USP8 encodes ubiquitin-specific protease 8/UBPY, a cysteine-type deubiquitinating enzyme that removes ubiquitin from protein substrates, including K48- and K63-linked ubiquitin chains. USP8 acts mainly in cytosolic and endosomal membrane contexts, where it regulates endosomal ubiquitin dynamics, ESCRT-associated cargo sorting, receptor down-regulation, and substrate stability. Somatic activating mutations in the USP8 14-3-3-binding region increase deubiquitinase activity toward EGFR in corticotroph adenomas, linking USP8 to ACTH-producing pituitary adenoma/Cushing disease.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0007032 endosome organization | IBA GO_REF:0000033 | ACCEPT | Summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo sorting. Reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY studies. Supporting Evidence: PMID:16520378 localizes to endosomes PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. PMID:16520378 UBPY function is essential for growth factor receptor down-regulation |
| GO:0007265 Ras protein signal transduction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Ras/MAPK signaling is a downstream consequence of receptor turnover regulation and is not USP8 catalytic activity itself. Reason: USP8 removes ubiquitin from EGFR and can affect downstream MAPK/Ras signaling, but deubiquitination/endosomal sorting is the core function. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. |
| GO:0004843 cysteine-type deubiquitinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity on K48- and K63-linked ubiquitin chains where tested. Reason: This is the core molecular function of USP8 and is supported by direct biochemical and cellular evidence. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease file:human/USP8/USP8-uniprot.txt Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0014069 postsynaptic density | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Postsynaptic/glutamatergic-synapse annotations are plausible context-specific consequences of USP8 substrate trafficking but are not core gene function. Reason: Retain as non-core neuronal context; core function remains deubiquitination and endosomal cargo regulation. Supporting Evidence: PMID:27302062 regulates the ubiquitination, trafficking, and lysosomal degradation of |
| GO:0030496 midbody | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: USP8 has direct evidence for midbody recruitment and cytokinesis defects after depletion, but this is a context-specific role outside the main endosomal deubiquitination function. Reason: The cytokinesis annotation is supported by PMID:18388320 and should be retained as non-core. Supporting Evidence: PMID:18388320 UBPY was detected only in the final stage of cytokinesis at the midbody PMID:18388320 Depletion of cellular UBPY or AMSH led to defects in cytokinesis. |
| GO:0004843 cysteine-type deubiquitinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity on K48- and K63-linked ubiquitin chains where tested. Reason: This is the core molecular function of USP8 and is supported by direct biochemical and cellular evidence. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease file:human/USP8/USP8-uniprot.txt Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nuclear localization is weakly supported relative to cytosol/endosome and appears context-dependent. Reason: Nonmutant corticotroph tumors show cytoplasmic USP8, whereas mutant tumors can show more nuclear staining; this should not be treated as the core normal location. Supporting Evidence: PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors PMID:28505279 its expression was more nuclear in the mutated tumors |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0005768 endosome | IEA GO_REF:0000117 | ACCEPT | Summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo sorting. Reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY studies. Supporting Evidence: PMID:16520378 localizes to endosomes PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. PMID:16520378 UBPY function is essential for growth factor receptor down-regulation |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: USP8 can associate peripherally with cell/endosomal membranes, but this is not the principal location term. Reason: Retain as non-core localization; endosome membrane/cytosol are more informative for normal USP8 function. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. |
| GO:0010008 endosome membrane | IEA GO_REF:0000120 | ACCEPT | Summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo sorting. Reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY studies. Supporting Evidence: PMID:16520378 localizes to endosomes PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. PMID:16520378 UBPY function is essential for growth factor receptor down-regulation |
| GO:0016579 protein deubiquitination | IEA GO_REF:0000120 | ACCEPT | Summary: USP8-mediated protein deubiquitination is central to its regulation of receptor and cargo turnover. Reason: The process term correctly captures the biological consequence of the USP8 catalytic activity. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease PMID:27302062 USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501 |
