Affinage

OTUD6A

OTU domain-containing protein 6A · UniProt Q7L8S5

Length
288 aa
Mass
33.3 kDa
Annotated
2026-06-10
18 papers in source corpus 16 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OTUD6A is an OTU-family deubiquitinase that controls the abundance and activity of diverse substrate proteins by removing specific polyubiquitin linkages, thereby shaping inflammation, the DNA damage response, cell proliferation, and tissue-specific stress responses (PMID:36932155, PMID:35233061, PMID:38685067). Its dominant biochemical action is reversal of K48-linked degradative ubiquitination, which stabilizes substrates including NLRP3 (cleaved at K430/K689) to amplify IL-1β-driven inflammation (PMID:36932155), STING to sustain NF-κB signaling in cardiomyocytes (PMID:38342418), C/EBPβ (at K253) to drive microglial proinflammatory cytokine production (PMID:42242445), EZH2 to raise H3K27me3 and limit hepatocyte ER stress (PMID:41049752), and ACTG1, whose stabilization promotes p53 nuclear translocation and dopaminergic neuronal apoptosis (PMID:41685148). OTUD6A also resolves non-canonical chains, removing K27-linked ubiquitin from Brg1 and AKT, K11-linked from the androgen receptor, K6/K33/K48 chains from CDC6, and K63-linked chains from STAT3 to promote its Y705 phosphorylation and profibrotic transcription (PMID:35233061, PMID:38685067, PMID:38105755, PMID:41188598). Substrate stabilization is frequently coupled to downstream activation: OTUD6A deubiquitinates Aurora-A and increases its activating T288 phosphorylation (PMID:33669244), and for AKT it erases TRIM21-deposited K27 chains that otherwise block activating K63 ubiquitination and membrane recruitment (PMID:41188598). The enzyme's reach is gated by post-translational control of its localization and catalysis—PP2A dephosphorylates OTUD6A at S70/71/74 to drive nuclear entry where it stabilizes TopBP1 and sustains CHK1 signaling under replication stress, while S6K1 phosphorylates and inactivates OTUD6A to form a negative feedback loop on AKT (PMID:35768646, PMID:41188598). Catalytically inactive mutants (C157A) abolish substrate stabilization, confirming dependence on its deubiquitinase activity (PMID:42242445). Through these substrates OTUD6A promotes prostate, bladder, and lung tumorigenesis, mitochondrial fission via Drp1 stabilization, cardiac hypertrophy, kidney fibrosis, and neurodegeneration in mouse models (PMID:33070427, PMID:35233061, PMID:38685067, PMID:38342418, PMID:38105755, PMID:41685148).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2020 Medium

    Established OTUD6A as a functional deubiquitinase acting on a physiological substrate, linking it to mitochondrial dynamics.

    Evidence Deubiquitination and CHX-chase half-life assays of Drp1 with OTUD6A gain/loss in cancer cells plus mitochondrial morphology imaging

    PMID:33070427

    Open questions at the time
    • Ubiquitin linkage specificity on Drp1 not defined
    • No in vivo model
    • Recruitment mechanism to Drp1 unaddressed
  2. 2021 Medium

    Showed OTUD6A not only stabilizes a substrate but enhances its catalytic activation, coupling deubiquitination to kinase signaling output.

    Evidence DUB-library pull-down, Co-IP, deubiquitination and half-life assays, and Aurora-A T288 phosphorylation readout

    PMID:33669244

    Open questions at the time
    • Ubiquitin linkage type on Aurora-A not mapped
    • No in vivo validation
    • Mechanism connecting deubiquitination to T288 phosphorylation unresolved
  3. 2022 High

    Defined how OTUD6A activity is spatially regulated and connected it to the replication-stress checkpoint via TopBP1 stabilization.

