing NRF2 via C320 and the ETGE motif to limit ischemia/reperfusion injury, and integrated upstream m6A regulation (METTL3/METTL14) controlling OTUD1 expression in cardiac disease.

    Evidence Co-IP, C320 and ETGE mutagenesis, NRF2 stability assays, m6A-RIP, and in vivo I/R and TAC mouse models with peptide/ASK1 rescue

    PMID:38185350 PMID:38996928 PMID:39079388 PMID:39118286 PMID:39309432 PMID:40007014 PMID:41910113

    Open questions at the time
    • Diverse cardiac substrates (PDE5A, PGAM5, CARD9, DUSP6, TIPE2) not placed in a single hierarchy
    • Many findings are single-lab and disease-model-specific
  13. 2025 Medium

    Expanded OTUD1 into metabolic, neurological, regenerative, and oncologic contexts through new substrates including AMPKα2, HK2, β-catenin, MST1/2, C/EBPβ, RACK1, PRDX1, p53, and the RAD23B-XPC repair complex, repeatedly engaging NF-κB, oxidative stress, and cell-death programs.

    Evidence IP-MS/LC-MS/MS, site-specific and C320 mutagenesis, tissue-specific OTUD1 KO/KD mouse models, and pharmacological rescue across diabetic, neuroinflammatory, bone, and tumor models

    PMID:37 PMID:40300668 PMID:40335710 PMID:40394237 PMID:40500776 PMID:40585986 PMID:40683882 PMID:41286308 PMID:41967174 PMID:42229703

    Open questions at the time
    • Substrate list is broad with limited cross-validation between labs
    • No framework predicting which substrates dominate in a given tissue

Open questions

Synthesis pass · forward-looking unresolved questions
  • How OTUD1 achieves substrate specificity and switches between opposing (pro- vs anti-inflammatory, pro- vs anti-apoptotic) outputs across tissues, and how its catalytic, UIM, and IDR functions are coordinated, remains unresolved.
  • No structural model of substrate engagement
  • Determinants of context-dependent directionality unknown
  • Endogenous targeting/recruitment factors uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 13 GO:0016787 hydrolase activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005840 ribosome 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-8953854 Metabolism of RNA 1
Partners
CARD9IRF3KEAP1NRF2RIPK1SMAD7STAT3YAP1

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 OTUD1 directly deubiquitinates SMAD7, preventing its degradation and suppressing TGF-β pro-metastatic signaling. Specifically, OTUD1 cleaves K33-linked poly-ubiquitin chains from SMAD7 at K220, which exposes the SMAD7 PY motif to enable SMURF2 binding and subsequent TβRI turnover at the cell surface. Loss-of-function screen in mice, co-IP, deubiquitination assay, ubiquitin linkage analysis, in vivo xenograft and orthotopic transplantation models Nature communications High 29235476
2018 OTUD1 removes K63-linked polyubiquitin chains from YAP, reversing SCFSKP2-mediated non-proteolytic K63-linked ubiquitination of YAP at K321 and K497. This ubiquitination (reversed by OTUD1) enhances YAP interaction with TEAD, promotes YAP nuclear localization and transcriptional activity independently of Hippo pathway phosphorylation. Overexpression of OTUD1 retains YAP in the cytoplasm and inhibits its activity. DUB library screen, co-IP, ubiquitination assays, nuclear/cytoplasmic fractionation, reporter assays, mutagenesis of ubiquitination sites Nature communications High 29891922 31225491
2018 During RNA virus infection, OTUD1 is induced by NF-κB-dependent mechanisms and stabilizes the E3 ubiquitin ligase Smurf1 by removing its ubiquitination. Elevated Smurf1 then binds to MAVS, TRAF3, and TRAF6, promoting ubiquitination-dependent degradation of the entire MAVS/TRAF3/TRAF6 signalosome, thereby potently inhibiting type I IFN production. Co-IP, ubiquitination assays, OTUD1-deficient mice, viral infection models, overexpression/knockdown experiments PLoS pathogens High 29734366
