OTUD3

UniProt ID: Q5T2D3
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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-

Core Functions

OTU-family cysteine-protease deubiquitinase that hydrolyzes ubiquitin isopeptide bonds with a preference for atypical Lys-6- and Lys-11-linked polyubiquitin chains (also heterotypic/branched chains), via its OTU domain (catalytic Cys76).

Molecular Function:
cysteine-type deubiquitinase activity
Cellular Locations:
cytoplasm nucleus
Supporting Evidence:
  • file:human/OTUD3/OTUD3-uniprot.txt
    Deubiquitinating enzyme that hydrolyzes
  • file:human/OTUD3/OTUD3-uniprot.txt
    hydrolyzes 'Lys-6'- and 'Lys-

Substrate-specific deubiquitinase that stabilizes target proteins by removing degradative ubiquitin, including PTEN (suppressing PI3K-AKT signaling), PPARD (regulating metabolism in response to nutritional stress), and KPTN (suppressing mTORC1), and that deubiquitinates 40S ribosomal proteins to negatively regulate ribosome-associated quality control.

Molecular Function:
cysteine-type deubiquitinase activity
Cellular Locations:
cytoplasm nucleus
Supporting Evidence:
  • file:human/OTUD3/OTUD3-uniprot.txt
    deubiquitinates and stabilizes the nuclear receptor PPARD
  • file:human/OTUD3/OTUD3-uniprot.txt
    acts as a negative regulator of the ribosome quality control

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB keywords
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:23827681
OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis.
  • OTUD3 is a linkage-specific OTU DUB with preference for K6- and K11-linked polyubiquitin; crystal structure of the OTU domain (residues 52-209).
PMID:26280536
Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis.
  • OTUD3 deubiquitinates and stabilizes PTEN, suppressing PI3K-AKT signaling and tumorigenesis.
PMID:32011234
Distinct regulatory ribosomal ubiquitylation events are reversible and hierarchically organized.
  • OTUD3 (and USP21) antagonize ZNF598-mediated 40S ribosomal ubiquitylation, deubiquitinating eS10 and limiting RQC activation; Cys76 is the catalytic nucleophile.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35675826
Deubiquitinase OTUD3 regulates metabolism homeostasis in response to nutritional stresses.
  • OTUD3 deubiquitinates and stabilizes PPARD in the nucleus to regulate glucose/lipid metabolism and oxidative phosphorylation; glucose/fatty acids drive CBP-dependent acetylation and nuclear translocation.
PMID:38288086
OTUD3 suppresses the mTORC1 signaling by deubiquitinating KPTN.
  • OTUD3 deubiquitinates KPTN to suppress mTORC1 signaling.
Reactome:R-HSA-5688426
Reactome: Deubiquitination
Reactome:R-HSA-6807206
Reactome: Ovarian tumor domain proteases
Reactome:R-HSA-8873946
Reactome: Regulation of PTEN stability and activity

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(OTUD3-notes.md)

OTUD3 (Q5T2D3) research notes

Summary

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.

Core functions (from review)

  • GO:0004843 cysteine-type deubiquitinase activity — OTU-family cysteine-protease deubiquitinase that hydrolyzes ubiquitin isopeptide bonds with a preference for atypical Lys-6- and Lys-11-linked polyubiquitin chains (also heterotypic/branched chains), via its OTU domain (catalytic Cys76).
  • GO:0004843 cysteine-type deubiquitinase activity — Substrate-specific deubiquitinase that stabilizes target proteins by removing degradative ubiquitin, including PTEN (suppressing PI3K-AKT signaling), PPARD (regulating metabolism in response to nutritional stress), and KPTN (suppressing mTORC1), and that deubiquitinates 40S ribosomal proteins to negatively regulate ribosome-associated quality control.

Provenance

Research and verbatim supporting quotes are recorded inline in OTUD3-ai-review.yaml (per-annotation supported_by and references findings). This notes file summarizes the completed review; see the YAML for evidence citations.