| GO:0005515 protein binding | IPI PMID:15161933 Comprehensive proteomic analysis of interphase and mitotic 1... | MODIFY | Summary: USP8 binds the 14-3-3 protein YWHAZ; the interaction is mediated by the phospho-Ser718 14-3-3-binding motif of USP8 and is reproduced across targeted and proteome-scale studies. Reason: Generic protein binding is uninformative. The partner (YWHAZ) is a 14-3-3 protein, and USP8 carries a phosphorylation-dependent 14-3-3-binding motif (Ser718) that restrains its catalytic activity and is the hotspot for Cushing disease mutations. The interaction is therefore recorded with the informative term 14-3-3 protein binding (GO:0071889). This is a regulatory binding activity, not the core catalytic function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: file:human/USP8/USP8-uniprot.txt P40818; P63104: YWHAZ; NbExp=7 file:human/USP8/USP8-uniprot.txt Phosphorylation of Ser-718 is essential for interaction with YWHAE file:human/USP8/USP8-deep-research-falcon.md Ser718 phosphorylation permits 14-3-3 binding, which stabilizes autoinhibition. |
| GO:0005515 protein binding | IPI PMID:15778465 Targeted proteomic analysis of 14-3-3 sigma, a p53 effector ... | MODIFY | Summary: USP8 binds the 14-3-3 protein SFN; the interaction is mediated by the phospho-Ser718 14-3-3-binding motif of USP8 and is reproduced across targeted and proteome-scale studies. Reason: Generic protein binding is uninformative. The partner (SFN) is a 14-3-3 protein, and USP8 carries a phosphorylation-dependent 14-3-3-binding motif (Ser718) that restrains its catalytic activity and is the hotspot for Cushing disease mutations. The interaction is therefore recorded with the informative term 14-3-3 protein binding (GO:0071889). This is a regulatory binding activity, not the core catalytic function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: file:human/USP8/USP8-uniprot.txt P40818; P31947: SFN; NbExp=5 file:human/USP8/USP8-uniprot.txt Phosphorylation of Ser-718 is essential for interaction with YWHAE file:human/USP8/USP8-deep-research-falcon.md Ser718 phosphorylation permits 14-3-3 binding, which stabilizes autoinhibition. |
| GO:0005515 protein binding | IPI PMID:17711858 The MIT domain of UBPY constitutes a CHMP binding and endoso... | REMOVE | Summary: USP8 binds the ESCRT-III subunit CHMP1B through its N-terminal MIT domain; the interaction recruits USP8 to endosomes. Reason: Generic protein binding carries no functional information. The MIT-domain interaction with CHMP1B is real and functionally important for endosomal recruitment, but GO has no informative MF term for ESCRT-III subunit binding that fits better, and the functional consequence is already captured by the endosome localization and endosome organization annotations. Removal does not imply the interaction is false. Supporting Evidence: file:human/USP8/USP8-uniprot.txt The MIT domain is required for endosomal localization, CHMP1B- PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. |
| GO:0005515 protein binding | IPI PMID:19302785 Ab initio protein modelling reveals novel human MIT domains. | REMOVE | Summary: USP8 binds the ESCRT-III subunit CHMP1B through its N-terminal MIT domain; the interaction recruits USP8 to endosomes. Reason: Generic protein binding carries no functional information. The MIT-domain interaction with CHMP1B is real and functionally important for endosomal recruitment, but GO has no informative MF term for ESCRT-III subunit binding that fits better, and the functional consequence is already captured by the endosome localization and endosome organization annotations. Removal does not imply the interaction is false. Supporting Evidence: file:human/USP8/USP8-uniprot.txt The MIT domain is required for endosomal localization, CHMP1B- PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. |
| GO:0005515 protein binding | IPI PMID:19427866 Interactions with LC3 and polyubiquitin chains link nbr1 to ... | REMOVE | Summary: USP8 interacts with the autophagy receptor NBR1. Reason: Generic protein binding is uninformative and no more specific MF term describes the USP8 side of the NBR1 interaction. Removal does not imply the interaction is false. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with NBR1, RASGRF1, RNF41 and IST1. |
| GO:0005515 protein binding | IPI PMID:24378640 HIF1Ξ± deubiquitination by USP8 is essential for ciliogenesis... | REMOVE | Summary: HIF1A co-purifies with USP8; HIF1A is reported as a USP8 deubiquitination substrate. Reason: Generic protein binding is uninformative. Binding to HIF1A reflects an enzyme-substrate relationship that is better represented by the cysteine-type deubiquitinase activity and protein deubiquitination annotations. Removal does not imply the interaction is false. Supporting Evidence: file:human/USP8/USP8-uniprot.txt P40818; Q16665: HIF1A; NbExp=2 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: USP8 binds the 14-3-3 protein YWHAZ; the interaction is mediated by the phospho-Ser718 14-3-3-binding motif of USP8 and is reproduced across targeted and proteome-scale studies. Reason: Generic protein binding is uninformative. The partner (YWHAZ) is a 14-3-3 protein, and USP8 carries a phosphorylation-dependent 14-3-3-binding motif (Ser718) that restrains its catalytic activity and is the hotspot for Cushing disease mutations. The interaction is therefore recorded with the informative term 14-3-3 protein binding (GO:0071889). This is a regulatory binding activity, not the core catalytic function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: file:human/USP8/USP8-uniprot.txt P40818; P63104: YWHAZ; NbExp=7 file:human/USP8/USP8-uniprot.txt Phosphorylation of Ser-718 is essential for interaction with YWHAE file:human/USP8/USP8-deep-research-falcon.md Ser718 phosphorylation permits 14-3-3 binding, which stabilizes autoinhibition. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: USP8 binds the 14-3-3 protein YWHAZ; the interaction is mediated by the phospho-Ser718 14-3-3-binding motif of USP8 and is reproduced across targeted and proteome-scale studies. Reason: Generic protein binding is uninformative. The partner (YWHAZ) is a 14-3-3 protein, and USP8 carries a phosphorylation-dependent 14-3-3-binding motif (Ser718) that restrains its catalytic activity and is the hotspot for Cushing disease mutations. The interaction is therefore recorded with the informative term 14-3-3 protein binding (GO:0071889). This is a regulatory binding activity, not the core catalytic function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: file:human/USP8/USP8-uniprot.txt P40818; P63104: YWHAZ; NbExp=7 file:human/USP8/USP8-uniprot.txt Phosphorylation of Ser-718 is essential for interaction with YWHAE file:human/USP8/USP8-deep-research-falcon.md Ser718 phosphorylation permits 14-3-3 binding, which stabilizes autoinhibition. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: USP8 binds the 14-3-3 protein YWHAE; the interaction is mediated by the phospho-Ser718 14-3-3-binding motif of USP8 and is reproduced across targeted and proteome-scale studies. Reason: Generic protein binding is uninformative. The partner (YWHAE) is a 14-3-3 protein, and USP8 carries a phosphorylation-dependent 14-3-3-binding motif (Ser718) that restrains its catalytic activity and is the hotspot for Cushing disease mutations. The interaction is therefore recorded with the informative term 14-3-3 protein binding (GO:0071889). This is a regulatory binding activity, not the core catalytic function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: file:human/USP8/USP8-uniprot.txt P40818; P62258: YWHAE; NbExp=5 file:human/USP8/USP8-uniprot.txt Phosphorylation of Ser-718 is essential for interaction with YWHAE file:human/USP8/USP8-deep-research-falcon.md Ser718 phosphorylation permits 14-3-3 binding, which stabilizes autoinhibition. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: USP8 binds the 14-3-3 protein SFN; the interaction is mediated by the phospho-Ser718 14-3-3-binding motif of USP8 and is reproduced across targeted and proteome-scale studies. Reason: Generic protein binding is uninformative. The partner (SFN) is a 14-3-3 protein, and USP8 carries a phosphorylation-dependent 14-3-3-binding motif (Ser718) that restrains its catalytic activity and is the hotspot for Cushing disease mutations. The interaction is therefore recorded with the informative term 14-3-3 protein binding (GO:0071889). This is a regulatory binding activity, not the core catalytic function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: file:human/USP8/USP8-uniprot.txt P40818; P31947: SFN; NbExp=5 file:human/USP8/USP8-uniprot.txt Phosphorylation of Ser-718 is essential for interaction with YWHAE file:human/USP8/USP8-deep-research-falcon.md Ser718 phosphorylation permits 14-3-3 binding, which stabilizes autoinhibition. |
| GO:0002080 acrosomal membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Acrosomal membrane localization is a specialized context inferred from orthologous sperm/acrosome biology, not the core human USP8 function. Reason: UniProt notes acrosome biogenesis through interaction with spermatid ESCRT-0 and microtubules, but the dominant supported function is endosomal deubiquitination. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. |
| GO:0005769 early endosome | IEA GO_REF:0000107 | ACCEPT | Summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo sorting. Reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY studies. Supporting Evidence: PMID:16520378 localizes to endosomes PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. PMID:16520378 UBPY function is essential for growth factor receptor down-regulation |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0007032 endosome organization | IEA GO_REF:0000107 | ACCEPT | Summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo sorting. Reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY studies. Supporting Evidence: PMID:16520378 localizes to endosomes PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. PMID:16520378 UBPY function is essential for growth factor receptor down-regulation |
| GO:0014069 postsynaptic density | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Postsynaptic/glutamatergic-synapse annotations are plausible context-specific consequences of USP8 substrate trafficking but are not core gene function. Reason: Retain as non-core neuronal context; core function remains deubiquitination and endosomal cargo regulation. Supporting Evidence: PMID:27302062 regulates the ubiquitination, trafficking, and lysosomal degradation of |