    Evidence Co-IP, phospho-site mutagenesis, subcellular fractionation, K48-specific deubiquitination assay, CHK1 phosphorylation, and KO xenograft irradiation model

    PMID:35768646

    Open questions at the time
    • Kinase opposing PP2A on S70/71/74 not identified here
    • Direct competition with UBR5 not structurally resolved
  4. 2022 High

    Demonstrated OTUD6A erases non-canonical linkages (K27 on Brg1, K11 on AR) and that its catalytic activity is required for oncogenic function in prostate cancer.

    Evidence MS substrate screen, linkage-specific deubiquitination assays, catalytic-mutant rescue, and PtenPC-/- and PDX models

    PMID:35233061

    Open questions at the time
    • Determinants of linkage selectivity not defined
    • Whether Brg1 and AR are deubiquitinated in the same complex unknown
  5. 2023 High

    Extended OTUD6A function to innate immunity and inflammation through NLRP3 and STAT3, including a K63-specific activity that promotes signaling rather than stability.

    Evidence Reciprocal Co-IP, site-specific (K430/K689) and K63-linkage-specific deubiquitination assays, in vivo Otud6a-/- colitis and kidney fibrosis models; plus UBC13-interaction MS and KO macrophage type I IFN assays

    PMID:36932155 PMID:37632103 PMID:38105755

    Open questions at the time
    • How K63 deubiquitination of STAT3 promotes its phosphorylation mechanistically unclear
    • Functional role of the OTUD6A-UBC13 interaction not fully resolved
    • Apparent opposing roles in different inflammatory contexts not reconciled
  6. 2024 High

    Broadened the substrate repertoire to CDC6, STING, and the YAP-TEAD axis, distinguishing stability-dependent from stability-independent transcriptional roles.

    Evidence DUB screening, linkage-specific deubiquitination assays, conditional and global KO mouse cancer/hypertrophy models, ChIP and domain mapping for TEAD4

    PMID:38342418 PMID:38594215 PMID:38685067

    Open questions at the time
    • For TEAD4, the mechanism of enhanced YAP recruitment independent of ubiquitin editing is undefined
    • Selectivity among multiple chain types on CDC6 not explained
  7. 2025 High

    Revealed reciprocal regulation between OTUD6A and the AKT/mTOR axis, plus new roles in neurodegeneration via ACTG1-p53 and PROTAC resistance via nuclear localization.

    Evidence K27-specific deubiquitination and AKT membrane localization assays, S6K1 phosphorylation of OTUD6A, KrasG12D lung cancer KO model; MS/domain mapping for ACTG1 with PD KO models; siRNA DUB screen and dTAG PROTAC assays for AURKA

    PMID:41188598 PMID:41685148

    Open questions at the time
    • S6K1 phosphosites on OTUD6A and their relation to PP2A sites not integrated
    • How OTUD6A discriminates AKT K27 chains from K63 chains unresolved
    • PROTAC-counteraction finding (idx 14) is a preprint awaiting peer review
  8. 2025 Medium

    Identified a tissue-restricted physiological role for OTUD6A in spermatogenesis independent of any defined substrate.

    Evidence CRISPR/Cas9 KO mouse with immunolocalization, sperm count/motility and germ-cell apoptosis analyses

    PMID:40134118

    Open questions at the time
    • No substrate identified in germ cells
    • Cytoplasmic localization here contrasts with regulated nuclear function elsewhere
  9. 2026 High

    Added EZH2 and C/EBPβ substrates and an upstream transcriptional brake (PRDM1), defining how OTUD6A is itself controlled at the gene level.

    Evidence K48/site-specific deubiquitination assays, C157A catalytic mutant, H3K27me3 immunoblot, ChIP for PRDM1 promoter binding, and KO mouse APAP, AD, and bladder cancer models

    PMID:41049752 PMID:41724787 PMID:42242445

    Open questions at the time
    • Signals controlling PRDM1 repression of OTUD6A not defined
    • Whether EZH2 and C/EBPβ regulation occurs in the same cell types not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How OTUD6A achieves selectivity across so many substrates and ubiquitin linkage types, and how its competing pro- and anti-inflammatory/oncogenic roles are partitioned across tissues, remains unresolved.
  • No structural basis for multi-linkage specificity
  • No unifying model for context-dependent substrate choice
  • Interplay of PP2A and S6K1 phospho-regulation not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12 GO:0016787 hydrolase activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-73894 DNA Repair 1
Partners
AKTARCDC6DRP1NLRP3STAT3STINGTOPBP1