Pn Notes

(OTUD3-pn-notes.md)

OTUD3 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q5T2D3
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07c
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: 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.
  • Existing/core annotation action counts: ACCEPT: 32; KEEP_AS_NON_CORE: 5

PN Consistency Summary

  • Consistency: Strong. Deep research, review, and PN all agree OTUD3 is an OTU-family Cys-protease DUB (Cys76) with K6/K11 preference; the RQC role (deubiquitinating 40S eS10/uS10, antagonizing ZNF598; PMID:32011234) is captured in description + IDA annotations. No contradictions. Nuance: review/description frame the RQC role as negative regulation (a brake on RQC); PN files OTUD3 as an RQC "Deubiquitination" member, which is correct directionally but the PN-group→GO:0006515 "protein quality control" projection slightly overstates OTUD3's role (it antagonizes, not drives, QC).
  • PN story / NEW pressure: GO:0101005 deubiquitinase activity (verified real) is entailed by the existing GO:0004843 cysteine-type DUB activity already annotated (IDA/IBA/TAS) — already captured, no NEW pressure on MF. GO:0006515 (verified real) is new_to_goa and absent from review; given OTUD3 antagonizes RQC, a positive "involved_in protein QC" assertion over-reaches. Conclude: MF already captured; process term over-reaches as a propagation.
  • Evidence alignment: PN cites only PMID:23827681 (OTU linkage-specificity); review has it (HIGH/VERIFIED) plus the full substrate literature (26280536 PTEN, 32011234 RQC, 35675826 PPARD, 38288086 KPTN). Review strictly superset; no divergence.
  • Verdict: Consistent; PN MF already captured, PN RQC-process projection (GO:0006515) over-reaches because OTUD3 is a negative regulator of RQC. No YAML change needed.

Full Consistency Review

  • UniProt: Q5T2D3 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE (rich, 40 annotations, all ACCEPT/KEEP_AS_NON_CORE)
  • PN placement: 3 rows — Translation|Cytosolic translation|Ribosome-associated QC|Deubiquitination; UPS|DUBs and UBL demodifiers|OTU|other; UPS|Ubiquitin and UBL binding|DUB|OTU|UBA-like (other). PN-node mapping: RQC-type→mapped GO:0101005 deubiquitinase activity; RQC-group→mapped GO:0006515 protein QC (new_to_goa); UPS OTU/UBL nodes mostly no_mapping/context_only. Projected: GO:0006515 (new), GO:0101005 (entailed).
  • Consistency: Strong. Deep research, review, and PN all agree OTUD3 is an OTU-family Cys-protease DUB (Cys76) with K6/K11 preference; the RQC role (deubiquitinating 40S eS10/uS10, antagonizing ZNF598; PMID:32011234) is captured in description + IDA annotations. No contradictions. Nuance: review/description frame the RQC role as negative regulation (a brake on RQC); PN files OTUD3 as an RQC "Deubiquitination" member, which is correct directionally but the PN-group→GO:0006515 "protein quality control" projection slightly overstates OTUD3's role (it antagonizes, not drives, QC).
  • PN story / NEW pressure: GO:0101005 deubiquitinase activity (verified real) is entailed by the existing GO:0004843 cysteine-type DUB activity already annotated (IDA/IBA/TAS) — already captured, no NEW pressure on MF. GO:0006515 (verified real) is new_to_goa and absent from review; given OTUD3 antagonizes RQC, a positive "involved_in protein QC" assertion over-reaches. Conclude: MF already captured; process term over-reaches as a propagation.
  • Mapping strategy: Does not change the node. RQC-type→GO:0101005 redundant with the review's GO:0004843. The group→GO:0006515 propagation is the only divergence and should NOT be projected to OTUD3 (antagonist).
  • Evidence alignment: PN cites only PMID:23827681 (OTU linkage-specificity); review has it (HIGH/VERIFIED) plus the full substrate literature (26280536 PTEN, 32011234 RQC, 35675826 PPARD, 38288086 KPTN). Review strictly superset; no divergence.
  • Verdict: Consistent; PN MF already captured, PN RQC-process projection (GO:0006515) over-reaches because OTUD3 is a negative regulator of RQC. No YAML change needed.
  • Recommended edits: [MAP] Do not propagate GO:0006515 (protein QC) to OTUD3 from the RQC-group node — OTUD3 antagonizes ZNF598-driven 40S ubiquitination (negative RQC regulator), so an involved_in protein quality control assertion mis-states direction; flag as do-not-project.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/OTUD3/OTUD3-ai-review.yaml
  • PN workbook rows: 3