| GO:0030496 midbody | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: USP8 has direct evidence for midbody recruitment and cytokinesis defects after depletion, but this is a context-specific role outside the main endosomal deubiquitination function. Reason: The cytokinesis annotation is supported by PMID:18388320 and should be retained as non-core. Supporting Evidence: PMID:18388320 UBPY was detected only in the final stage of cytokinesis at the midbody PMID:18388320 Depletion of cellular UBPY or AMSH led to defects in cytokinesis. |
| GO:0071549 cellular response to dexamethasone stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cellular response to dexamethasone is not a core USP8 function and appears to be a transferred context annotation. Reason: No direct evidence in the reviewed USP8 sources establishes normal USP8 as a dexamethasone-response effector; disease relevance is through corticotroph EGFR/POMC/ACTH signaling. Supporting Evidence: PMID:28505279 decreased EGFR degradation, which in turn leads to increased POMC expression and ACTH production |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Postsynaptic/glutamatergic-synapse annotations are plausible context-specific consequences of USP8 substrate trafficking but are not core gene function. Reason: Retain as non-core neuronal context; core function remains deubiquitination and endosomal cargo regulation. Supporting Evidence: PMID:27302062 regulates the ubiquitination, trafficking, and lysosomal degradation of |
| GO:0099576 regulation of protein catabolic process at postsynapse, modulating synaptic transmission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Postsynaptic/glutamatergic-synapse annotations are plausible context-specific consequences of USP8 substrate trafficking but are not core gene function. Reason: Retain as non-core neuronal context; core function remains deubiquitination and endosomal cargo regulation. Supporting Evidence: PMID:27302062 regulates the ubiquitination, trafficking, and lysosomal degradation of |
| GO:1990090 cellular response to nerve growth factor stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This annotation captures a substrate-specific consequence of USP8 deubiquitination and trafficking regulation. Reason: The process is true in specific substrate/pathway contexts, but the core function is the upstream deubiquitinase activity and endosomal cargo regulation. Supporting Evidence: PMID:27302062 regulates the ubiquitination, trafficking, and lysosomal degradation of |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0004843 cysteine-type deubiquitinase activity | TAS Reactome:R-HSA-4641236 | ACCEPT | Summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity on K48- and K63-linked ubiquitin chains where tested. Reason: This is the core molecular function of USP8 and is supported by direct biochemical and cellular evidence. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease file:human/USP8/USP8-uniprot.txt Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. |
| GO:0004843 cysteine-type deubiquitinase activity | TAS Reactome:R-HSA-8875443 | ACCEPT | Summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity on K48- and K63-linked ubiquitin chains where tested. Reason: This is the core molecular function of USP8 and is supported by direct biochemical and cellular evidence. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease file:human/USP8/USP8-uniprot.txt Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. |
| GO:0005737 cytoplasm | EXP PMID:16520378 The ubiquitin isopeptidase UBPY regulates endosomal ubiquiti... | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0005737 cytoplasm | EXP PMID:17711858 The MIT domain of UBPY constitutes a CHMP binding and endoso... | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0005737 cytoplasm | EXP PMID:19427866 Interactions with LC3 and polyubiquitin chains link nbr1 to ... | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0005737 cytoplasm | EXP PMID:28505279 Somatic USP8 Gene Mutations Are a Common Cause of Pediatric ... | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0005886 plasma membrane | EXP PMID:16520378 The ubiquitin isopeptidase UBPY regulates endosomal ubiquiti... | KEEP AS NON CORE | Summary: USP8 can associate peripherally with cell/endosomal membranes, but this is not the principal location term. Reason: Retain as non-core localization; endosome membrane/cytosol are more informative for normal USP8 function. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. |
| GO:0010008 endosome membrane | EXP PMID:16520378 The ubiquitin isopeptidase UBPY regulates endosomal ubiquiti... | ACCEPT | Summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo sorting. Reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY studies. Supporting Evidence: PMID:16520378 localizes to endosomes PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. PMID:16520378 UBPY function is essential for growth factor receptor down-regulation |
| GO:0010008 endosome membrane | EXP PMID:17711858 The MIT domain of UBPY constitutes a CHMP binding and endoso... | ACCEPT | Summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo sorting. Reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY studies. Supporting Evidence: PMID:16520378 localizes to endosomes PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. PMID:16520378 UBPY function is essential for growth factor receptor down-regulation |