2018 OTUD1 directly interacts with IRF3 and removes K63-linked poly-ubiquitin chains from IRF3 at K98, inhibiting IRF3 nuclear translocation and transcriptional activity. Loss-of-function mutations in OTUD1 associated with autoimmune diseases impair this suppressive activity. FOXO3 signaling is required for OTUD1 induction upon antigenic stimulation. Co-IP, ubiquitination assays, OTUD1 mutant analysis, OTUD1-deficient cells and mice, viral infection models Journal of autoimmunity High 30100102
2020 OTUD1 cleaves K6-linked (atypical) ubiquitin chains from IRF3, which are required for IRF3 DNA-binding capacity and subsequent induction of type I IFN target genes. OTUD1 deubiquitination of IRF3 does not affect protein stability, dimerization, or nuclear translocation, but specifically disrupts promoter binding. Otud1-/- cells and mice produce more type I IFNs and proinflammatory cytokines after viral infection. Co-IP, in vitro deubiquitination assays with linkage-specific ubiquitin, ChIP (IRF3 promoter binding), Otud1-/- mouse models, viral challenge Journal of immunology High 32075857
2021 OTUD1 is the deubiquitinase of IREB2 (iron-responsive element-binding protein 2), stabilizing it and thereby promoting TFRC-mediated iron transportation, increased ROS generation, and ferroptosis. OTUD1 also promotes release of damage-associated molecular patterns (DAMPs) to recruit leukocytes and strengthen host immune response. Co-IP, deubiquitination assay, OTUD1 knockdown/overexpression, cellular iron transport assays, in vivo tumor models EMBO reports High 33393230
2021 OTUD1 deubiquitinates AIF at K244 (disrupting mitochondrial structure and oxidative phosphorylation) and at K255 (enhancing AIF DNA-binding ability to promote parthanatos/caspase-independent apoptosis). OTUD1 also stabilizes DCAF10, recruits the CUL4A-DDB1 complex to promote MCL1 degradation, thereby activating caspase-dependent apoptotic signaling. Co-IP, in vitro deubiquitination assays, mutagenesis of specific AIF ubiquitination sites (K244, K255), mitochondrial functional assays, cell death assays Advanced science High 33898171
2021 OTUD1 physically interacts with RIPK1 and selectively cleaves K63-linked polyubiquitin chains from RIPK1, inhibiting NEMO recruitment and thereby suppressing NF-κB activation and colonic inflammation. A UC-associated OTUD1 G430V mutation abolishes this activity. Co-IP, ubiquitination assays with linkage specificity, OTUD1-/- mice, DSS-induced colitis model, bone marrow transplantation, mutant analysis Cellular & molecular immunology High 34876703
2021 OTUD1 directly interacts with CARD9 and cleaves polyubiquitin chains from CARD9, leading to activation of the canonical NF-κB and MAPK pathway in the context of antifungal innate immunity. Otud1-/- mice are more susceptible to fungal infection. Co-IP, deubiquitination assay, OTUD1-deficient mice, fungal infection models, NF-κB/MAPK signaling assays Journal of immunology High 33789983
2021 DDIT3 promotes NF-κB-dependent OTUD1 expression during BVDV infection; OTUD1 in turn stabilizes Smurf1 by deubiquitinating it, and Smurf1 degrades MAVS in a ubiquitination-dependent manner, thereby inhibiting IFN-I production to facilitate viral replication. Overexpression/knockdown of DDIT3 and OTUD1, co-IP, ubiquitination assays, DDIT3 knockout mice, viral replication assays Journal of virology Medium 33361422
2021 OTUD1 deubiquitinates MCL1 and promotes its protein stability in an enzymatic-activity-dependent manner. Knockdown of OTUD1 increases tumor cell sensitivity to the BH3-mimetic inhibitor ABT-263, while overexpression increases tolerance. DUB expression library screen, co-IP, ubiquitination assays, cycloheximide chase, cell viability assays Cancer cell international Medium 31467488
2022 OTUD1 suppresses canonical NF-κB activation by hydrolyzing K63-linked ubiquitin chains from NF-κB signaling factors including LUBAC components. OTUD1 binds KEAP1 via an ETGE motif in its N-terminal intrinsically disordered region (APGR), and is involved in KEAP1-mediated antioxidant response and ROS-induced oxeiptosis. In Otud1-/- mice, inflammation, oxidative damage, and cell death were enhanced in IBD, acute hepatitis, and sepsis models. DUB screen (88 DUBs), mass spectrometry, co-IP, OTUD1-/- mouse models (IBD, hepatitis, sepsis), ETGE motif mutagenesis, NF-κB reporter assays Cell death & disease High 35941131
