OTUD3 (OTU domain-containing protein 3) is a cysteine-protease deubiquitinase (DUB, EC 3.4.19.12) of the ovarian tumor (OTU) family. Its catalytic OTU domain (active-site nucleophile Cys76, with His182) hydrolyzes isopeptide bonds of ubiquitin chains with a preference for atypical Lys-6 (K6)- and Lys-11 (K11)-linked polyubiquitin, and it also processes heterotypic (mixed/branched) and other homotypic chains; a C-terminal UBA-like domain does not affect catalysis. OTUD3 acts on specific substrates: it deubiquitinates and stabilizes the tumor suppressor PTEN (suppressing PI3K-AKT signaling and tumorigenesis), stabilizes the nuclear receptor PPARD to regulate glucose and lipid metabolism and oxidative phosphorylation in response to nutritional stress (with glucose/fatty-acid-triggered, CBP/CREBBP-dependent acetylation driving its nuclear translocation), and deubiquitinates KPTN to suppress mTORC1 signaling. In ribosome-associated quality control, OTUD3 acts as a negative regulator by deubiquitinating 40S ribosomal proteins RPS10/eS10 and RPS20/uS10, antagonizing ZNF598-mediated 40S ubiquitination. OTUD3 shuttles between the cytoplasm and the nucleus.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004843 cysteine-type deubiquitinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: OTUD3 is an OTU-family cysteine-protease deubiquitinase, its core molecular function. Reason: Directly established by structure, catalytic-cysteine (Cys76) mutagenesis, and biochemical assays; the defining function of OTUD3. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Deubiquitinating enzyme that hydrolyzes |
| GO:0050821 protein stabilization | IBA GO_REF:0000033 | ACCEPT | Summary: By removing degradative ubiquitin chains, OTUD3 stabilizes substrate proteins (e.g. PTEN, PPARD). Reason: Directly supported; OTUD3 deubiquitinates and stabilizes specific substrates, a key biological outcome of its DUB activity. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt deubiquitinates and stabilizes the nuclear receptor PPARD |
| GO:0004843 cysteine-type deubiquitinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of the core DUB activity. Reason: Consistent with the experimentally established cysteine-type deubiquitinase activity. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Deubiquitinating enzyme that hydrolyzes |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization; OTUD3 translocates to the nucleus upon acetylation to deubiquitinate PPARD. Reason: Documented nuclear localization where OTUD3 acts on PPARD; supported by direct evidence. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:35675826}. Nucleus |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization, where OTUD3 acts on PTEN and on 40S ribosomal proteins in RQC. Reason: Documented cytoplasmic localization; the basal compartment of OTUD3 before nuclear translocation. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016579 protein deubiquitination | IEA GO_REF:0000117 | ACCEPT | Summary: Protein deubiquitination is the biological process carried out by OTUD3's catalytic activity. Reason: Core process directly supported by OTUD3's DUB activity. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Deubiquitinating enzyme that hydrolyzes |
| GO:0005515 protein binding | IPI PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | KEEP AS NON CORE | Summary: Interaction with PTEN (P60484-1), the substrate OTUD3 deubiquitinates and stabilizes. Bare protein binding term. Reason: A functionally important substrate interaction (PTEN), but bare protein binding is uninformative; the relevant activity is captured by the deubiquitination and PI3K/AKT-regulation annotations. Supporting Evidence: file:human/OTUD3/OTUD3-goa.tsv UniProtKB:P60484-1 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: HuRI interactome interaction with HSD17B14 (Q9BPX1). Bare protein binding. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/OTUD3/OTUD3-goa.tsv UniProtKB:Q9BPX1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex interactome interactions with KPTN (Q9Y664) and ITFG2 (Q969R8), part of the KICSTOR/mTORC1 regulatory context. Bare protein binding. Reason: Interactions are biologically relevant (KPTN is an OTUD3 substrate) but bare protein binding is uninformative; the KPTN deubiquitination role is the informative function. Supporting Evidence: file:human/OTUD3/OTUD3-goa.tsv UniProtKB:Q9Y664 |
| GO:0005515 protein binding | IPI PMID:38288086 OTUD3 suppresses the mTORC1 signaling by deubiquitinating KP... | KEEP AS NON CORE | Summary: Interactions with KPTN (Q9Y664) and ITFG2 (Q969R8); OTUD3 deubiquitinates KPTN to suppress mTORC1 signaling. Bare protein binding term. Reason: Functionally relevant (KPTN substrate, mTORC1) but bare protein binding is uninformative; the specific activity is OTUD3-mediated KPTN deubiquitination. Supporting Evidence: file:human/OTUD3/OTUD3-goa.tsv UniProtKB:Q9Y664 |
| GO:0016579 protein deubiquitination | TAS Reactome:R-HSA-5688426 | ACCEPT | Summary: Reactome annotation of OTUD3 protein deubiquitination. Reason: Core process supported by curated Reactome and experimental evidence. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Deubiquitinating enzyme that hydrolyzes |