| GO:0005769 early endosome | IDA PMID:16520378 The ubiquitin isopeptidase UBPY regulates endosomal ubiquiti... | ACCEPT | Summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo sorting. Reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY studies. Supporting Evidence: PMID:16520378 localizes to endosomes PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. PMID:16520378 UBPY function is essential for growth factor receptor down-regulation |
| GO:0005829 cytosol | IDA PMID:16520378 The ubiquitin isopeptidase UBPY regulates endosomal ubiquiti... | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0061578 K63-linked deubiquitinase activity | IDA PMID:16520378 The ubiquitin isopeptidase UBPY regulates endosomal ubiquiti... | ACCEPT | Summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity on K48- and K63-linked ubiquitin chains where tested. Reason: This is the core molecular function of USP8 and is supported by direct biochemical and cellular evidence. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease file:human/USP8/USP8-uniprot.txt Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. |
| GO:1990380 K48-linked deubiquitinase activity | IDA PMID:16520378 The ubiquitin isopeptidase UBPY regulates endosomal ubiquiti... | ACCEPT | Summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity on K48- and K63-linked ubiquitin chains where tested. Reason: This is the core molecular function of USP8 and is supported by direct biochemical and cellular evidence. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease file:human/USP8/USP8-uniprot.txt Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:27444016 Deubiquitinase Usp8 regulates Ξ±-synuclein clearance and modi... | ACCEPT | Summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity on K48- and K63-linked ubiquitin chains where tested. Reason: This is the core molecular function of USP8 and is supported by direct biochemical and cellular evidence. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease file:human/USP8/USP8-uniprot.txt Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. |
| GO:0005829 cytosol | IDA PMID:27444016 Deubiquitinase Usp8 regulates Ξ±-synuclein clearance and modi... | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:1905166 negative regulation of lysosomal protein catabolic process | IMP PMID:27444016 Deubiquitinase Usp8 regulates Ξ±-synuclein clearance and modi... | KEEP AS NON CORE | Summary: This annotation captures a substrate-specific consequence of USP8 deubiquitination and trafficking regulation. Reason: The process is true in specific substrate/pathway contexts, but the core function is the upstream deubiquitinase activity and endosomal cargo regulation. Supporting Evidence: PMID:27302062 regulates the ubiquitination, trafficking, and lysosomal degradation of |
| GO:1905908 positive regulation of amyloid fibril formation | IMP PMID:27444016 Deubiquitinase Usp8 regulates Ξ±-synuclein clearance and modi... | MARK AS OVER ANNOTATED | Summary: Positive regulation of amyloid fibril formation is a disease-model consequence of alpha-synuclein deubiquitination, not a core normal function. Reason: The direct molecular observation is USP8 removal of K63-linked ubiquitin from alpha-synuclein and reduced lysosomal degradation; fibril formation is downstream and pathological. Supporting Evidence: PMID:27444016 it deubiquitinated K63-linked chains on alpha-synuclein PMID:27444016 knockdown increased the lysosomal degradation of alpha-synuclein |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:18728397 Usp39 is essential for mitotic spindle checkpoint integrity ... | ACCEPT | Summary: The cited paper screened deubiquitinating enzymes and tested ubiquitin-protease activity of USP39; the abstract does not mention USP8, but the curator read the full text, which is not cached here. Reason: The abstract foregrounds USP39 (shown to lack DUB activity), and active USP-family enzymes are typically assayed alongside as comparators in such work; the curator who made this IDA had the full text. Per project policy, an experimental annotation is not overruled because the cached abstract names a different gene. The claim itself, that USP8 is a cysteine-type deubiquitinase, is independently established (PMID:9628861, PMID:16520378) and inherited from PAINT node PTN002538135, so the row is accepted, deferring to the curator. Supporting Evidence: PMID:16520378 UBPY is a ubiquitin-specific protease file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IMP PMID:20495530 Balanced ubiquitylation and deubiquitylation of Frizzled reg... | KEEP AS NON CORE | Summary: USP8 regulation of Wnt signaling through Frizzled deubiquitination is supported but pathway-specific and non-core. Reason: PMID:20495530 supports FZD deubiquitination and altered Wnt responsiveness, but this is one substrate/pathway context of the broader deubiquitinase role. Supporting Evidence: PMID:20495530 cell surface level of Frizzled is regulated by deubiquitylating enzyme UBPY/ubiquitin-specific protease 8 (USP8) |
| GO:0016579 protein deubiquitination | IMP PMID:27302062 The Endosome-associated Deubiquitinating Enzyme USP8 Regulat... | ACCEPT | Summary: USP8-mediated protein deubiquitination is central to its regulation of receptor and cargo turnover. Reason: The process term correctly captures the biological consequence of the USP8 catalytic activity. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease PMID:27302062 USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501 |