2022 OTUD1 suppresses Akt activation primarily through its N-terminal intrinsically disordered region (IDR), independently of deubiquitinase activity. A short peptide (OUN-36) within the IDR binds the Akt PH domain, competing with PtdIns(3,4,5)P3 recognition to disrupt Akt membrane localization and phosphorylation. Co-IP, peptide binding assays, Akt phosphorylation assays, membrane localization imaging, mutagenesis of PH domain residues, tumor cell proliferation assays Cell reports High 36640312
2022 OTUD1 deubiquitinates and stabilizes PTEN, and loss of OTUD1 triggers the AKT and NF-κB pathways in renal cancer cells. OTUD1 physically interacts with PTEN to regulate its stability. Co-IP, RNA-seq pathway analysis, Western blot stability assays, overexpression/knockdown in ccRCC cells International journal of biological sciences Medium 35280681
2022 OTUD1 associates with ribosome subunits, elongation factors, and the E3 ubiquitin ligase ZNF598. OTUD1 catalytic activity suppresses polyA-triggered ribosome stalling through inhibition of ZNF598-mediated RPS10 ubiquitination and stimulates polysome formation. OTUD1 also regulates the stability of rare-codon-rich mRNAs by antagonizing ZNF598. Proximity labeling-based interactome (BioID), co-IP, ribosome sedimentation/polysome profiling, ubiquitination assays for RPS10, mRNA stability assays Molecular and cellular biology High 36445135
2022 OTUD1 deubiquitinates and stabilizes KLF4 in non-small cell lung cancer cells, suppressing proliferation, migration, and invasion. Co-IP, cycloheximide chase, deubiquitination assay, CCK-8, Transwell assay, overexpression/knockdown Thoracic cancer Medium 35098684
2023 OTUD1 binds to the SH2 domain of STAT3 and catalyzes K63-linked deubiquitination of STAT3 via its catalytic cysteine C320, promoting STAT3 phosphorylation and nuclear translocation, thereby increasing STAT3 transcriptional activity to induce inflammatory responses, fibrosis, and hypertrophy in cardiomyocytes. LC-MS/MS, co-IP, ubiquitination assays, C320 mutagenesis, OTUD1 knockout mice (Ang II/TAC models), AAV9-mediated OTUD1 overexpression, STAT3 inhibitor rescue Theranostics High 37153745
2023 OTUD1 interacts with RIP2 and removes K63-linked polyubiquitin chains from RIP2, thereby inhibiting NF-κB activation and reducing neuroinflammation after cerebral ischemia. OTUD1 deficiency exacerbates cerebral ischemic injury. Co-IP, immunofluorescence, Western blot, dual-luciferase NF-κB assay, OTUD1-/- mice with MCAO model, OGD/R cell models Journal of neuroinflammation Medium 38012669
2023 OTUD1 interacts with SEC23B (a COPII complex component) and removes K63-linked polyubiquitin chains from SEC23B at K81, negatively regulating COPII secretory machinery and limiting ER-to-Golgi protein trafficking, thereby restricting surface expression of CD9 and CD47 on neutrophils and limiting secretory neutrophil polarization. Co-IP, ubiquitination assays with site-specific mutagenesis (K81), surface expression flow cytometry, OTUD1-deficient mice with periodontitis model, Brefeldin A rescue Advanced science High 37639212
2023 OTUD1 interacts with Notch2-ICD (NICD) and cleaves ubiquitin from NICD at K1770, stabilizing NICD protein in T cells and promoting Th1/Th17 differentiation, thereby amplifying acute graft-versus-host disease. CD4+ T cell activation after allo-HSCT elevates OTUD1 levels. Co-IP, ubiquitination assays with site mapping (K1770), T cell differentiation assays, aGVHD mouse model, FDA-drug screening (dapagliflozin identified as inhibitor) Blood High 36574342
2023 OTUD1 deubiquitinates and stabilizes FHL1 in lung adenocarcinoma cells, inhibiting tumor proliferation and migration in vitro and in vivo. IP-MS, co-IP, deubiquitination assay, xenograft mouse models, urethane-induced lung cancer model Cellular oncology Medium 36929488