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | Deubiquitination

  • UniProt: Q5T2D3
  • In branches: TR, UPS
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Ribosome-associated QC|Deubiquitination
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0101005 deubiquitinase activity]
      rationale: This PN RQC type denotes deubiquitinases acting in ribosome-associated quality control. Deubiquitinase activity is the shared molecular-function target.
    • [group] Translation|Cytosolic translation|Ribosome-associated QC
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
      rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
    • [class] Translation|Cytosolic translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
      rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
    • [branch] Translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
      rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

PN row 2: Ubiquitin Proteasome System | DUBs and UBL demodifiers | OTU | other

  • UniProt: Q5T2D3
  • In branches: TR, UPS
  • Signature domains: IPR003323
  • Auxiliary domains: (none)
  • PN references (titles):
    • 23827681
  • PN-node mapping records (path + ancestors):
    • [type] Ubiquitin Proteasome System|DUBs and UBL demodifiers|OTU|other
      status=no_mapping scope= GO=[]
      rationale: Reviewed as an OTU-family subtype. Because the family branch includes inactive or ambiguous OTU-like cases, no automatic DUB propagation is made from this subtype.
    • [group] Ubiquitin Proteasome System|DUBs and UBL demodifiers|OTU
      status=context_only scope=too_broad_to_propagate GO=[GO:0101005 deubiquitinase activity]
      rationale: This OTU-family group is DUB-related context, but the subtree includes inactive or ambiguous OTU-like cases. Direct DUB propagation should come from narrower gene-level review rather than this whole family bucket.
    • [class] Ubiquitin Proteasome System|DUBs and UBL demodifiers
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | DUB | OTU | UBA-like (other)

  • UniProt: Q5T2D3
  • In branches: TR, UPS
  • Signature domains: PMID: 23827681 (likely @ 228-276)
  • Auxiliary domains: IPR003323
  • PN references (titles):
    • 23827681
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|DUB|OTU|UBA-like (other)
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower UBL-binding DUB-domain subdivision. Because this subtree includes noncatalytic or pseudo-DUB cases, active DUB propagation is handled by the DUB-family branch rather than this binding-domain node.
    • [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|DUB|OTU
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower UBL-binding DUB-domain subdivision. Because this subtree includes noncatalytic or pseudo-DUB cases, active DUB propagation is handled by the DUB-family branch rather than this binding-domain node.
    • [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|DUB
      status=context_only scope=too_broad_to_propagate GO=[GO:0101005 deubiquitinase activity]
      rationale: This UBL-binding group is DUB-related context, but it includes noncatalytic or pseudo-DUB domain cases such as NPLOC4/USP39-like entries. Active DUB propagation is handled from the DUB-family branch.
    • [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
      status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
      rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (2)

  • GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC
  • GO:0101005 deubiquitinase activity | scope=ok_for_propagation_to_go | goa_status=entailed_by_goa_closure | from=Translation|Cytosolic translation|Ribosome-associated QC|Deubiquitination