| GO:0004843 cysteine-type deubiquitinase activity | TAS Reactome:R-HSA-6807206 | ACCEPT | Summary: Reactome annotation of OTUD3 cysteine-type deubiquitinase activity. Reason: Core molecular function supported by curated Reactome and experimental evidence. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Deubiquitinating enzyme that hydrolyzes |
| GO:0004843 cysteine-type deubiquitinase activity | TAS Reactome:R-HSA-8873946 | ACCEPT | Summary: Reactome annotation of OTUD3 cysteine-type deubiquitinase activity (PTEN regulation pathway). Reason: Core molecular function supported by curated Reactome and experimental evidence. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Deubiquitinating enzyme that hydrolyzes |
| GO:0005737 cytoplasm | EXP PMID:35675826 Deubiquitinase OTUD3 regulates metabolism homeostasis in res... | ACCEPT | Summary: Experimental cytoplasmic localization (basal compartment before nutrient-triggered nuclear translocation). Reason: Directly supported by experimental subcellular-localization data. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:32011234 Distinct regulatory ribosomal ubiquitylation events are reve... | ACCEPT | Summary: Direct demonstration of OTUD3 DUB activity, with Cys76 active-site mutagenesis, in the context of 40S ribosomal deubiquitination during RQC. Reason: Core molecular function established by direct evidence with catalytic-cysteine mutagenesis. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt acts as a negative regulator of the ribosome quality control |
| GO:0016579 protein deubiquitination | IDA PMID:32011234 Distinct regulatory ribosomal ubiquitylation events are reve... | ACCEPT | Summary: OTUD3 deubiquitinates 40S ribosomal proteins (RPS10/eS10), antagonizing ZNF598-mediated ubiquitination. Reason: Directly demonstrated protein deubiquitination in the RQC context. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt deubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS20/uS10 |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:35675826 Deubiquitinase OTUD3 regulates metabolism homeostasis in res... | ACCEPT | Summary: Direct demonstration of OTUD3 DUB activity in the metabolic/PPARD-stabilization context. Reason: Core molecular function established by direct evidence. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Deubiquitinating enzyme that hydrolyzes |
| GO:0005634 nucleus | IDA PMID:35675826 Deubiquitinase OTUD3 regulates metabolism homeostasis in res... | ACCEPT | Summary: OTUD3 is active in the nucleus, where it deubiquitinates and stabilizes PPARD after nutrient-triggered translocation. Reason: Directly supported; nuclear OTUD3 acts on PPARD. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt deubiquitinates and stabilizes the nuclear receptor PPARD |
| GO:0031669 cellular response to nutrient levels | IDA PMID:35675826 Deubiquitinase OTUD3 regulates metabolism homeostasis in res... | ACCEPT | Summary: OTUD3 responds to nutritional stress; glucose/fatty acids drive its acetylation and nuclear translocation to regulate metabolic gene expression. Reason: Directly supported; OTUD3 is a regulator of metabolism homeostasis in response to nutritional stresses. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Glucose and fatty acids trigger its nuclear translocation |
| GO:0050821 protein stabilization | IDA PMID:35675826 Deubiquitinase OTUD3 regulates metabolism homeostasis in res... | ACCEPT | Summary: OTUD3 deubiquitinates and stabilizes PPARD. Reason: Directly supported substrate stabilization. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt deubiquitinates and stabilizes the nuclear receptor PPARD |
| GO:0071108 protein K48-linked deubiquitination | IDA PMID:35675826 Deubiquitinase OTUD3 regulates metabolism homeostasis in res... | ACCEPT | Summary: OTUD3 removes K48-linked (degradative) ubiquitin chains from PPARD to stabilize it. Reason: Supported in the PPARD-stabilization context; removal of K48-linked chains explains the stabilization phenotype. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt deubiquitinates and stabilizes the nuclear receptor PPARD |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | ACCEPT | Summary: Direct demonstration of OTUD3 DUB activity in the PTEN-stabilization study. Reason: Core molecular function established by direct evidence. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Deubiquitinating enzyme that hydrolyzes |
| GO:0004843 cysteine-type deubiquitinase activity | IMP PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | ACCEPT | Summary: Mutational evidence (catalytic-dead OTUD3) supporting its DUB activity on PTEN. Reason: Core molecular function supported by IMP (catalytic mutant). Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Deubiquitinating enzyme that hydrolyzes |
| GO:0005737 cytoplasm | IDA PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | ACCEPT | Summary: Cytoplasmic localization where OTUD3 acts on PTEN. Reason: Directly supported cytoplasmic localization. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0035871 protein K11-linked deubiquitination | IDA PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | ACCEPT | Summary: OTUD3 hydrolyzes K11-linked polyubiquitin, one of its preferred linkage types. Reason: Directly supported; OTUD3 has K6/K11 linkage preference. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt hydrolyzes 'Lys-6'- and 'Lys- |
