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.