{"gene":"OTUD6A","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, deubiquitination assay, Otud6a-/- mice with DSS/TNBS colitis models, bone marrow transplantation","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo KO model with specific phenotypic readout, bone marrow transplantation for cell-type specificity, site-specific ubiquitination mapping","pmids":["36932155"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Deubiquitination assay, protein half-life (CHX chase), overexpression/depletion of OTUD6A in cancer cells, mitochondrial morphology imaging","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct deubiquitination assay and half-life experiment, single lab, two orthogonal methods","pmids":["33070427"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, deubiquitination assay, phosphorylation site mutagenesis, subcellular fractionation, nuclear localization imaging, CHK1 phosphorylation assay, OTUD6A-KO mouse xenograft irradiation model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, deubiquitination assay, in vivo KO), single lab with rigorous controls","pmids":["35768646"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Mass spectrometry substrate screening, Co-immunoprecipitation, deubiquitination assay with linkage-specific analysis, catalytic mutant rescue experiment, in vivo PtenPC-/- mouse model and PDX model","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS substrate identification, Co-IP, linkage-specific deubiquitination assay, catalytic mutant, in vivo models; multiple orthogonal methods","pmids":["35233061"],"is_preprint":false},{"year":2024,"finding":"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.","method":"DUB screening, Co-immunoprecipitation, deubiquitination assay with linkage-specific analysis, protein half-life assay, conditional KO mouse model, xenograft model","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteome-wide DUB screen, Co-IP, linkage-specific deubiquitination assay, in vivo CKO mouse model; multiple orthogonal methods single lab","pmids":["38685067"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Immunoprecipitation, mass spectrometry, deubiquitination assay, OTUD6A-/- mouse model with TAC/Ang II-induced hypertrophy, STING inhibition rescue experiment","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP/MS substrate identification, deubiquitination assay, KO mouse model with specific phenotypic readout, pathway rescue","pmids":["38342418"],"is_preprint":false},{"year":2021,"finding":"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).","method":"Pull-down assay with DUB library, Co-immunoprecipitation, deubiquitination assay, protein half-life (CHX chase), T288 phosphorylation assay, qPCR screening for downstream targets","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down DUB library screen, deubiquitination assay, half-life assay, single lab","pmids":["33669244"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, deubiquitination assay with K63-linkage specificity, STAT3 phosphorylation and nuclear translocation assays, Otud6a-KO mouse with Ang II chronic infusion","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, K63-specific deubiquitination assay, phosphorylation/localization assay, in vivo KO model; multiple orthogonal methods","pmids":["38105755"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Mass spectrometry identification of OTUD6A-interacting proteins, Co-immunoprecipitation, Otud6a-/- mouse macrophage stimulation assay, viral infection (HSV-1, VSV) and LPS challenge in vivo","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interaction identification, Co-IP, KO mouse functional assay; single lab, mechanistic link to UBC13 function not fully resolved","pmids":["37632103"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (K27-specific deubiquitination assay, membrane localization, kinase phosphorylation, in vivo KO cancer model), published in high-impact journal","pmids":["41188598"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, structural domain mapping, transcriptional reporter assays, chromatin immunoprecipitation (ChIP), protein stability assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, ChIP, functional transcription assays; single lab","pmids":["38594215"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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)","journal":"Acta pharmaceutica Sinica. B","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS substrate identification, Co-IP with domain mapping, K48-specific deubiquitination assay, p53 pathway functional validation, in vivo KO models","pmids":["41685148"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation, deubiquitination assay (K48-specific), protein stability assay, H3K27me3 immunoblot, OTUD6A-KO mouse APAP model","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K48-specific deubiquitination assay, in vivo KO model; single