2023 OTUD1 binds CDK9 and catalyzes K63-linked deubiquitination of CDK9 via its C320 residue, promoting CDK9 phosphorylation and activation, thereby inducing inflammatory responses and fibrosis in kidney epithelial cells under hypertensive conditions. Co-IP, ubiquitination assays, C320 mutagenesis, OTUD1 knockout mice (Ang II model), CDK9 inhibitor rescue Acta pharmacologica Sinica Medium 38110583
2023 OTUD1 has an N-terminal OTU catalytic domain and a C-terminal ubiquitin-interacting motif (UIM); the UIM-containing region enhances enzymatic activity and confers strong preference for K63-linked substrates in vitro. Ubiquitin variant (UbV) inhibitors (UbVOD.1 and UbVOD.2) were identified that inhibit OTUD1 activity toward mono-Ub, K63-linked di-Ub, and poly-Ub chains of other linkages with nanomolar IC50. Phage display UbV library screen, in vitro DUB activity assays with linkage-specific ubiquitin substrates, cellular UbV expression and RIPK1 deubiquitination assay The Biochemical journal High 37589489
2024 OTUD1 deubiquitinates NRF2 through its catalytic site C320 and ETGE motif, preventing NRF2 degradation and activating its antioxidant activity to alleviate hepatic ischemia/reperfusion injury. A short ETGE-motif peptide also mitigates hepatic I/R injury in mice. Co-IP, deubiquitination assays, C320 mutagenesis, ETGE motif deletion, NRF2 stability assays, in vivo hepatic I/R mouse model, ETGE peptide administration Redox biology High 39079388
2024 OTUD1 directly binds to CARD9 and removes K33-linked ubiquitin from CARD9 to promote assembly of the CARD9-BCL10-MALT1 (CBM) complex without affecting CARD9 stability, leading to NF-κB activation and macrophage inflammatory gene production in the context of isoproterenol-induced heart failure. Co-IP, ubiquitination assays with K33-linkage specificity, Card9-/- and Otud1-/- bone marrow reconstitution, ISO-induced heart failure mouse model, primary macrophages Clinical and translational medicine High 39118286
2024 OTUD1 directly binds to the GAF1 and PDEase domains of PDE5A and reverses K48-linked ubiquitin chains on PDE5A via C320, preventing its proteasomal degradation and stabilizing PDE5A. Stabilized PDE5A inactivates the cGMP-PKG-SERCA2a signaling axis, dysregulating calcium handling in cardiomyocytes and promoting heart failure. LC-MS/MS, co-IP, ubiquitination assays with K48-linkage specificity, C320 mutagenesis, OTUD1 KO and OE in mice (ISO/MI models), SERCA2a/cGMP pathway readouts Biochimica et biophysica acta. Molecular basis of disease High 38185350
2024 METTL3-mediated m6A modification of OTUD1 mRNA promotes mRNA stability and elevated OTUD1 protein expression under cardiac hypertrophic stress. OTUD1 promotes cardiac hypertrophy by targeting PGAM5, leading to activation of the ASK1-p38/JNK signaling pathway. RNA immunoprecipitation (m6A-RIP), co-IP, IP-MS, cardiac-specific Otud1 knockout mice (TAC model), AAV9-OTUD1 overexpression, ASK1 knockdown rescue International journal of biological sciences Medium 39309432
2024 OTUD1 interacts with and deubiquitinates TIPE2 (TNFAIP8L2), stabilizing it. This OTUD1-TIPE2 axis suppresses TAK1-mediated MAPK and NF-κB signaling, playing a protective role in sepsis-induced lung injury. Co-IP, immunofluorescence co-localization, Western blotting, in vivo sepsis models, multiomics analysis Biochemical pharmacology Medium 38996928
2024 OTUD1 deubiquitinates DUSP6, regulating its protein stability. METTL14-mediated m6A modification promotes OTUD1 mRNA stability and expression, thereby influencing DUSP6 expression through OTUD1-mediated ubiquitination regulation in myocardial infarction. Me-RIP, PAR-CLIP, co-IP, protein stability assays, MI mouse model (LAD ligation), METTL14 silencing The Kaohsiung journal of medical sciences Medium 41910113
2024 OTUD1 interacts with and deubiquitinates BST-2, reducing K48- and K63-linked ubiquitination of BST-2, thereby increasing BST-2 protein stability and subsequently inhibiting HIV-1 release. siRNA screening of human DUBs, co-IP, ubiquitination assays (K48/K63 linkage-specific), BST-2 stability assays, HIV-1 release assays Viruses Medium 40007014
