USP8

UniProt ID: P40818
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
Cell membrane
file:human/USP8/USP8-uniprot.txt
Peripheral membrane protein
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
HIF1α 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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
Cell membrane
file:human/USP8/USP8-uniprot.txt
Peripheral membrane protein
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
SUBCELLULAR LOCATION: Cytoplasm
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 α-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 α-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
SUBCELLULAR LOCATION: Cytoplasm
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 α-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 α-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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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
SUBCELLULAR LOCATION: Cytoplasm
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.
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.

Core Functions

USP8 removes ubiquitin from protein substrates, including K48- and K63-linked ubiquitin chains, to regulate endosomal ubiquitin dynamics, receptor/cargo sorting, and substrate stability.

Molecular Function:
cysteine-type deubiquitinase activity
Directly Involved In:
protein deubiquitination endosome organization
Cellular Locations:
cytosol endosome membrane early endosome
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:17711858
    The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes.

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:15161933
Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.
PMID:15778465
Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer.
PMID:16520378
The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential for receptor down-regulation.
PMID:17711858
The MIT domain of UBPY constitutes a CHMP binding and endosomal localization signal required for efficient epidermal growth factor receptor degradation.
PMID:18329369
Final stages of cytokinesis and midbody ring formation are controlled by BRUCE.
PMID:18388320
Dynamic regulation of ubiquitylation and deubiquitylation at the central spindle during cytokinesis.
PMID:18728397
Usp39 is essential for mitotic spindle checkpoint integrity and controls mRNA-levels of aurora B.
PMID:19302785
Ab initio protein modelling reveals novel human MIT domains.
PMID:19427866
Interactions with LC3 and polyubiquitin chains link nbr1 to autophagic protein turnover.
PMID:20495530
Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt.
PMID:24378640
HIF1α deubiquitination by USP8 is essential for ciliogenesis in normoxia.
PMID:25468996
E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
PMID:27302062
The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation.
PMID:27444016
Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease.
PMID:28505279
Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:36931259
A central chaperone-like role for 14-3-3 proteins in human cells.
PMID:9628861
UBPY: a growth-regulated human ubiquitin isopeptidase.
PMID:9827704
Deubiquitinating enzymes: a new class of biological regulators.
Reactome:R-HSA-1358791
Phosphorylation of USP8 by P-AKT
Reactome:R-HSA-1358795
Deubiquitination of RNF41 by P-USP8
Reactome:R-HSA-1358797
Ubiquitinated RNF41 binds P-USP8
Reactome:R-HSA-4641236
USP8 deubiquitinates FZD to potentiate WNT signaling
Reactome:R-HSA-5690196
USP8 deubiquitinates RNF128
Reactome:R-HSA-6782628
USP8 deubiquitinates STAM2:HGS
Reactome:R-HSA-8875443
USP8 deubiquitinates LRIG1
file:human/USP8/USP8-uniprot.txt
UniProt record for USP8

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(USP8-notes.md)

USP8 notes

2026-06-02

PITA context: USP8 corresponds to PITA4 / ACTH-producing corticotroph adenoma/Cushing disease. Pediatric Cushing disease work concluded that "Somatic USP8 gene mutations are a common cause of pediatric CD" and that mutations decrease EGFR degradation, leading to increased POMC and ACTH production [PMID:28505279 "Somatic USP8 gene mutations are a common cause of pediatric CD"; PMID:28505279 "decreased EGFR degradation, which in turn leads to increased POMC expression and ACTH production"].

Deep research status: just deep-research-falcon human USP8 --fallback perplexity-lite timed out on Falcon after 600 seconds, and the fallback failed with a Perplexity quota error. I proceeded using fetched UniProt, GOA, Reactome-derived references, and cached publications.

Functional summary: USP8/UBPY is a cysteine-type deubiquitinase. UniProt summarizes it as a "Hydrolase that can remove conjugated ubiquitin from proteins" [file:human/USP8/USP8-uniprot.txt "Hydrolase that can remove conjugated ubiquitin from proteins"]. The endosomal UBPY paper states "UBPY is a ubiquitin-specific protease" and that UBPY function is essential for growth factor receptor down-regulation [PMID:16520378 "UBPY is a ubiquitin-specific protease"; PMID:16520378 "UBPY function is essential for growth factor receptor down-regulation"]. The MIT-domain paper supports endosomal targeting: "essential for its localization to endosomes" PMID:17711858.