lab","pmids":["41049752"],"is_preprint":false},{"year":2026,"finding":"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.","method":"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","journal":"Pharmacological research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, site-specific deubiquitination assay, catalytic mutant validation, KO and cell-type-specific KD in vivo models, pathway rescue","pmids":["42242445"],"is_preprint":false},{"year":2025,"finding":"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).","method":"siRNA screen of 97 human DUBs, orthogonal dTAG PROTAC assay, subcellular fractionation/localization imaging","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic siRNA DUB screen, orthogonal PROTAC assays, subcellular localization analysis; preprint, single lab","pmids":[],"is_preprint":true},{"year":2026,"finding":"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.","method":"ChIP/promoter binding assay, PRDM1 gain- and loss-of-function experiments, CDC6 and OTUD6A protein level analysis, in vitro and in vivo models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, functional rescue experiments; single lab","pmids":["41724787"],"is_preprint":false},{"year":2025,"finding":"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.","method":"CRISPR/Cas9 knockout mouse generation, immunolocalization, sperm count and motility analysis, apoptosis assay","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO mouse model with specific spermatogenesis phenotype and subcellular localization; single lab, no direct substrate identified","pmids":["40134118"],"is_preprint":false}],"current_model":"OTUD6A is an OTU-family deubiquitinase that stabilizes multiple substrates (NLRP3, Drp1, TopBP1, Brg1, AR, CDC6, Aurora-A, STING, STAT3, ACTG1, EZH2, AKT, C/EBPβ) by removing K48-, K27-, K63-, K11-, K6-, or K33-linked polyubiquitin chains, with its activity and nuclear localization regulated by post-translational modifications (PP2A-mediated dephosphorylation promoting nuclear entry; S6K1-mediated phosphorylation causing inactivation), thereby controlling diverse processes including inflammasome activation, mitochondrial fission, DNA damage response, innate immunity, cardiac hypertrophy, kidney fibrosis, neurodegeneration, and tumorigenesis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2020,"claim":"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","pmids":["33070427"],"confidence":"Medium","gaps":["Ubiquitin linkage specificity on Drp1 not defined","No in vivo model","Recruitment mechanism to Drp1 unaddressed"]},{"year":2021,"claim":"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","pmids":["33669244"],"confidence":"Medium","gaps":["Ubiquitin linkage type on Aurora-A not mapped","No in vivo validation","Mechanism connecting deubiquitination to T288 phosphorylation unresolved"]},{"year":2022,"claim":"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","pmids":["35768646"],"confidence":"High","gaps":["Kinase opposing PP2A on S70/71/74 not identified here","Direct competition with UBR5 not structurally resolved"]},{"year":2022,"claim":"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","pmids":["35233061"],"confidence":"High","gaps":["Determinants of linkage selectivity not defined","Whether Brg1 and AR are deubiquitinated in the same complex unknown"]},{"year":2023,"claim":"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","pmids":["36932155","38105755","37632103"],"confidence":"High","gaps":["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"]},{"year":2024,"claim":"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","pmids":["38685067","38342418","38594215"],"confidence":"High","gaps":["For TEAD4, the mechanism of enhanced YAP recruitment independent of ubiquitin editing is undefined","Selectivity among multiple chain types on CDC6 not explained"]},{"year":2025,"claim":"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","pmids":["41188598","41685148"],"confidence":"High","gaps":["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"]},{"year":2025,"claim":"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","pmids":["40134118"],"confidence":"Medium","gaps":["No substrate identified in germ cells","Cytoplasmic localization here contrasts with regulated nuclear function elsewhere"]},{"year":2026,"claim":"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","pmids":["41049752","42242445","41724787"],"confidence":"High","gaps":["Signals controlling PRDM1 repression of OTUD6A not defined","Whether EZH2 and C/EBPβ regulation occurs in the same cell types not addressed"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,4,5,6,7,9,11,12,13]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2,3,4,11,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,9,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,16]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,5,7,8,13]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,9,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,4,11,12,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,5,7,11]}],"complexes":[],"partners":["NLRP3","TOPBP1","DRP1","AR","CDC6","STING","STAT3","AKT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7L8S5","full_name":"OTU