| GO:0044313 protein K6-linked deubiquitination | IDA PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | ACCEPT | Summary: OTUD3 hydrolyzes K6-linked polyubiquitin, a preferred linkage type. Reason: Directly supported; OTUD3 has K6/K11 linkage preference. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt hydrolyzes 'Lys-6'- and 'Lys- |
| GO:0050821 protein stabilization | IDA PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | ACCEPT | Summary: OTUD3 deubiquitinates and stabilizes PTEN, suppressing tumorigenesis. Reason: Directly supported substrate stabilization (PTEN). Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Also hydrolyzes heterotypic |
| GO:0050821 protein stabilization | IMP PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | ACCEPT | Summary: Mutational evidence that OTUD3 catalytic activity is required to stabilize PTEN. Reason: Supported by IMP; catalytic-dead OTUD3 fails to stabilize PTEN. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Also hydrolyzes heterotypic |
| GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IDA PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | ACCEPT | Summary: By stabilizing PTEN, OTUD3 negatively regulates PI3K-AKT signaling. Reason: Directly supported; PTEN stabilization suppresses PI3K-AKT signaling and tumorigenesis. Supporting Evidence: PMID:26280536 Depletion of OTUD3 leads to the activation of Akt signalling, induction of cellular transformation and cancer metastasis. |
| GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IMP PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | ACCEPT | Summary: Mutational/knockdown evidence linking OTUD3 to PI3K-AKT suppression via PTEN. Reason: Supported by IMP in the PTEN/PI3K-AKT study. Supporting Evidence: PMID:26280536 Depletion of OTUD3 leads to the activation of Akt signalling, induction of cellular transformation and cancer metastasis. |
| GO:0071108 protein K48-linked deubiquitination | IDA PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | ACCEPT | Summary: OTUD3 removes K48-linked ubiquitin from PTEN to stabilize it. Reason: Supported; OTUD3 can process K48-linked chains to stabilize substrates. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Also hydrolyzes heterotypic |
| GO:1990167 protein K27-linked deubiquitination | IDA PMID:26280536 Deubiquitylase OTUD3 regulates PTEN stability and suppresses... | KEEP AS NON CORE | Summary: OTUD3 can hydrolyze K27-linked ubiquitin in some assays. Reason: OTUD3's principal preference is K6/K11; K27 activity is plausible (broad heterotypic-chain processing) but a minor/non-core specificity. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Also hydrolyzes heterotypic |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6807206 | ACCEPT | Summary: Reactome cytosolic localization. Reason: Consistent with documented cytoplasmic/cytosolic localization. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8873946 | ACCEPT | Summary: Reactome cytosolic localization (PTEN regulation pathway). Reason: Consistent with documented cytoplasmic/cytosolic localization. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:23827681 OTU deubiquitinases reveal mechanisms of linkage specificity... | ACCEPT | Summary: Comprehensive OTU-family DUB study; structure and biochemistry establish OTUD3's catalytic activity and K6/K11 linkage preference. Reason: Core molecular function established by direct biochemical/structural evidence. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt Deubiquitinating enzyme that hydrolyzes |
| GO:0035871 protein K11-linked deubiquitination | IDA PMID:23827681 OTU deubiquitinases reveal mechanisms of linkage specificity... | ACCEPT | Summary: OTUD3 hydrolyzes K11-linked polyubiquitin (linkage-specificity profiling). Reason: Directly supported preferred linkage activity. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt hydrolyzes 'Lys-6'- and 'Lys- |
| GO:0044313 protein K6-linked deubiquitination | IDA PMID:23827681 OTU deubiquitinases reveal mechanisms of linkage specificity... | ACCEPT | Summary: OTUD3 hydrolyzes K6-linked polyubiquitin (linkage-specificity profiling). Reason: Directly supported preferred linkage activity. Supporting Evidence: file:human/OTUD3/OTUD3-uniprot.txt hydrolyzes 'Lys-6'- and 'Lys- |
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Download this section (compressed HTML)Q: What governs OTUD3 substrate selection (PTEN vs PPARD vs KPTN vs 40S ribosomal proteins) across the cytoplasm and nucleus, and is it determined by linkage type, acetylation state, or compartment?
Q: Is the negative regulation of RQC by OTUD3-mediated 40S deubiquitination a homeostatic brake, and how is it balanced against ZNF598-driven ubiquitination?
Q: Does the disease-associated G288D variant (reduced stability/activity) contribute to early-onset diabetes through impaired PPARD-dependent metabolic regulation?
Experiment: Linkage-resolved ubiquitin-chain panels with purified OTUD3 (WT vs Cys76 mutant) to quantitatively rank K6/K11/K48/K27/heterotypic cleavage activity.
Experiment: Compartment-resolved substrate trapping (catalytically inactive OTUD3) coupled to mass spectrometry to define the full nuclear vs cytoplasmic substrate repertoire.
Experiment: Acetylation-site mutants (K66/K105/etc.) to test how CBP-dependent acetylation controls OTUD3 nuclear translocation and substrate switching.
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