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
id: Q5T2D3
gene_symbol: OTUD3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
existing_annotations:
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: OTUD3 is an OTU-family cysteine-protease deubiquitinase, its core molecular function.
    action: ACCEPT
    reason: Directly established by structure, catalytic-cysteine (Cys76) mutagenesis, and biochemical assays; the defining function of OTUD3.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Deubiquitinating enzyme that hydrolyzes
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: By removing degradative ubiquitin chains, OTUD3 stabilizes substrate proteins (e.g. PTEN, PPARD).
    action: ACCEPT
    reason: Directly supported; OTUD3 deubiquitinates and stabilizes specific substrates, a key biological outcome of its DUB activity.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: deubiquitinates and stabilizes the nuclear receptor PPARD
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation of the core DUB activity.
    action: ACCEPT
    reason: Consistent with the experimentally established cysteine-type deubiquitinase activity.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Deubiquitinating enzyme that hydrolyzes
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization; OTUD3 translocates to the nucleus upon acetylation to deubiquitinate PPARD.
    action: ACCEPT
    reason: Documented nuclear localization where OTUD3 acts on PPARD; supported by direct evidence.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:35675826}. Nucleus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic localization, where OTUD3 acts on PTEN and on 40S ribosomal proteins in RQC.
    action: ACCEPT
    reason: Documented cytoplasmic localization; the basal compartment of OTUD3 before nuclear translocation.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0016579
    label: protein deubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Protein deubiquitination is the biological process carried out by OTUD3's catalytic activity.
    action: ACCEPT
    reason: Core process directly supported by OTUD3's DUB activity.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Deubiquitinating enzyme that hydrolyzes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26280536
  qualifier: enables
  review:
    summary: Interaction with PTEN (P60484-1), the substrate OTUD3 deubiquitinates and stabilizes. Bare protein binding term.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-goa.tsv
      supporting_text: UniProtKB:P60484-1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: HuRI interactome interaction with HSD17B14 (Q9BPX1). Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-goa.tsv
      supporting_text: UniProtKB:Q9BPX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex interactome interactions with KPTN (Q9Y664) and ITFG2 (Q969R8), part of the KICSTOR/mTORC1 regulatory context. Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Interactions are biologically relevant (KPTN is an OTUD3 substrate) but bare protein binding is uninformative; the KPTN deubiquitination role is the informative function.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-goa.tsv
      supporting_text: UniProtKB:Q9Y664
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38288086
  qualifier: enables
  review:
    summary: Interactions with KPTN (Q9Y664) and ITFG2 (Q969R8); OTUD3 deubiquitinates KPTN to suppress mTORC1 signaling. Bare protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Functionally relevant (KPTN substrate, mTORC1) but bare protein binding is uninformative; the specific activity is OTUD3-mediated KPTN deubiquitination.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-goa.tsv
      supporting_text: UniProtKB:Q9Y664
- term:
    id: GO:0016579
    label: protein deubiquitination
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5688426
  qualifier: involved_in
  review:
    summary: Reactome annotation of OTUD3 protein deubiquitination.
    action: ACCEPT
    reason: Core process supported by curated Reactome and experimental evidence.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Deubiquitinating enzyme that hydrolyzes
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6807206
  qualifier: enables
  review:
    summary: Reactome annotation of OTUD3 cysteine-type deubiquitinase activity.
    action: ACCEPT
    reason: Core molecular function supported by curated Reactome and experimental evidence.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Deubiquitinating enzyme that hydrolyzes
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8873946
  qualifier: enables
  review:
    summary: Reactome annotation of OTUD3 cysteine-type deubiquitinase activity (PTEN regulation pathway).
    action: ACCEPT
    reason: Core molecular function supported by curated Reactome and experimental evidence.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Deubiquitinating enzyme that hydrolyzes