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 OTUD6A directly binds to the NACHT domain of NLRP3 inflammasome and selectively cleaves K48-linked polyubiquitin chains from NLRP3 at K430 and K689, enhancing NLRP3 stability and increasing IL-1β-mediated inflammation. OTUD6A deficiency in myeloid cells attenuated colitis in vivo. Co-immunoprecipitation, deubiquitination assay, Otud6a-/- mice with DSS/TNBS colitis models, bone marrow transplantation Cell death and differentiation High 36932155
2020 OTUD6A deubiquitylates and stabilizes Drp1 (dynamin-related protein 1), extending its protein half-life and facilitating mitochondrial fission. OTUD6A depletion leads to lower Drp1 levels and suppressed mitochondrial fission. Deubiquitination assay, protein half-life (CHX chase), overexpression/depletion of OTUD6A in cancer cells, mitochondrial morphology imaging Molecular oncology Medium 33070427
2022 In response to DNA damage, PP2A interacts with OTUD6A and dephosphorylates it at S70/71/74, promoting nuclear localization of OTUD6A. Nuclear OTUD6A interacts with TopBP1, blocks its interaction with E3 ligase UBR5, and removes K48-linked polyubiquitination from TopBP1, stabilizing it and sustaining CHK1 S345 phosphorylation during replication stress. Co-immunoprecipitation, deubiquitination assay, phosphorylation site mutagenesis, subcellular fractionation, nuclear localization imaging, CHK1 phosphorylation assay, OTUD6A-KO mouse xenograft irradiation model Cell death and differentiation High 35768646
2022 OTUD6A deubiquitinates Brg1 by erasing K27-linked polyubiquitination and deubiquitinates AR (androgen receptor) by erasing K11-linked polyubiquitination, stabilizing both substrates and promoting prostate cancer progression. Catalytically inactive OTUD6A mutant failed to support cancer cell progression. Mass spectrometry substrate screening, Co-immunoprecipitation, deubiquitination assay with linkage-specific analysis, catalytic mutant rescue experiment, in vivo PtenPC-/- mouse model and PDX model Communications biology High 35233061
2024 OTUD6A interacts with CDC6 and removes K6-, K33-, and K48-linked polyubiquitination from CDC6, stabilizing it and promoting cell proliferation and chemoresistance. Conditional Otud6a knockout mice were less prone to BBN-induced bladder cancer tumorigenesis. DUB screening, Co-immunoprecipitation, deubiquitination assay with linkage-specific analysis, protein half-life assay, conditional KO mouse model, xenograft model Molecular cancer High 38685067
2024 OTUD6A directly binds STING and removes K48-linked ubiquitin chains from STING, maintaining STING stability and activating downstream NF-κB signaling and inflammatory gene expression in cardiomyocytes, thereby promoting cardiac hypertrophy. Immunoprecipitation, mass spectrometry, deubiquitination assay, OTUD6A-/- mouse model with TAC/Ang II-induced hypertrophy, STING inhibition rescue experiment Biochimica et biophysica acta. Molecular basis of disease High 38342418
2021 OTUD6A is an Aurora kinase A (Aurora-A)-specific deubiquitinase that interacts with Aurora-A through the OTU domain of OTUD6A and kinase domain of Aurora-A, deubiquitinates Aurora-A, extends its protein half-life, and increases phosphorylation at T288 (activation site). OTUD6A overexpression upregulates CKS2 (Cyclin-dependent kinases regulatory subunit 2). Pull-down assay with DUB library, Co-immunoprecipitation, deubiquitination assay, protein half-life (CHX chase), T288 phosphorylation assay, qPCR screening for downstream targets International journal of molecular sciences Medium 33669244
2023 OTUD6A binds to STAT3 and removes K63-linked ubiquitin chains, promoting STAT3 phosphorylation at Y705 and nuclear translocation, which induces profibrotic gene transcription in tubular epithelial cells and exacerbates Ang II-induced kidney fibrosis. Co-immunoprecipitation, deubiquitination assay with K63-linkage specificity, STAT3 phosphorylation and nuclear translocation assays, Otud6a-KO mouse with Ang II chronic infusion American journal of physiology. Cell physiology High 38105755
