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... | MARK AS OVER ANNOTATED | Summary: The interaction is retained as context, but generic protein binding is too vague for USP8 functional curation. Reason: USP8 has many real partners, including CHMP proteins, 14-3-3 proteins, NBR1, RNF41, BIRC6, and KIF23, but the GO term should describe specific binding or the deubiquitination/endosomal process rather than generic protein binding. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with NBR1, RASGRF1, RNF41 and IST1. |
| GO:0005515 protein binding | IPI PMID:15778465 Targeted proteomic analysis of 14-3-3 sigma, a p53 effector ... | MARK AS OVER ANNOTATED | Summary: The interaction is retained as context, but generic protein binding is too vague for USP8 functional curation. Reason: USP8 has many real partners, including CHMP proteins, 14-3-3 proteins, NBR1, RNF41, BIRC6, and KIF23, but the GO term should describe specific binding or the deubiquitination/endosomal process rather than generic protein binding. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with NBR1, RASGRF1, RNF41 and IST1. |
| GO:0005515 protein binding | IPI PMID:17711858 The MIT domain of UBPY constitutes a CHMP binding and endoso... | MARK AS OVER ANNOTATED | Summary: The interaction is retained as context, but generic protein binding is too vague for USP8 functional curation. Reason: USP8 has many real partners, including CHMP proteins, 14-3-3 proteins, NBR1, RNF41, BIRC6, and KIF23, but the GO term should describe specific binding or the deubiquitination/endosomal process rather than generic protein binding. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with NBR1, RASGRF1, RNF41 and IST1. |
| GO:0005515 protein binding | IPI PMID:19302785 Ab initio protein modelling reveals novel human MIT domains. | MARK AS OVER ANNOTATED | Summary: The interaction is retained as context, but generic protein binding is too vague for USP8 functional curation. Reason: USP8 has many real partners, including CHMP proteins, 14-3-3 proteins, NBR1, RNF41, BIRC6, and KIF23, but the GO term should describe specific binding or the deubiquitination/endosomal process rather than generic protein binding. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with NBR1, RASGRF1, RNF41 and IST1. |
| GO:0005515 protein binding | IPI PMID:19427866 Interactions with LC3 and polyubiquitin chains link nbr1 to ... | MARK AS OVER ANNOTATED | Summary: The interaction is retained as context, but generic protein binding is too vague for USP8 functional curation. Reason: USP8 has many real partners, including CHMP proteins, 14-3-3 proteins, NBR1, RNF41, BIRC6, and KIF23, but the GO term should describe specific binding or the deubiquitination/endosomal process rather than generic protein binding. 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... | MARK AS OVER ANNOTATED | Summary: The interaction is retained as context, but generic protein binding is too vague for USP8 functional curation. Reason: USP8 has many real partners, including CHMP proteins, 14-3-3 proteins, NBR1, RNF41, BIRC6, and KIF23, but the GO term should describe specific binding or the deubiquitination/endosomal process rather than generic protein binding. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with NBR1, RASGRF1, RNF41 and IST1. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: The interaction is retained as context, but generic protein binding is too vague for USP8 functional curation. Reason: USP8 has many real partners, including CHMP proteins, 14-3-3 proteins, NBR1, RNF41, BIRC6, and KIF23, but the GO term should describe specific binding or the deubiquitination/endosomal process rather than generic protein binding. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with NBR1, RASGRF1, RNF41 and IST1. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: The interaction is retained as context, but generic protein binding is too vague for USP8 functional curation. Reason: USP8 has many real partners, including CHMP proteins, 14-3-3 proteins, NBR1, RNF41, BIRC6, and KIF23, but the GO term should describe specific binding or the deubiquitination/endosomal process rather than generic protein binding. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with NBR1, RASGRF1, RNF41 and IST1. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: The interaction is retained as context, but generic protein binding is too vague for USP8 functional curation. Reason: USP8 has many real partners, including CHMP proteins, 14-3-3 proteins, NBR1, RNF41, BIRC6, and KIF23, but the GO term should describe specific binding or the deubiquitination/endosomal process rather than generic protein binding. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with NBR1, RASGRF1, RNF41 and IST1. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MARK AS OVER ANNOTATED | Summary: The interaction is retained as context, but generic protein binding is too vague for USP8 functional curation. Reason: USP8 has many real partners, including CHMP proteins, 14-3-3 proteins, NBR1, RNF41, BIRC6, and KIF23, but the GO term should describe specific binding or the deubiquitination/endosomal process rather than generic protein binding. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with NBR1, RASGRF1, RNF41 and IST1. |