Annotation decisions: I accepted deubiquitinase, protein deubiquitination, cytosol/cytoplasm, early endosome/endosome membrane, and endosome organization annotations as core or directly supportive. I kept cytokinesis/midbody, Wnt/FZD, BACE1, postsynaptic, and acrosomal contexts as non-core. Generic high-throughput protein binding, cadherin binding, dexamethasone response, and amyloid fibril formation were marked as over-annotated because they are indirect or too generic relative to the deubiquitinase/endosomal cargo-sorting mechanism.

📄 View Raw YAML

 
id: P40818
gene_symbol: USP8
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: '1'
  id: P40818-1
- name: '2'
  id: P40818-2
  sequence_note: VSP_054594, VSP_054595
existing_annotations:
- term:
    id: GO:0007032
    label: endosome organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo
      sorting.
    action: ACCEPT
    reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY
      studies.
    supported_by:
    - &id003
      reference_id: PMID:16520378
      supporting_text: localizes to endosomes
    - &id004
      reference_id: PMID:17711858
      supporting_text: The UBPY MIT domain is dispensable for its catalytic activity but is essential
        for its localization to endosomes.
    - reference_id: PMID:16520378
      supporting_text: UBPY function is essential for growth factor receptor down-regulation
- term:
    id: GO:0007265
    label: Ras protein signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Ras/MAPK signaling is a downstream consequence of receptor turnover regulation and
      is not USP8 catalytic activity itself.
    action: KEEP_AS_NON_CORE
    reason: USP8 removes ubiquitin from EGFR and can affect downstream MAPK/Ras signaling, but
      deubiquitination/endosomal sorting is the core function.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation
        and downstream MAPK signaling.
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity
      on K48- and K63-linked ubiquitin chains where tested.
    action: ACCEPT
    reason: This is the core molecular function of USP8 and is supported by direct biochemical
      and cellular evidence.
    supported_by:
    - &id001
      reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Hydrolase that can remove conjugated ubiquitin from proteins
    - &id002
      reference_id: PMID:16520378
      supporting_text: UBPY is a ubiquitin-specific protease
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Postsynaptic/glutamatergic-synapse annotations are plausible context-specific consequences
      of USP8 substrate trafficking but are not core gene function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core neuronal context; core function remains deubiquitination and endosomal
      cargo regulation.
    supported_by:
    - reference_id: PMID:27302062
      supporting_text: regulates the ubiquitination, trafficking, and lysosomal degradation of
- term:
    id: GO:0030496
    label: midbody
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: The cytokinesis annotation is supported by PMID:18388320 and should be retained as
      non-core.
    supported_by:
    - reference_id: PMID:18388320
      supporting_text: UBPY was detected only in the final stage of cytokinesis at the midbody
    - reference_id: PMID:18388320
      supporting_text: Depletion of cellular UBPY or AMSH led to defects in cytokinesis.
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity
      on K48- and K63-linked ubiquitin chains where tested.
    action: ACCEPT
    reason: This is the core molecular function of USP8 and is supported by direct biochemical
      and cellular evidence.
    supported_by:
    - *id001
    - *id002
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization is weakly supported relative to cytosol/endosome and appears
      context-dependent.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
    - reference_id: PMID:28505279
      supporting_text: its expression was more nuclear in the mutated tumors
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo
      sorting.
    action: ACCEPT
    reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY
      studies.
    supported_by:
    - *id003
    - *id004
    - reference_id: PMID:16520378
      supporting_text: UBPY function is essential for growth factor receptor down-regulation
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: USP8 can associate peripherally with cell/endosomal membranes, but this is not the
      principal location term.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core localization; endosome membrane/cytosol are more informative for
      normal USP8 function.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Cell membrane
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo
      sorting.
    action: ACCEPT
    reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY
      studies.
    supported_by:
    - *id003
    - *id004
    - reference_id: PMID:16520378
      supporting_text: UBPY function is essential for growth factor receptor down-regulation
- term:
    id: GO:0016579
    label: protein deubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: USP8-mediated protein deubiquitination is central to its regulation of receptor and
      cargo turnover.
    action: ACCEPT
    reason: The process term correctly captures the biological consequence of the USP8 catalytic
      activity.
    supported_by:
    - *id001
    - *id002
    - reference_id: PMID:27302062
      supporting_text: USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating
        lysine 501
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15161933
  qualifier: enables
  review:
    summary: The interaction is retained as context, but generic protein binding is too vague
      for USP8 functional curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Interacts with NBR1, RASGRF1, RNF41 and IST1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15778465
  qualifier: enables
  review:
    summary: The interaction is retained as context, but generic protein binding is too vague
      for USP8 functional curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Interacts with NBR1, RASGRF1, RNF41 and IST1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17711858
  qualifier: enables
  review:
    summary: The interaction is retained as context, but generic protein binding is too vague