2021 Melatonin upregulates OTUD1 at the transcriptional level via Sp1, and OTUD1 directly interacts with Bim and inhibits its ubiquitination by deubiquitinating Bim at K3, stabilizing Bim and inducing apoptosis in cancer cells. Co-IP, ubiquitination assays with K3 mutagenesis, siRNA knockdown, Sp1 inhibitor/siRNA, xenograft mouse model Journal of pineal research Medium 34826170
2025 OTUD1 directly binds to the C-terminal domain of HK2 through its Ala-rich domain and selectively cleaves K63-linked polyubiquitin chains on HK2, promoting HK2 dissociation from mitochondria, activating the NLRP3 inflammasome, and triggering microglia pyroptosis in sepsis-associated encephalopathy. Molecular docking, 3D confocal microscopy, co-IP, ubiquitination assays, OTUD1 KO mice (CLP model), primary microglia and BV2 cells, NLRP3 inflammasome assays Journal of neuroinflammation Medium 40500776
2025 OTUD1 binds to AMPKα2 and deubiquitinates it at K60 and K379, inhibiting AMPKT172 phosphorylation by impairing the interaction of AMPKα2 with its upstream kinase CAMKK2, thereby suppressing AMPK activity and mitochondrial function in cardiomyocytes during diabetic cardiomyopathy. Co-IP, ubiquitination assays with site mapping (K60, K379), cardiomyocyte-specific OTUD1 KO mice (T1DM/T2DM models), CAMKK2 interaction assays, AMPKα2 silencing rescue Nature communications High 40683882
2025 OTUD1 directly binds to C/EBPβ and maintains its stability by removing K48-linked ubiquitin chains at K253 of C/EBPβ, thereby activating C/EBPβ-NF-κB-mediated inflammatory responses in microglia and promoting Alzheimer's disease pathology. LC-MS/MS coupled with co-IP, ubiquitination assays with K253 site mapping, OTUD1 knockdown in microglia, AD mouse model, cognitive behavioral testing Acta pharmacologica Sinica Medium 40335710
2025 OTUD1 directly binds RACK1 and cleaves K63-linked polyubiquitin chains from RACK1, enhancing RACK1 phosphorylation and thereby modulating downstream MAPKs and NF-κB signaling, promoting I/R-induced myocardial apoptosis. IP-MS, co-IP, ubiquitination assays, OTUD1 global KO mice (I/R model), RACK1 silencing rescue, MAPK/NF-κB signaling readouts Acta pharmacologica Sinica Medium 40394237
2025 OTUD1 promotes MST1/2 K63-linked deubiquitination at K285/K282 via its Cys320 catalytic site, enhancing MST1/2 phosphorylation, nuclear translocation, and activation in a TAOK1/2/3-dependent manner, triggering oxidative stress, apoptosis, pyroptosis, and mitochondrial injury leading to depressive-like phenotypes. Transcriptomics, co-IP, ubiquitination assays with site-specific mapping, Cys320 mutagenesis, OTUD1 KO mice (CUMS/LPS models), MST1/2 inhibitor rescue Brain, behavior, and immunity Medium 42229703
2025 OTUD1 promotes degradation of the RAD23B-XPC nucleotide excision repair complex by cleaving K63-linked ubiquitin chains from RAD23B and XPC, while enhancing PRKN-mediated K48-linked ubiquitination and subsequent proteasomal degradation of the complex, thereby sensitizing NSCLC cells to cisplatin. Co-IP, ubiquitination assays (K63 and K48 linkage-specific), overexpression/knockdown in vitro and in vivo xenograft, DNA repair functional assays Oncogene Medium 41286308
2025 OTUD1 directly interacts with β-catenin and reduces K63-linked ubiquitination at K496, K508, and K625 via its catalytic site C320, facilitating β-catenin phosphorylation and restricting its nuclear translocation, thereby downregulating angiogenesis-related factors and delaying diabetic wound healing. IP-MS, co-IP, ubiquitination assays with site mapping (K496/K508/K625), C320 mutagenesis, OTUD1 KO mice (T1DM/T2DM wound models), endothelial-specific AAV KD, β-catenin inhibitor rescue Journal of advanced research High 40300668
2025 OTUD1 stabilizes PRDX1 by reversing K48-linked ubiquitination on PRDX1, thereby mitigating mitochondrial dysfunction and suppressing osteoclast differentiation. OTUD1 deficiency (whole-body or myeloid-specific) results in reduced bone mass driven by enhanced osteoclastogenesis. LC-MS/MS, co-IP, ubiquitination assays (K48-linkage), OTUD1 KO and myeloid-specific KO mice, micro-CT/histomorphometry, mitochondrial function assays, MitoQ rescue Theranostics Medium 40585986