| GO:0031647 regulation of protein stability | IMP PMID:27302062 The Endosome-associated Deubiquitinating Enzyme USP8 Regulat... | KEEP AS NON CORE | Summary: This annotation captures a substrate-specific consequence of USP8 deubiquitination and trafficking regulation. Reason: The process is true in specific substrate/pathway contexts, but the core function is the upstream deubiquitinase activity and endosomal cargo regulation. Supporting Evidence: PMID:27302062 regulates the ubiquitination, trafficking, and lysosomal degradation of |
| GO:0032880 regulation of protein localization | IMP PMID:27302062 The Endosome-associated Deubiquitinating Enzyme USP8 Regulat... | KEEP AS NON CORE | Summary: This annotation captures a substrate-specific consequence of USP8 deubiquitination and trafficking regulation. Reason: The process is true in specific substrate/pathway contexts, but the core function is the upstream deubiquitinase activity and endosomal cargo regulation. Supporting Evidence: PMID:27302062 regulates the ubiquitination, trafficking, and lysosomal degradation of |
| GO:0045296 cadherin binding | HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | MARK AS OVER ANNOTATED | Summary: Cadherin binding comes from a high-throughput E-cadherin interactome and is not a defining USP8 function. Reason: The source can be retained as interaction context, but cadherin binding should not be treated as a core molecular function of USP8. Supporting Evidence: PMID:25468996 E-cadherin interactome |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1358791 | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1358795 | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1358797 | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0005829 cytosol | TAS Reactome:R-HSA-4641236 | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5690196 | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6782628 | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8875443 | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0000281 mitotic cytokinesis | IMP PMID:18388320 Dynamic regulation of ubiquitylation and deubiquitylation at... | KEEP AS NON CORE | Summary: USP8 has direct evidence for midbody recruitment and cytokinesis defects after depletion, but this is a context-specific role outside the main endosomal deubiquitination function. Reason: The cytokinesis annotation is supported by PMID:18388320 and should be retained as non-core. Supporting Evidence: PMID:18388320 UBPY was detected only in the final stage of cytokinesis at the midbody PMID:18388320 Depletion of cellular UBPY or AMSH led to defects in cytokinesis. |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:18388320 Dynamic regulation of ubiquitylation and deubiquitylation at... | ACCEPT | Summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity on K48- and K63-linked ubiquitin chains where tested. Reason: This is the core molecular function of USP8 and is supported by direct biochemical and cellular evidence. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease file:human/USP8/USP8-uniprot.txt Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. |
| GO:0005737 cytoplasm | IDA PMID:18388320 Dynamic regulation of ubiquitylation and deubiquitylation at... | ACCEPT | Summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme recruited to endosomal membranes and other cytoplasmic structures. Reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization studies. Supporting Evidence: file:human/USP8/USP8-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}. PMID:28505279 USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors |
| GO:0016579 protein deubiquitination | IMP PMID:18388320 Dynamic regulation of ubiquitylation and deubiquitylation at... | ACCEPT | Summary: USP8-mediated protein deubiquitination is central to its regulation of receptor and cargo turnover. Reason: The process term correctly captures the biological consequence of the USP8 catalytic activity. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease PMID:27302062 USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501 |
| GO:0030496 midbody | IDA PMID:18388320 Dynamic regulation of ubiquitylation and deubiquitylation at... | KEEP AS NON CORE | Summary: USP8 has direct evidence for midbody recruitment and cytokinesis defects after depletion, but this is a context-specific role outside the main endosomal deubiquitination function. Reason: The cytokinesis annotation is supported by PMID:18388320 and should be retained as non-core. Supporting Evidence: PMID:18388320 UBPY was detected only in the final stage of cytokinesis at the midbody PMID:18388320 Depletion of cellular UBPY or AMSH led to defects in cytokinesis. |
| GO:0005515 protein binding | IPI PMID:18329369 Final stages of cytokinesis and midbody ring formation are c... | REMOVE | Summary: USP8 interacts with BIRC6/BRUCE at the midbody and deubiquitinates it. Reason: Generic protein binding is uninformative. The BIRC6 interaction is an enzyme-substrate relationship already captured by the deubiquitinase activity, midbody and cytokinesis annotations. Removal does not imply the interaction is false. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with BIRC6/bruce and file:human/USP8/USP8-uniprot.txt Deubiquitinates BIRC6/bruce and KIF23/MKLP1. |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:16520378 The ubiquitin isopeptidase UBPY regulates endosomal ubiquiti... | ACCEPT | Summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity on K48- and K63-linked ubiquitin chains where tested. Reason: This is the core molecular function of USP8 and is supported by direct biochemical and cellular evidence. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease file:human/USP8/USP8-uniprot.txt Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. |