domain-containing protein 6A","aliases":["DUBA-2"],"length_aa":288,"mass_kda":33.3,"function":"Deubiquitinating enzyme that hydrolyzes 'Lys-27'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitin chains. Also able to hydrolyze 'Lys-11'-linked ubiquitin chains","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q7L8S5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OTUD6A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OTUD6A","total_profiled":1310},"omim":[{"mim_id":"300714","title":"OTU DOMAIN-CONTAINING PROTEIN 6A; OTUD6A","url":"https://www.omim.org/entry/300714"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":4.5}],"url":"https://www.proteinatlas.org/search/OTUD6A"},"hgnc":{"alias_symbol":["FLJ25831","HSHIN6","DUBA2"],"prev_symbol":[]},"alphafold":{"accession":"Q7L8S5","domains":[{"cath_id":"3.90.70.80","chopping":"142-275","consensus_level":"high","plddt":90.6935,"start":142,"end":275},{"cath_id":"1.10.287","chopping":"9-68","consensus_level":"medium","plddt":81.4705,"start":9,"end":68}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L8S5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L8S5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L8S5-F1-predicted_aligned_error_v6.png","plddt_mean":82.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OTUD6A","jax_strain_url":"https://www.jax.org/strain/search?query=OTUD6A"},"sequence":{"accession":"Q7L8S5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7L8S5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7L8S5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L8S5"}},"corpus_meta":[{"pmid":"36932155","id":"PMC_36932155","title":"Deubiquitinase OTUD6A in macrophages promotes intestinal inflammation and colitis via deubiquitination of NLRP3.","date":"2023","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/36932155","citation_count":67,"is_preprint":false},{"pmid":"33070427","id":"PMC_33070427","title":"Deubiquitinase OTUD6A promotes proliferation of cancer cells via regulating Drp1 stability and mitochondrial fission.","date":"2020","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33070427","citation_count":45,"is_preprint":false},{"pmid":"35768646","id":"PMC_35768646","title":"Deubiquitinase OTUD6A promotes breast cancer progression by increasing TopBP1 stability and rendering tumor cells resistant to DNA-damaging therapy.","date":"2022","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/35768646","citation_count":43,"is_preprint":false},{"pmid":"35233061","id":"PMC_35233061","title":"OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/35233061","citation_count":22,"is_preprint":false},{"pmid":"38685067","id":"PMC_38685067","title":"Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance.","date":"2024","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38685067","citation_count":20,"is_preprint":false},{"pmid":"38342418","id":"PMC_38342418","title":"Deubiquitinase OTUD6a drives cardiac inflammation and hypertrophy by deubiquitination of STING.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38342418","citation_count":15,"is_preprint":false},{"pmid":"33669244","id":"PMC_33669244","title":"OTUD6A Is an Aurora Kinase A-Specific Deubiquitinase.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33669244","citation_count":10,"is_preprint":false},{"pmid":"38105755","id":"PMC_38105755","title":"OTUD6A in tubular epithelial cells mediates angiotensin II-induced kidney injury by targeting STAT3.","date":"2023","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38105755","citation_count":10,"is_preprint":false},{"pmid":"37632103","id":"PMC_37632103","title":"Deubiquitinase OTUD6A Regulates Innate Immune Response via Targeting UBC13.","date":"2023","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/37632103","citation_count":8,"is_preprint":false},{"pmid":"40134118","id":"PMC_40134118","title":"Otud6a Knockout Leads to Male Subfertility in Mice.","date":"2025","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/40134118","citation_count":2,"is_preprint":false},{"pmid":"38594215","id":"PMC_38594215","title":"OTUD6A orchestrates complex modulation of TEAD4-mediated transcriptional programs.","date":"2024","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/38594215","citation_count":1,"is_preprint":false},{"pmid":"41685148","id":"PMC_41685148","title":"OTUD6A drives dopaminergic neuronal degeneration of Parkinson's disease through deubiquitinating ACTG1 in neuronal cells.","date":"2025","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/41685148","citation_count":1,"is_preprint":false},{"pmid":"41188598","id":"PMC_41188598","title":"TRIM21 and OTUD6A orchestrate AKT K27-linked atypical ubiquitination to modulate cancer chemoresistance.","date":"2025","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41188598","citation_count":0,"is_preprint":false},{"pmid":"41049752","id":"PMC_41049752","title":"Deubiquitinase OTUD6A alleviates acetaminophen-induced liver injury by targeting EZH2 to reduce cell death in hepatocytes.","date":"2025","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/41049752","citation_count":0,"is_preprint":false},{"pmid":"41122004","id":"PMC_41122004","title":"Reduced OTUD6A Impairs Spermatogonia Proliferation and Contributes to Spermatogenic Arrest in Cattleyak.","date":"2025","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/41122004","citation_count":0,"is_preprint":false},{"pmid":"41724787","id":"PMC_41724787","title":"PRDM1 restricts bladder cancer progression and enhances chemosensitivity by suppressing OTUD6A-mediated deubiquitination of CDC6.