| 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 ... | UNDECIDED | Summary: The cited PMID:18728397 does not support this annotation. The cached publication for PMID:18728397 is "Usp39 is essential for mitotic spindle checkpoint integrity and controls mRNA-levels of aurora B" (van Leuken et al., Cell Cycle 2008), which is about USP39, not USP8. The biological claim (USP8 is a cysteine-type deubiquitinase) is correct and well-supported by other annotations, but this specific GOA entry has an erroneous reference and should be flagged to source curators. Reason: This specific GOA entry cites PMID:18728397, but the publication is about USP39 (not USP8). The underlying molecular function (GO:0004843) is well-supported by other evidence (e.g., the IBA/IEA annotations and PMID:16520378), so the term itself is correct, but this individual annotation cannot be evaluated against the cited reference. Recommend surfacing the PMID mismatch to the source database curators. Supporting Evidence: file:publications/PMID_18728397.md Usp39 is essential for mitotic spindle checkpoint integrity and controls mRNA-levels of aurora B. |
| 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... | MARK AS OVER ANNOTATED | Summary: The interaction is retained as context, but generic protein binding is too vague for USP8 functional curation. Reason: USP8 has many real partners, including CHMP proteins, 14-3-3 proteins, NBR1, RNF41, BIRC6, and KIF23, but the GO term should describe specific binding or the deubiquitination/endosomal process rather than generic protein binding. Supporting Evidence: file:human/USP8/USP8-uniprot.txt Interacts with NBR1, RASGRF1, RNF41 and IST1. |
| 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... | KEEP AS NON CORE | Summary: The reported physical interaction is retained as non-core; generic protein binding does not specify the catalytic mechanism. Reason: Physical interaction and catalytic function are distinct claims. The observed interaction does not independently establish a new enzyme activity. |
| GO:0005515 protein binding | IPI PMID:17711858 The MIT domain of UBPY constitutes a CHMP binding and endoso... | KEEP AS NON CORE | Summary: The reported physical interaction is retained as non-core; generic protein binding does not specify the catalytic mechanism. Reason: Physical interaction and catalytic function are distinct claims. The observed interaction does not independently establish a new enzyme activity. |
| GO:0005515 protein binding | IPI PMID:19302785 Ab initio protein modelling reveals novel human MIT domains. | KEEP AS NON CORE | Summary: The reported physical interaction is retained as non-core; generic protein binding does not specify the catalytic mechanism. Reason: Physical interaction and catalytic function are distinct claims. The observed interaction does not independently establish a new enzyme activity. |
| GO:0005515 protein binding | IPI PMID:19302785 Ab initio protein modelling reveals novel human MIT domains. | KEEP AS NON CORE | Summary: The reported physical interaction is retained as non-core; generic protein binding does not specify the catalytic mechanism. Reason: Physical interaction and catalytic function are distinct claims. The observed interaction does not independently establish a new enzyme activity. |
| GO:0005515 protein binding | IPI PMID:24378640 HIF1Ξ± deubiquitination by USP8 is essential for ciliogenesis... | KEEP AS NON CORE | Summary: The reported physical interaction is retained as non-core; generic protein binding does not specify the catalytic mechanism. Reason: Physical interaction and catalytic function are distinct claims. The observed interaction does not independently establish a new enzyme activity. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | KEEP AS NON CORE | Summary: The reported physical interaction is retained as non-core; generic protein binding does not specify the catalytic mechanism. Reason: Physical interaction and catalytic function are distinct claims. The observed interaction does not independently establish a new enzyme activity. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | KEEP AS NON CORE | Summary: The reported physical interaction is retained as non-core; generic protein binding does not specify the catalytic mechanism. Reason: Physical interaction and catalytic function are distinct claims. The observed interaction does not independently establish a new enzyme activity. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | KEEP AS NON CORE | Summary: The reported physical interaction is retained as non-core; generic protein binding does not specify the catalytic mechanism. Reason: Physical interaction and catalytic function are distinct claims. The observed interaction does not independently establish a new enzyme activity. |
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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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