| GO:0070536 protein K63-linked deubiquitination | IDA PMID:16520378 The ubiquitin isopeptidase UBPY regulates endosomal ubiquiti... | ACCEPT | Summary: USP8-mediated protein deubiquitination is central to its regulation of receptor and cargo turnover. Reason: The process term correctly captures the biological consequence of the USP8 catalytic activity. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease PMID:27302062 USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501 |
| GO:0071108 protein K48-linked deubiquitination | IDA PMID:16520378 The ubiquitin isopeptidase UBPY regulates endosomal ubiquiti... | ACCEPT | Summary: USP8-mediated protein deubiquitination is central to its regulation of receptor and cargo turnover. Reason: The process term correctly captures the biological consequence of the USP8 catalytic activity. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease PMID:27302062 USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501 |
| GO:0004197 cysteine-type endopeptidase activity | TAS PMID:9827704 Deubiquitinating enzymes: a new class of biological regulato... | MODIFY | Summary: Cysteine-type endopeptidase activity is too broad for USP8; the specific deubiquitinase activity term should be used. Reason: USP8 is a cysteine protease in the deubiquitinating enzyme family, but GO:0004843 captures the biologically relevant activity. Proposed replacements: cysteine-type deubiquitinase activity Supporting Evidence: PMID:9827704 Deubiquitinating enzymes are cysteine proteases that specifically cleave ubiquitin from ubiquitin-conjugated protein substrates. |
| GO:0004843 cysteine-type deubiquitinase activity | TAS PMID:9628861 UBPY: a growth-regulated human ubiquitin isopeptidase. | ACCEPT | Summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity on K48- and K63-linked ubiquitin chains where tested. Reason: This is the core molecular function of USP8 and is supported by direct biochemical and cellular evidence. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Hydrolase that can remove conjugated ubiquitin from proteins PMID:16520378 UBPY is a ubiquitin-specific protease file:human/USP8/USP8-uniprot.txt Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. |
| GO:0005515 protein binding | IPI PMID:17711858 The MIT domain of UBPY constitutes a CHMP binding and endoso... | REMOVE | Summary: USP8 binds the ESCRT-III subunit CHMP4C through its N-terminal MIT domain; the interaction recruits USP8 to endosomes. Reason: Generic protein binding carries no functional information. The MIT-domain interaction with CHMP4C is real and functionally important for endosomal recruitment, but GO has no informative MF term for ESCRT-III subunit binding that fits better, and the functional consequence is already captured by the endosome localization and endosome organization annotations. Removal does not imply the interaction is false. Supporting Evidence: file:human/USP8/USP8-uniprot.txt The MIT domain is required for endosomal localization, CHMP1B- PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. |
| GO:0005515 protein binding | IPI PMID:17711858 The MIT domain of UBPY constitutes a CHMP binding and endoso... | REMOVE | Summary: USP8 binds the ESCRT-III subunit CHMP1A through its N-terminal MIT domain; the interaction recruits USP8 to endosomes. Reason: Generic protein binding carries no functional information. The MIT-domain interaction with CHMP1A is real and functionally important for endosomal recruitment, but GO has no informative MF term for ESCRT-III subunit binding that fits better, and the functional consequence is already captured by the endosome localization and endosome organization annotations. Removal does not imply the interaction is false. Supporting Evidence: file:human/USP8/USP8-uniprot.txt The MIT domain is required for endosomal localization, CHMP1B- PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. |
| GO:0005515 protein binding | IPI PMID:19302785 Ab initio protein modelling reveals novel human MIT domains. | REMOVE | Summary: USP8 binds the ESCRT-III subunit CHMP4C through its N-terminal MIT domain; the interaction recruits USP8 to endosomes. Reason: Generic protein binding carries no functional information. The MIT-domain interaction with CHMP4C is real and functionally important for endosomal recruitment, but GO has no informative MF term for ESCRT-III subunit binding that fits better, and the functional consequence is already captured by the endosome localization and endosome organization annotations. Removal does not imply the interaction is false. Supporting Evidence: file:human/USP8/USP8-uniprot.txt The MIT domain is required for endosomal localization, CHMP1B- PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. |