2025 OTUD1 interacts with and deubiquitinates SMAD7 (MADH7) in endometriosis, stabilizing SMAD7 to inhibit TGF-β-mediated fibrosis and reduce lesion growth in vitro and in vivo. Co-IP, deubiquitination assay, OTUD1 knockdown/overexpression in human primary stromal endometriosis cells, in vivo mouse endometriosis model Molecular human reproduction Medium 40279273
2025 OTUD1 interacts with p53 via its 300–481 region and catalyzes K48-dependent deubiquitination of p53, stabilizing p53 protein. In DEHP-exposed endothelial cells, ROS-induced OTUD1 upregulation stabilizes p53, which transcriptionally upregulates procoagulant genes, establishing a detrimental ROS-OTUD1-p53 feedback loop. An L357 point mutation of OTUD1 rescues this endothelial homeostasis disruption. Network toxicology, co-IP, ubiquitination assays (K48-linkage), domain mapping (300–481 region), L357 mutagenesis, in vivo thrombus models, ROS scavenger/p53 inhibitor rescue Environment international Medium 41967174
2025 OTUD1 stabilizes NRF2 via deubiquitination (OTUD1-NRF2 regulatory axis), and ApoEVs enriched in OTUD1 inhibit ferroptosis and provide neuroprotection in spinal cord injury. Silencing OTUD1 in ApoEVs significantly diminishes their anti-ferroptotic and neuroprotective effects. Proteomics of ApoEVs, co-IP, deubiquitination assay, OTUD1 silencing in ApoEVs, in vivo SCI mouse model, ferroptosis marker assays Free radical biology & medicine Medium 41151199
2025 OTUD1 deubiquitinates BALF1 (EBV-encoded protein), stabilizing it, and BALF1 in turn regulates Bcl-2 stability through deubiquitination, contributing to EBV-associated gastric cancer progression. Screening of 69 DUBs, co-IP, ubiquitination/deubiquitination assays, BALF1 overexpression/knockdown functional assays Biochimica et biophysica acta. Molecular basis of disease Medium 38565386
2025 Leptin treatment increases OTUD1 protein levels, causing OTUD1 aggresome formation and ASK1 recruitment, activating the JNK/c-Jun pathway, which further promotes c-Jun chromatin enrichment at the OTUD1 gene enhancer, creating a positive feedback loop that maintains ovarian cancer stem cell properties. Chromatin immunoprecipitation, aggresome formation assays, co-IP, JNK/c-Jun pathway assays, pharmacological inhibition of c-Jun/ASK1/JNK, tumor sphere/tumorigenicity assays Oncogene Medium 40108305
2025 OTUD1 deubiquitinates and stabilizes SLC25A11, leading to increased ROS and apoptosis, thereby enhancing NPC radiosensitivity. The transcription factor TFAP2C regulates OTUD1 expression epigenetically. Co-IP, deubiquitination assay, overexpression/knockdown in vitro and in vivo, ROS/apoptosis assays, decitabine treatment Cell death & disease Medium 40664662

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity. Nature communications 147 29891922
2021 The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity. EMBO reports 133 33393230
2017 Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7. Nature communications 107 29235476
2021 The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NF-κB signaling. Cellular & molecular immunology 94 34876703
2018 Induction of OTUD1 by RNA viruses potently inhibits innate immune responses by promoting degradation of the MAVS/TRAF3/TRAF6 signalosome. PLoS pathogens 89 29734366
2022 OTUD1 deubiquitinase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways. Cell death & disease 69 35941131
2021 OTUD1 Activates Caspase-Independent and Caspase-Dependent Apoptosis by Promoting AIF Nuclear Translocation and MCL1 Degradation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 67 33898171
2023 OTUD1 promotes pathological cardiac remodeling and heart failure by targeting STAT3 in cardiomyocytes. Theranostics 66 37153745