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41724787","citation_count":0,"is_preprint":false},{"pmid":"42229000","id":"PMC_42229000","title":"Expression patterns and proliferative effect of OTUD6A on Sertoli cells and Leydig cells in cattleyak.","date":"2026","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/42229000","citation_count":0,"is_preprint":false},{"pmid":"42242445","id":"PMC_42242445","title":"Microglial OTUD6A promotes neuroinflammation and Alzheimer's disease pathogenesis by deubiquitinating C/EBPβ.","date":"2026","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/42242445","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.23.650020","title":"Efficiency and localisation of AURKA degradation by PROTACs is modulated by deubiquitinases UCHL5 and target-selective OTUD6A","date":"2025-04-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.23.650020","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11186,"output_tokens":4616,"usd":0.051399,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12588,"output_tokens":3946,"usd":0.080795,"stage2_stop_reason":"end_turn"},"total_usd":0.132194,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, Otud6a-/- mice with DSS/TNBS colitis models, bone marrow transplantation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo KO model with specific phenotypic readout, bone marrow transplantation for cell-type specificity, site-specific ubiquitination mapping\",\n      \"pmids\": [\"36932155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Deubiquitination assay, protein half-life (CHX chase), overexpression/depletion of OTUD6A in cancer cells, mitochondrial morphology imaging\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct deubiquitination assay and half-life experiment, single lab, two orthogonal methods\",\n      \"pmids\": [\"33070427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, phosphorylation site mutagenesis, subcellular fractionation, nuclear localization imaging, CHK1 phosphorylation assay, OTUD6A-KO mouse xenograft irradiation model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis, deubiquitination assay, in vivo KO), single lab with rigorous controls\",\n      \"pmids\": [\"35768646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry substrate screening, Co-immunoprecipitation, deubiquitination assay with linkage-specific analysis, catalytic mutant rescue experiment, in vivo PtenPC-/- mouse model and PDX model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS substrate identification, Co-IP, linkage-specific deubiquitination assay, catalytic mutant, in vivo models; multiple orthogonal methods\",\n      \"pmids\": [\"35233061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"DUB screening, Co-immunoprecipitation, deubiquitination assay with linkage-specific analysis, protein half-life assay, conditional KO mouse model, xenograft model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteome-wide DUB screen, Co-IP, linkage-specific deubiquitination assay, in vivo CKO mouse model; multiple orthogonal methods single lab\",\n      \"pmids\": [\"38685067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, deubiquitination assay, OTUD6A-/- mouse model with TAC/Ang II-induced hypertrophy, STING inhibition rescue experiment\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP/MS substrate identification, deubiquitination assay, KO mouse model with specific phenotypic readout, pathway rescue\",\n      \"pmids\": [\"38342418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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).