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:35675826
  qualifier: located_in
  review:
    summary: Experimental cytoplasmic localization (basal compartment before nutrient-triggered nuclear translocation).
    action: ACCEPT
    reason: Directly supported by experimental subcellular-localization data.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IDA
  original_reference_id: PMID:32011234
  qualifier: enables
  review:
    summary: Direct demonstration of OTUD3 DUB activity, with Cys76 active-site mutagenesis, in the context of 40S ribosomal deubiquitination during RQC.
    action: ACCEPT
    reason: Core molecular function established by direct evidence with catalytic-cysteine mutagenesis.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: acts as a negative regulator of the ribosome quality control
- term:
    id: GO:0016579
    label: protein deubiquitination
  evidence_type: IDA
  original_reference_id: PMID:32011234
  qualifier: involved_in
  review:
    summary: OTUD3 deubiquitinates 40S ribosomal proteins (RPS10/eS10), antagonizing ZNF598-mediated ubiquitination.
    action: ACCEPT
    reason: Directly demonstrated protein deubiquitination in the RQC context.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: deubiquitination of 40S ribosomal proteins RPS10/eS10 and RPS20/uS10
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IDA
  original_reference_id: PMID:35675826
  qualifier: enables
  review:
    summary: Direct demonstration of OTUD3 DUB activity in the metabolic/PPARD-stabilization context.
    action: ACCEPT
    reason: Core molecular function established by direct evidence.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Deubiquitinating enzyme that hydrolyzes
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:35675826
  qualifier: is_active_in
  review:
    summary: OTUD3 is active in the nucleus, where it deubiquitinates and stabilizes PPARD after nutrient-triggered translocation.
    action: ACCEPT
    reason: Directly supported; nuclear OTUD3 acts on PPARD.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: deubiquitinates and stabilizes the nuclear receptor PPARD
- term:
    id: GO:0031669
    label: cellular response to nutrient levels
  evidence_type: IDA
  original_reference_id: PMID:35675826
  qualifier: involved_in
  review:
    summary: OTUD3 responds to nutritional stress; glucose/fatty acids drive its acetylation and nuclear translocation to regulate metabolic gene expression.
    action: ACCEPT
    reason: Directly supported; OTUD3 is a regulator of metabolism homeostasis in response to nutritional stresses.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Glucose and fatty acids trigger its nuclear translocation
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:35675826
  qualifier: involved_in
  review:
    summary: OTUD3 deubiquitinates and stabilizes PPARD.
    action: ACCEPT
    reason: Directly supported substrate stabilization.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: deubiquitinates and stabilizes the nuclear receptor PPARD
- term:
    id: GO:0071108
    label: protein K48-linked deubiquitination
  evidence_type: IDA
  original_reference_id: PMID:35675826
  qualifier: involved_in
  review:
    summary: OTUD3 removes K48-linked (degradative) ubiquitin chains from PPARD to stabilize it.
    action: ACCEPT
    reason: Supported in the PPARD-stabilization context; removal of K48-linked chains explains the stabilization phenotype.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: deubiquitinates and stabilizes the nuclear receptor PPARD
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IDA
  original_reference_id: PMID:26280536
  qualifier: enables
  review:
    summary: Direct demonstration of OTUD3 DUB activity in the PTEN-stabilization study.
    action: ACCEPT
    reason: Core molecular function established by direct evidence.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Deubiquitinating enzyme that hydrolyzes
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IMP
  original_reference_id: PMID:26280536
  qualifier: enables
  review:
    summary: Mutational evidence (catalytic-dead OTUD3) supporting its DUB activity on PTEN.
    action: ACCEPT
    reason: Core molecular function supported by IMP (catalytic mutant).
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Deubiquitinating enzyme that hydrolyzes
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:26280536
  qualifier: located_in
  review:
    summary: Cytoplasmic localization where OTUD3 acts on PTEN.
    action: ACCEPT
    reason: Directly supported cytoplasmic localization.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0035871
    label: protein K11-linked deubiquitination
  evidence_type: IDA
  original_reference_id: PMID:26280536
  qualifier: acts_upstream_of_or_within
  review:
    summary: OTUD3 hydrolyzes K11-linked polyubiquitin, one of its preferred linkage types.
    action: ACCEPT