2020 OTUD1 Negatively Regulates Type I IFN Induction by Disrupting Noncanonical Ubiquitination of IRF3. Journal of immunology (Baltimore, Md. : 1950) 65 32075857
2021 DDIT3 Targets Innate Immunity via the DDIT3-OTUD1-MAVS Pathway To Promote Bovine Viral Diarrhea Virus Replication. Journal of virology 60 33361422
2022 OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs. International journal of biological sciences 51 35280681
2018 Mutations of deubiquitinase OTUD1 are associated with autoimmune disorders. Journal of autoimmunity 50 30100102
2023 The Deubiquitinase OTUD1 Suppresses Secretory Neutrophil Polarization And Ameliorates Immunopathology of Periodontitis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 26 37639212
2019 The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein. Cancer cell international 25 31467488
2023 Pleiotropic Roles of a KEAP1-Associated Deubiquitinase, OTUD1. Antioxidants (Basel, Switzerland) 24 36829909
2023 OTUD1 ameliorates cerebral ischemic injury through inhibiting inflammation by disrupting K63-linked deubiquitination of RIP2. Journal of neuroinflammation 24 38012669
2021 OTUD1 Regulates Antifungal Innate Immunity through Deubiquitination of CARD9. Journal of immunology (Baltimore, Md. : 1950) 22 33789983
2021 Melatonin induces apoptotic cell death through Bim stabilization by Sp1-mediated OTUD1 upregulation. Journal of pineal research 22 34826170
2024 The deubiquitinase OTUD1 stabilizes NRF2 to alleviate hepatic ischemia/reperfusion injury. Redox biology 20 39079388
2023 VE-822 upregulates the deubiquitinase OTUD1 to stabilize FHL1 to inhibit the progression of lung adenocarcinoma. Cellular oncology (Dordrecht, Netherlands) 19 36929488
2022 The deubiquitinase OTUD1 inhibits non-small cell lung cancer progression by deubiquitinating and stabilizing KLF4. Thoracic cancer 19 35098684
2024 Macrophage OTUD1-CARD9 axis drives isoproterenol-induced inflammatory heart remodelling. Clinical and translational medicine 18 39118286
2025 OTUD1 exacerbates sepsis-associated encephalopathy by promoting HK2 mitochondrial release to drive microglia pyroptosis. Journal of neuroinflammation 17 40500776
2022 Deubiquitylase OTUD1 confers Erlotinib sensitivity in non-small cell lung cancer through inhibition of nuclear translocation of YAP1. Cell death discovery 16 36182943
2024 OTUD1 promotes isoprenaline- and myocardial infarction-induced heart failure by targeting PDE5A in cardiomyocytes. Biochimica et biophysica acta. Molecular basis of disease 15 38185350
2022 The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region. Cell reports 15 36640312
2023 The OTUD1-Notch2-ICD axis orchestrates allogeneic T cell-mediated graft-versus-host disease. Blood 13 36574342
2023 OTUD1 promotes hypertensive kidney fibrosis and injury by deubiquitinating CDK9 in renal epithelial cells. Acta pharmacologica Sinica 13 38110583
2024 METTL3-mediated m6A modification of OTUD1 aggravates press overload induced myocardial hypertrophy by deubiquitinating PGAM5. International journal of biological sciences 10 39309432
2023 OTUD1 chemosensitizes triple-negative breast cancer to doxorubicin by modulating P16 expression. Pathology, research and practice 10 37257246
2018 SKP2 and OTUD1 govern non-proteolytic ubiquitination of YAP that promotes YAP nuclear localization and activity. Cell stress 8 31225491
2025 Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 and inducing mitochondrial dysfunction. Nature communications 7 40683882
2024 The deubiquitinase OTUD1 deubiquitinates TIPE2 and plays a protective role in sepsis-induced lung injury by targeting TAK1-mediated MAPK and NF-κB signaling. Biochemical pharmacology 7 38996928
2022 Deubiquitinase OTUD1 Resolves Stalled Translation on polyA and Rare Codon Rich mRNAs. Molecular and cellular biology 7 36445135
2024 OTUD1 enhances gastric cancer aggressiveness by deubiquitinating EBV-encoded protein BALF1 to stabilize the apoptosis inhibitor Bcl-2. Biochimica et biophysica acta. Molecular basis of disease 6 38565386
2025 A positive feedback loop of OTUD1 and c-Jun driven by leptin expedites stemness maintenance in ovarian cancer. Oncogene 5 40108305