\",\n      \"method\": \"Pull-down assay with DUB library, Co-immunoprecipitation, deubiquitination assay, protein half-life (CHX chase), T288 phosphorylation assay, qPCR screening for downstream targets\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down DUB library screen, deubiquitination assay, half-life assay, single lab\",\n      \"pmids\": [\"33669244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay with K63-linkage specificity, STAT3 phosphorylation and nuclear translocation assays, Otud6a-KO mouse with Ang II chronic infusion\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, K63-specific deubiquitination assay, phosphorylation/localization assay, in vivo KO model; multiple orthogonal methods\",\n      \"pmids\": [\"38105755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry identification of OTUD6A-interacting proteins, Co-immunoprecipitation, Otud6a-/- mouse macrophage stimulation assay, viral infection (HSV-1, VSV) and LPS challenge in vivo\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interaction identification, Co-IP, KO mouse functional assay; single lab, mechanistic link to UBC13 function not fully resolved\",\n      \"pmids\": [\"37632103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (K27-specific deubiquitination assay, membrane localization, kinase phosphorylation, in vivo KO cancer model), published in high-impact journal\",\n      \"pmids\": [\"41188598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, structural domain mapping, transcriptional reporter assays, chromatin immunoprecipitation (ChIP), protein stability assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, ChIP, functional transcription assays; single lab\",\n      \"pmids\": [\"38594215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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)\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS substrate identification, Co-IP with domain mapping, K48-specific deubiquitination assay, p53 pathway functional validation, in vivo KO models\",\n      \"pmids\": [\"41685148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay (K48-specific), protein stability assay, H3K27me3 immunoblot, OTUD6A-KO mouse APAP model\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K48-specific deubiquitination assay, in vivo KO model; single lab\",\n      \"pmids\": [\"41049752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, site-specific deubiquitination assay, catalytic mutant validation, KO and cell-type-specific KD in vivo models, pathway rescue\",\n      \"pmids\": [\"42242445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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).\",\n      \"method\": \"siRNA screen of 97 human DUBs, orthogonal dTAG PROTAC assay, subcellular fractionation/localization imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic siRNA DUB screen, orthogonal PROTAC assays, subcellular localization analysis; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP/promoter binding assay, PRDM1 gain- and loss-of-function experiments, CDC6 and OTUD6A protein level analysis, in vitro and in vivo models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, functional rescue experiments; single lab\",\n      \"pmids\": [\"41724787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR/Cas9 knockout mouse generation, immunolocalization, sperm count and motility analysis, apoptosis assay\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO mouse model with specific spermatogenesis phenotype and subcellular localization; single lab, no direct substrate identified\",\n      \"pmids\": [\"40134118\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OTUD6A is an OTU-family deubiquitinase that stabilizes multiple substrates (NLRP3, Drp1, TopBP1, Brg1, AR, CDC6, Aurora-A, STING, STAT3, ACTG1, EZH2, AKT, C/EBPβ) by removing K48-, K27-, K63-, K11-, K6-, or K33-linked polyubiquitin chains, with its activity and nuclear localization regulated by post-translational modifications (PP2A-mediated dephosphorylation promoting nuclear entry; S6K1-mediated phosphorylation causing inactivation), thereby controlling diverse processes including inflammasome activation, mitochondrial fission, DNA damage response, innate immunity, cardiac hypertrophy, kidney fibrosis, neurodegeneration, and tumorigenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #3, #4]. Its dominant biochemical action is reversal of K48-linked degradative ubiquitination, which stabilizes substrates including NLRP3 (cleaved at K430/K689) to amplify IL-1\\u03b2-driven inflammation [#0], STING to sustain NF-\\u03baB signaling in cardiomyocytes [#5], C/EBP\\u03b2 (at K253) to drive microglial proinflammatory cytokine production [#13], EZH2 to raise H3K27me3 and limit hepatocyte ER stress [#12], and ACTG1, whose stabilization promotes p53 nuclear translocation and dopaminergic neuronal apoptosis [#11]. 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 [#3, #4, #7, #9]. Substrate stabilization is frequently coupled to downstream activation: OTUD6A deubiquitinates Aurora-A and increases its activating T288 phosphorylation [#6], and for AKT it erases TRIM21-deposited K27 chains that otherwise block activating K63 ubiquitination and membrane recruitment [#9]. The enzyme's reach is gated by post-translational control of its localization and catalysis\\u2014PP2A 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 [#2, #9]. Catalytically inactive mutants (C157A) abolish substrate stabilization, confirming dependence on its deubiquitinase activity [#13]. Through these substrates OTUD6A promotes prostate, bladder, and lung tumorigenesis, mitochondrial fission via Drp1 stabilization, cardiac hypertrophy, kidney fibrosis, and neurodegeneration in mouse models [#1, #3, #4, #5, #7, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established OTUD6A as a functional deubiquitinase acting on a physiological substrate, linking it to mitochondrial dynamics.