2023 OTUD6A interacts with UBC13 (an E2 ubiquitin-conjugating enzyme), and this interaction is enhanced after HSV-1 stimulation. OTUD6A significantly inhibits type I interferon production; macrophages from Otud6a-/- mice produce more type I interferon after virus infection. Mass spectrometry identification of OTUD6A-interacting proteins, Co-immunoprecipitation, Otud6a-/- mouse macrophage stimulation assay, viral infection (HSV-1, VSV) and LPS challenge in vivo Viruses Medium 37632103
2025 TRIM21 E3 ligase adds K27-linked ubiquitination to AKT, and OTUD6A specifically removes this K27-linked ubiquitination from AKT. TRIM21-mediated K27 ubiquitination disrupts SKP2- or TRAF6-mediated K63 ubiquitination, blocking AKT membrane localization and kinase activity. Upon amino acid stimulation, S6K1 phosphorylates and inactivates OTUD6A, creating a negative feedback loop on AKT activity. Co-immunoprecipitation, deubiquitination assay with linkage-specific analysis (K27), AKT membrane localization assay, S6K1 phosphorylation of OTUD6A in vitro/in vivo, Otud6a-/- KrasG12D lung cancer mouse model Nature structural & molecular biology High 41188598
2024 OTUD6A interacts with TEAD4 through its N-terminal domain (interacting with the YAP-binding domain of TEAD4) and positively influences TEAD-driven transcription without altering TEAD4 stability or nuclear localization. OTUD6A selectively enhances YAP-TEAD4 complex formation while suppressing VGLL4-TEAD4 interaction, and facilitates YAP-TEAD4 binding to target gene promoters. Co-immunoprecipitation, structural domain mapping, transcriptional reporter assays, chromatin immunoprecipitation (ChIP), protein stability assay FEBS letters Medium 38594215
2025 OTUD6A drives dopaminergic neuronal degeneration by specifically interacting with the 8-181 aa domain of ACTG1 (actin gamma 1) and cleaving K48-linked polyubiquitin chains from ACTG1, stabilizing it. Stabilized ACTG1 binds p53 and facilitates its nuclear translocation, leading to transcriptional activation of pro-apoptotic genes and neuronal apoptosis. Mass spectrometry, Co-immunoprecipitation with domain mapping, deubiquitination assay (K48-specific), protein stability assay, p53 nuclear translocation assay, OTUD6A-KO mouse PD models (acute and chronic) Acta pharmaceutica Sinica. B High 41685148
2025 OTUD6A directly interacts with EZH2 and removes K48-linked polyubiquitin chains from EZH2, enhancing EZH2 stability and increasing H3K27me3 levels, resulting in reduced ER stress and cell death in hepatocytes. OTUD6A knockout exacerbated APAP-induced liver injury while overexpression was protective. Co-immunoprecipitation, deubiquitination assay (K48-specific), protein stability assay, H3K27me3 immunoblot, OTUD6A-KO mouse APAP model Acta pharmaceutica Sinica. B Medium 41049752
2026 OTUD6A binds C/EBPβ and removes K48-linked ubiquitin chains at K253 of C/EBPβ, stabilizing C/EBPβ and enhancing NF-κB signaling and proinflammatory cytokine production in microglia. A catalytic mutant C157A of OTUD6A abolished deubiquitination activity and C/EBPβ stabilization. Co-immunoprecipitation, deubiquitination assay with site-specific (K253) and K48-linkage analysis, OTUD6A catalytic mutant (C157A), Otud6a-KO and microglia-specific knockdown in AD mouse models, C/EBPβ knockdown rescue experiment Pharmacological research High 42242445
2025 OTUD6A counteracts PROTAC-mediated degradation of AURKA in a target-specific manner. The differential sensitivity of the nuclear pool of AURKA to PROTAC degradation is fully explained by the specific subcellular localization pattern of OTUD6A (nuclear localization). siRNA screen of 97 human DUBs, orthogonal dTAG PROTAC assay, subcellular fractionation/localization imaging bioRxivpreprint Medium
2026 PRDM1 transcription factor directly binds the OTUD6A promoter and suppresses its transcription, thereby reducing OTUD6A-mediated CDC6 deubiquitination and promoting CDC6 degradation in bladder cancer cells. ChIP/promoter binding assay, PRDM1 gain- and loss-of-function experiments, CDC6 and OTUD6A protein level analysis, in vitro and in vivo models Cell death & disease Medium 41724787
2025 OTUD6A is predominantly expressed in the testis, localized to the cytoplasm of spermatogonia and spermatocytes. Otud6a-knockout mice exhibit increased germ cell apoptosis, decreased epididymal sperm counts, abnormal sperm motility, and subfertility. CRISPR/Cas9 knockout mouse generation, immunolocalization, sperm count and motility analysis, apoptosis assay Molecular reproduction and development Medium 40134118