2025 OTUD1 delays wound healing by regulating endothelial function and angiogenesis in diabetic mice. Journal of advanced research 4 40300668
2025 METTL3‑mediated m6A methylation and its impact on OTUD1 expression in chronic obstructive pulmonary disease. Molecular medicine reports 4 40417884
2025 Combining decitabine with radiotherapy to enhance nasopharyngeal carcinoma radiosensitivity via the TFAP2C-OTUD1-SLC25A11 axis. Cell death & disease 4 40664662
2024 BECN1 regulates FADD/RIPK1/Caspase-8 complex formation via RIPK1 ubiquitination by downregulating OTUD1 in MI/R induced myocyte apoptosis. International journal of cardiology 4 38744338
2023 Herpesvirus latent infection promotes stroke via activating the OTUD1/NF-κB signaling pathway. Aging 4 37695739
2025 Black carp OTUD1 negatively regulates antiviral innate immunity via deubiquitination and degradation of IRF3/7. Fish & shellfish immunology 3 40350101
2025 OTUD1 downregulates PD-L1 expression by deubiquitinating STAT3 and promotes the immune response in ccRCC. Cellular oncology (Dordrecht, Netherlands) 3 40506611
2025 OTUD1 positively regulates microglia neuroinflammation and promotes the pathogenesis of Alzheimer's disease by deubiquitinating C/EBPβ. Acta pharmacologica Sinica 2 40335710
2025 OTUD1 deficiency attenuates myocardial ischemia/reperfusion induced cardiomyocyte apoptosis by regulating RACK1 phosphorylation. Acta pharmacologica Sinica 2 40394237
2025 Allicin alleviates cerebral ischemia/reperfusion injury by inhibiting neuronal mitochondrial oxidative stress via OTUD1/NRF2 axis. Phytomedicine : international journal of phytotherapy and phytopharmacology 2 41172920
2023 Development of an OTUD1 ubiquitin variant inhibitor. The Biochemical journal 2 37589489
2026 METTL14 Regulates Myocardial Infarction Progression via m6A-Dependent Modulation of OTUD1-Mediated Deubiquitination of DUSP6. The Kaohsiung journal of medical sciences 1 41910113
2025 The Deubiquitinase OTUD1 Influences HIV-1 Release by Regulating the Host Restriction Factor BST-2. Viruses 1 40007014
2025 OTUD1 inhibits endometriosis fibrosis by deubiquitinating MADH7. Molecular human reproduction 1 40279273
2025 OTUD1 inhibits osteoclast differentiation and osteoclastic bone loss through deubiquitinating and stabilizing PRDX1. Theranostics 1 40585986
2025 Apoptotic extracellular vesicles derived from UC-MSCs promote spinal cord injury repair by inhibiting ferroptosis via OTUD1. Free radical biology & medicine 1 41151199
2024 OTUD1 Deficiency Alleviates LPS-Induced Acute Lung Injury in Mice by Reducing Inflammatory Response. Inflammation 1 39037666
2024 OTUD1 regulates cytokine expression and related pathways in goose fatty liver by promoting deubiquitination of its target proteins. Poultry science 1 39437555
2026 OTUD1 Relieves Coxsackievirus-Induced Ferroptosis and Inflammation in Myocardial Cells by Stabilizing NRF2 and Inhibiting NF-κB Signaling. IUBMB life 0 41853919
2026 From phthalate exposure to venous thrombotic risk: Decoding the DEHP-ROS mediated OTUD1- p53 stabilization loop in endothelium. Environment international 0 41967174
2026 Fluoxetine alleviates vascular cognitive impairment by activating the Nrf2/ARE pathway via Sp1-mediated OTUD1 transcription. Free radical research 0 41969155
2026 OTUD1 promotes the progession of depression through mitochondrial damage by targeting MST1/2. Brain, behavior, and immunity 0 42229703
2025 OTUD1 inhibits macrophage ferroptosis via regulation of AMPK and GSK3β/β-catenin signaling pathways exerting protective effects in sepsis-induced acute lung injury. International immunopharmacology 0 40460602
2025 The deubiquitinase OTUD1 orchestrates cisplatin chemosensitivity of non-small cell lung cancer through destabilizing RAD23B/XPC. Oncogene 0 41286308
2024 Pigeon novel-miR-741 targets OTUD1 to inhibit proliferation and promote apoptosis of crop fibroblasts. Poultry science 0 38479099

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