\",\n      \"evidence\": \"Deubiquitination and CHX-chase half-life assays of Drp1 with OTUD6A gain/loss in cancer cells plus mitochondrial morphology imaging\",\n      \"pmids\": [\"33070427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage specificity on Drp1 not defined\", \"No in vivo model\", \"Recruitment mechanism to Drp1 unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed OTUD6A not only stabilizes a substrate but enhances its catalytic activation, coupling deubiquitination to kinase signaling output.\",\n      \"evidence\": \"DUB-library pull-down, Co-IP, deubiquitination and half-life assays, and Aurora-A T288 phosphorylation readout\",\n      \"pmids\": [\"33669244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage type on Aurora-A not mapped\", \"No in vivo validation\", \"Mechanism connecting deubiquitination to T288 phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined how OTUD6A activity is spatially regulated and connected it to the replication-stress checkpoint via TopBP1 stabilization.\",\n      \"evidence\": \"Co-IP, phospho-site mutagenesis, subcellular fractionation, K48-specific deubiquitination assay, CHK1 phosphorylation, and KO xenograft irradiation model\",\n      \"pmids\": [\"35768646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase opposing PP2A on S70/71/74 not identified here\", \"Direct competition with UBR5 not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"MS substrate screen, linkage-specific deubiquitination assays, catalytic-mutant rescue, and PtenPC-/- and PDX models\",\n      \"pmids\": [\"35233061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of linkage selectivity not defined\", \"Whether Brg1 and AR are deubiquitinated in the same complex unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended OTUD6A function to innate immunity and inflammation through NLRP3 and STAT3, including a K63-specific activity that promotes signaling rather than stability.\",\n      \"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\",\n      \"pmids\": [\"36932155\", \"38105755\", \"37632103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened the substrate repertoire to CDC6, STING, and the YAP-TEAD axis, distinguishing stability-dependent from stability-independent transcriptional roles.\",\n      \"evidence\": \"DUB screening, linkage-specific deubiquitination assays, conditional and global KO mouse cancer/hypertrophy models, ChIP and domain mapping for TEAD4\",\n      \"pmids\": [\"38685067\", \"38342418\", \"38594215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"For TEAD4, the mechanism of enhanced YAP recruitment independent of ubiquitin editing is undefined\", \"Selectivity among multiple chain types on CDC6 not explained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed reciprocal regulation between OTUD6A and the AKT/mTOR axis, plus new roles in neurodegeneration via ACTG1-p53 and PROTAC resistance via nuclear localization.\",\n      \"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\",\n      \"pmids\": [\"41188598\", \"41685148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a tissue-restricted physiological role for OTUD6A in spermatogenesis independent of any defined substrate.\",\n      \"evidence\": \"CRISPR/Cas9 KO mouse with immunolocalization, sperm count/motility and germ-cell apoptosis analyses\",\n      \"pmids\": [\"40134118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate identified in germ cells\", \"Cytoplasmic localization here contrasts with regulated nuclear function elsewhere\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Added EZH2 and C/EBP\\u03b2 substrates and an upstream transcriptional brake (PRDM1), defining how OTUD6A is itself controlled at the gene level.\",\n      \"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\",\n      \"pmids\": [\"41049752\", \"42242445\", \"41724787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling PRDM1 repression of OTUD6A not defined\", \"Whether EZH2 and C/EBP\\u03b2 regulation occurs in the same cell types not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for multi-linkage specificity\", \"No unifying model for context-dependent substrate choice\", \"Interplay of PP2A and S6K1 phospho-regulation not reconstituted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2, 3, 4, 11, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 5, 7, 8, 13]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 9, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 4, 11, 12, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 5, 7, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NLRP3\", \"TopBP1\", \"Drp1\", \"AR\", \"CDC6\", \"STING\", \"STAT3\", \"AKT\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}