| GO:0005515 protein binding | IPI PMID:19302785 Ab initio protein modelling reveals novel human MIT domains. | REMOVE | Summary: USP8 binds the ESCRT-III subunit CHMP1A through its N-terminal MIT domain; the interaction recruits USP8 to endosomes. Reason: Generic protein binding carries no functional information. The MIT-domain interaction with CHMP1A is real and functionally important for endosomal recruitment, but GO has no informative MF term for ESCRT-III subunit binding that fits better, and the functional consequence is already captured by the endosome localization and endosome organization annotations. Removal does not imply the interaction is false. Supporting Evidence: file:human/USP8/USP8-uniprot.txt The MIT domain is required for endosomal localization, CHMP1B- PMID:17711858 The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. |
| GO:0005515 protein binding | IPI PMID:24378640 HIF1Ξ± deubiquitination by USP8 is essential for ciliogenesis... | REMOVE | Summary: EPAS1 co-purifies with USP8; HIF1A is reported as a USP8 deubiquitination substrate. Reason: Generic protein binding is uninformative. Binding to EPAS1 reflects an enzyme-substrate relationship that is better represented by the cysteine-type deubiquitinase activity and protein deubiquitination annotations. Removal does not imply the interaction is false. Supporting Evidence: file:human/USP8/USP8-uniprot.txt P40818; Q99814: EPAS1; NbExp=2 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MODIFY | Summary: USP8 binds the 14-3-3 protein YWHAZ; the interaction is mediated by the phospho-Ser718 14-3-3-binding motif of USP8 and is reproduced across targeted and proteome-scale studies. Reason: Generic protein binding is uninformative. The partner (YWHAZ) is a 14-3-3 protein, and USP8 carries a phosphorylation-dependent 14-3-3-binding motif (Ser718) that restrains its catalytic activity and is the hotspot for Cushing disease mutations. The interaction is therefore recorded with the informative term 14-3-3 protein binding (GO:0071889). This is a regulatory binding activity, not the core catalytic function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: file:human/USP8/USP8-uniprot.txt P40818; P63104: YWHAZ; NbExp=7 file:human/USP8/USP8-uniprot.txt Phosphorylation of Ser-718 is essential for interaction with YWHAE file:human/USP8/USP8-deep-research-falcon.md Ser718 phosphorylation permits 14-3-3 binding, which stabilizes autoinhibition. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: USP8 binds the 14-3-3 protein YWHAE; the interaction is mediated by the phospho-Ser718 14-3-3-binding motif of USP8 and is reproduced across targeted and proteome-scale studies. Reason: Generic protein binding is uninformative. The partner (YWHAE) is a 14-3-3 protein, and USP8 carries a phosphorylation-dependent 14-3-3-binding motif (Ser718) that restrains its catalytic activity and is the hotspot for Cushing disease mutations. The interaction is therefore recorded with the informative term 14-3-3 protein binding (GO:0071889). This is a regulatory binding activity, not the core catalytic function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: file:human/USP8/USP8-uniprot.txt P40818; P62258: YWHAE; NbExp=5 file:human/USP8/USP8-uniprot.txt Phosphorylation of Ser-718 is essential for interaction with YWHAE file:human/USP8/USP8-deep-research-falcon.md Ser718 phosphorylation permits 14-3-3 binding, which stabilizes autoinhibition. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MODIFY | Summary: USP8 binds the 14-3-3 protein YWHAZ; the interaction is mediated by the phospho-Ser718 14-3-3-binding motif of USP8 and is reproduced across targeted and proteome-scale studies. Reason: Generic protein binding is uninformative. The partner (YWHAZ) is a 14-3-3 protein, and USP8 carries a phosphorylation-dependent 14-3-3-binding motif (Ser718) that restrains its catalytic activity and is the hotspot for Cushing disease mutations. The interaction is therefore recorded with the informative term 14-3-3 protein binding (GO:0071889). This is a regulatory binding activity, not the core catalytic function. Proposed replacements: 14-3-3 protein binding Supporting Evidence: file:human/USP8/USP8-uniprot.txt P40818; P63104: YWHAZ; NbExp=7 file:human/USP8/USP8-uniprot.txt Phosphorylation of Ser-718 is essential for interaction with YWHAE file:human/USP8/USP8-deep-research-falcon.md Ser718 phosphorylation permits 14-3-3 binding, which stabilizes autoinhibition. |
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Download this section (compressed HTML)Q: Which normal pituitary USP8 substrates best explain why activating USP8 mutations drive corticotroph adenoma biology?
Q: Should USP8 substrate-specific pathway annotations be represented as non-core contexts unless direct substrate deubiquitination is shown?
Experiment: Compare ubiquitination, stability, and trafficking of EGFR and other candidate substrates in corticotroph cells expressing wild-type versus PITA4-associated USP8 mutants.
Hypothesis: Activating USP8 mutations will shift substrate ubiquitination and trafficking in corticotroph cells.
Experiment: Map endogenous USP8 interaction/substrate changes at endosomes using catalytic-trap mutants and ubiquitin-remnant proteomics.
Hypothesis: Catalytic-trap and ubiquitin-remnant profiling will distinguish direct USP8 substrates from downstream pathway effects.
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