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 Deubiquitinase OTUD6A in macrophages promotes intestinal inflammation and colitis via deubiquitination of NLRP3. Cell death and differentiation 67 36932155
2020 Deubiquitinase OTUD6A promotes proliferation of cancer cells via regulating Drp1 stability and mitochondrial fission. Molecular oncology 45 33070427
2022 Deubiquitinase OTUD6A promotes breast cancer progression by increasing TopBP1 stability and rendering tumor cells resistant to DNA-damaging therapy. Cell death and differentiation 43 35768646
2022 OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR. Communications biology 22 35233061
2024 Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance. Molecular cancer 20 38685067
2024 Deubiquitinase OTUD6a drives cardiac inflammation and hypertrophy by deubiquitination of STING. Biochimica et biophysica acta. Molecular basis of disease 15 38342418
2023 OTUD6A in tubular epithelial cells mediates angiotensin II-induced kidney injury by targeting STAT3. American journal of physiology. Cell physiology 10 38105755
2021 OTUD6A Is an Aurora Kinase A-Specific Deubiquitinase. International journal of molecular sciences 10 33669244
2023 Deubiquitinase OTUD6A Regulates Innate Immune Response via Targeting UBC13. Viruses 8 37632103
2025 Otud6a Knockout Leads to Male Subfertility in Mice. Molecular reproduction and development 2 40134118
2025 OTUD6A drives dopaminergic neuronal degeneration of Parkinson's disease through deubiquitinating ACTG1 in neuronal cells. Acta pharmaceutica Sinica. B 1 41685148
2024 OTUD6A orchestrates complex modulation of TEAD4-mediated transcriptional programs. FEBS letters 1 38594215
2026 PRDM1 restricts bladder cancer progression and enhances chemosensitivity by suppressing OTUD6A-mediated deubiquitination of CDC6. Cell death & disease 0 41724787
2026 Expression patterns and proliferative effect of OTUD6A on Sertoli cells and Leydig cells in cattleyak. Theriogenology 0 42229000
2026 Microglial OTUD6A promotes neuroinflammation and Alzheimer's disease pathogenesis by deubiquitinating C/EBPβ. Pharmacological research 0 42242445
2025 Deubiquitinase OTUD6A alleviates acetaminophen-induced liver injury by targeting EZH2 to reduce cell death in hepatocytes. Acta pharmaceutica Sinica. B 0 41049752
2025 Reduced OTUD6A Impairs Spermatogonia Proliferation and Contributes to Spermatogenic Arrest in Cattleyak. Reproduction in domestic animals = Zuchthygiene 0 41122004
2025 TRIM21 and OTUD6A orchestrate AKT K27-linked atypical ubiquitination to modulate cancer chemoresistance. Nature structural & molecular biology 0 41188598

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