    reason: Directly supported; OTUD3 has K6/K11 linkage preference.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: hydrolyzes 'Lys-6'- and 'Lys-
- term:
    id: GO:0044313
    label: protein K6-linked deubiquitination
  evidence_type: IDA
  original_reference_id: PMID:26280536
  qualifier: acts_upstream_of_or_within
  review:
    summary: OTUD3 hydrolyzes K6-linked polyubiquitin, a preferred linkage type.
    action: ACCEPT
    reason: Directly supported; OTUD3 has K6/K11 linkage preference.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: hydrolyzes 'Lys-6'- and 'Lys-
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:26280536
  qualifier: acts_upstream_of_or_within
  review:
    summary: OTUD3 deubiquitinates and stabilizes PTEN, suppressing tumorigenesis.
    action: ACCEPT
    reason: Directly supported substrate stabilization (PTEN).
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Also hydrolyzes heterotypic
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:26280536
  qualifier: acts_upstream_of_or_within
  review:
    summary: Mutational evidence that OTUD3 catalytic activity is required to stabilize PTEN.
    action: ACCEPT
    reason: Supported by IMP; catalytic-dead OTUD3 fails to stabilize PTEN.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Also hydrolyzes heterotypic
- term:
    id: GO:0051898
    label: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence_type: IDA
  original_reference_id: PMID:26280536
  qualifier: acts_upstream_of_or_within
  review:
    summary: By stabilizing PTEN, OTUD3 negatively regulates PI3K-AKT signaling.
    action: ACCEPT
    reason: Directly supported; PTEN stabilization suppresses PI3K-AKT signaling and tumorigenesis.
    supported_by:
    - reference_id: PMID:26280536
      supporting_text: >-
        Depletion of OTUD3 leads to the activation of Akt signalling, induction of cellular
        transformation and cancer metastasis.
- term:
    id: GO:0051898
    label: negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence_type: IMP
  original_reference_id: PMID:26280536
  qualifier: acts_upstream_of_or_within
  review:
    summary: Mutational/knockdown evidence linking OTUD3 to PI3K-AKT suppression via PTEN.
    action: ACCEPT
    reason: Supported by IMP in the PTEN/PI3K-AKT study.
    supported_by:
    - reference_id: PMID:26280536
      supporting_text: >-
        Depletion of OTUD3 leads to the activation of Akt signalling, induction of cellular
        transformation and cancer metastasis.
- term:
    id: GO:0071108
    label: protein K48-linked deubiquitination
  evidence_type: IDA
  original_reference_id: PMID:26280536
  qualifier: acts_upstream_of_or_within
  review:
    summary: OTUD3 removes K48-linked ubiquitin from PTEN to stabilize it.
    action: ACCEPT
    reason: Supported; OTUD3 can process K48-linked chains to stabilize substrates.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Also hydrolyzes heterotypic
- term:
    id: GO:1990167
    label: protein K27-linked deubiquitination
  evidence_type: IDA
  original_reference_id: PMID:26280536
  qualifier: acts_upstream_of_or_within
  review:
    summary: OTUD3 can hydrolyze K27-linked ubiquitin in some assays.
    action: KEEP_AS_NON_CORE
    reason: OTUD3's principal preference is K6/K11; K27 activity is plausible (broad heterotypic-chain processing) but a minor/non-core specificity.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Also hydrolyzes heterotypic
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6807206
  qualifier: located_in
  review:
    summary: Reactome cytosolic localization.
    action: ACCEPT
    reason: Consistent with documented cytoplasmic/cytosolic localization.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8873946
  qualifier: located_in
  review:
    summary: Reactome cytosolic localization (PTEN regulation pathway).
    action: ACCEPT
    reason: Consistent with documented cytoplasmic/cytosolic localization.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IDA
  original_reference_id: PMID:23827681
  qualifier: enables
  review:
    summary: Comprehensive OTU-family DUB study; structure and biochemistry establish OTUD3's catalytic activity and K6/K11 linkage preference.
    action: ACCEPT
    reason: Core molecular function established by direct biochemical/structural evidence.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: Deubiquitinating enzyme that hydrolyzes
- term:
    id: GO:0035871
    label: protein K11-linked deubiquitination
  evidence_type: IDA
  original_reference_id: PMID:23827681
  qualifier: involved_in
  review:
    summary: OTUD3 hydrolyzes K11-linked polyubiquitin (linkage-specificity profiling).
    action: ACCEPT
    reason: Directly supported preferred linkage activity.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: hydrolyzes 'Lys-6'- and 'Lys-
- term:
    id: GO:0044313
    label: protein K6-linked deubiquitination
  evidence_type: IDA
  original_reference_id: PMID:23827681
  qualifier: involved_in
  review:
    summary: OTUD3 hydrolyzes K6-linked polyubiquitin (linkage-specificity profiling).
    action: ACCEPT
    reason: Directly supported preferred linkage activity.
    supported_by:
    - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
      supporting_text: hydrolyzes 'Lys-6'- and 'Lys-
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB keywords
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:23827681
  title: OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis.
  findings:
  - statement: OTUD3 is a linkage-specific OTU DUB with preference for K6- and K11-linked polyubiquitin; crystal structure of the OTU domain (residues 52-209).
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached; establishes OTUD3 catalytic activity and K6/K11 linkage preference.
- id: PMID:26280536
  title: Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis.
  findings:
  - statement: OTUD3 deubiquitinates and stabilizes PTEN, suppressing PI3K-AKT signaling and tumorigenesis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached (abstract); establishes the PTEN-stabilization / PI3K-AKT suppression role.
- id: PMID:32011234
  title: Distinct regulatory ribosomal ubiquitylation events are reversible and hierarchically organized.
  findings:
  - statement: OTUD3 (and USP21) antagonize ZNF598-mediated 40S ribosomal ubiquitylation, deubiquitinating eS10 and limiting RQC activation; Cys76 is the catalytic nucleophile.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached; establishes the RQC-deubiquitination role on 40S ribosomal proteins.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: HuRI interactome; captures an OTUD3-HSD17B14 interaction (bare protein binding).
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: BioPlex interactome; captures OTUD3-KPTN/ITFG2 interactions (bare protein binding).
- id: PMID:35675826
  title: Deubiquitinase OTUD3 regulates metabolism homeostasis in response to nutritional stresses.
  findings:
  - statement: OTUD3 deubiquitinates and stabilizes PPARD in the nucleus to regulate glucose/lipid metabolism and oxidative phosphorylation; glucose/fatty acids drive CBP-dependent acetylation and nuclear translocation.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached (abstract); establishes the PPARD-stabilization / metabolic and nutrient-response roles and nuclear translocation.
- id: PMID:38288086
  title: OTUD3 suppresses the mTORC1 signaling by deubiquitinating KPTN.
  findings:
  - statement: OTUD3 deubiquitinates KPTN to suppress mTORC1 signaling.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached; establishes the KPTN-deubiquitination / mTORC1-suppression role.
- id: Reactome:R-HSA-5688426
  title: 'Reactome: Deubiquitination'
  findings: []
- id: Reactome:R-HSA-6807206
  title: 'Reactome: Ovarian tumor domain proteases'
  findings: []
- id: Reactome:R-HSA-8873946
  title: 'Reactome: Regulation of PTEN stability and activity'
  findings: []
core_functions:
- description: OTU-family cysteine-protease deubiquitinase that hydrolyzes ubiquitin isopeptide bonds with a preference for atypical Lys-6- and Lys-11-linked polyubiquitin chains (also heterotypic/branched chains), via its OTU domain (catalytic Cys76).
  molecular_function:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
    supporting_text: Deubiquitinating enzyme that hydrolyzes
  - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
    supporting_text: hydrolyzes 'Lys-6'- and 'Lys-
- description: Substrate-specific deubiquitinase that stabilizes target proteins by removing degradative ubiquitin, including PTEN (suppressing PI3K-AKT signaling), PPARD (regulating metabolism in response to nutritional stress), and KPTN (suppressing mTORC1), and that deubiquitinates 40S ribosomal proteins to negatively regulate ribosome-associated quality control.
  molecular_function:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
    supporting_text: deubiquitinates and stabilizes the nuclear receptor PPARD
  - reference_id: file:human/OTUD3/OTUD3-uniprot.txt
    supporting_text: acts as a negative regulator of the ribosome quality control
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: Is the negative regulation of RQC by OTUD3-mediated 40S deubiquitination a homeostatic brake, and how is it balanced against ZNF598-driven ubiquitination?
- question: Does the disease-associated G288D variant (reduced stability/activity) contribute to early-onset diabetes through impaired PPARD-dependent metabolic regulation?
suggested_experiments:
- description: Linkage-resolved ubiquitin-chain panels with purified OTUD3 (WT vs Cys76 mutant) to quantitatively rank K6/K11/K48/K27/heterotypic cleavage activity.
- description: Compartment-resolved substrate trapping (catalytically inactive OTUD3) coupled to mass spectrometry to define the full nuclear vs cytoplasmic substrate repertoire.
- description: Acetylation-site mutants (K66/K105/etc.) to test how CBP-dependent acetylation controls OTUD3 nuclear translocation and substrate switching.