      for USP8 functional curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Interacts with NBR1, RASGRF1, RNF41 and IST1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19302785
  qualifier: enables
  review:
    summary: The interaction is retained as context, but generic protein binding is too vague
      for USP8 functional curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Interacts with NBR1, RASGRF1, RNF41 and IST1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19427866
  qualifier: enables
  review:
    summary: The interaction is retained as context, but generic protein binding is too vague
      for USP8 functional curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Interacts with NBR1, RASGRF1, RNF41 and IST1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24378640
  qualifier: enables
  review:
    summary: The interaction is retained as context, but generic protein binding is too vague
      for USP8 functional curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Interacts with NBR1, RASGRF1, RNF41 and IST1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: The interaction is retained as context, but generic protein binding is too vague
      for USP8 functional curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Interacts with NBR1, RASGRF1, RNF41 and IST1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: The interaction is retained as context, but generic protein binding is too vague
      for USP8 functional curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Interacts with NBR1, RASGRF1, RNF41 and IST1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: The interaction is retained as context, but generic protein binding is too vague
      for USP8 functional curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Interacts with NBR1, RASGRF1, RNF41 and IST1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36931259
  qualifier: enables
  review:
    summary: The interaction is retained as context, but generic protein binding is too vague
      for USP8 functional curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Interacts with NBR1, RASGRF1, RNF41 and IST1.
- term:
    id: GO:0002080
    label: acrosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Acrosomal membrane localization is a specialized context inferred from orthologous
      sperm/acrosome biology, not the core human USP8 function.
    action: KEEP_AS_NON_CORE
    reason: UniProt notes acrosome biogenesis through interaction with spermatid ESCRT-0 and microtubules,
      but the dominant supported function is endosomal deubiquitination.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Involved in acrosome biogenesis through interaction with the spermatid
        ESCRT-0 complex and microtubules.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo
      sorting.
    action: ACCEPT
    reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY
      studies.
    supported_by:
    - *id003
    - *id004
    - reference_id: PMID:16520378
      supporting_text: UBPY function is essential for growth factor receptor down-regulation
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0007032
    label: endosome organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo
      sorting.
    action: ACCEPT
    reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY
      studies.
    supported_by:
    - *id003
    - *id004
    - reference_id: PMID:16520378
      supporting_text: UBPY function is essential for growth factor receptor down-regulation
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Postsynaptic/glutamatergic-synapse annotations are plausible context-specific consequences
      of USP8 substrate trafficking but are not core gene function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core neuronal context; core function remains deubiquitination and endosomal
      cargo regulation.
    supported_by:
    - reference_id: PMID:27302062
      supporting_text: regulates the ubiquitination, trafficking, and lysosomal degradation of
- term:
    id: GO:0030496
    label: midbody
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: The cytokinesis annotation is supported by PMID:18388320 and should be retained as
      non-core.
    supported_by:
    - reference_id: PMID:18388320
      supporting_text: UBPY was detected only in the final stage of cytokinesis at the midbody
    - reference_id: PMID:18388320
      supporting_text: Depletion of cellular UBPY or AMSH led to defects in cytokinesis.
- term:
    id: GO:0071549
    label: cellular response to dexamethasone stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Cellular response to dexamethasone is not a core USP8 function and appears to be
      a transferred context annotation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:28505279
      supporting_text: decreased EGFR degradation, which in turn leads to increased POMC expression
        and ACTH production
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Postsynaptic/glutamatergic-synapse annotations are plausible context-specific consequences
      of USP8 substrate trafficking but are not core gene function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core neuronal context; core function remains deubiquitination and endosomal
      cargo regulation.
    supported_by:
    - reference_id: PMID:27302062
      supporting_text: regulates the ubiquitination, trafficking, and lysosomal degradation of
- term:
    id: GO:0099576
    label: regulation of protein catabolic process at postsynapse, modulating synaptic transmission
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Postsynaptic/glutamatergic-synapse annotations are plausible context-specific consequences
      of USP8 substrate trafficking but are not core gene function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core neuronal context; core function remains deubiquitination and endosomal
      cargo regulation.
    supported_by:
    - reference_id: PMID:27302062
      supporting_text: regulates the ubiquitination, trafficking, and lysosomal degradation of
- term:
    id: GO:1990090
    label: cellular response to nerve growth factor stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: This annotation captures a substrate-specific consequence of USP8 deubiquitination
      and trafficking regulation.
    action: KEEP_AS_NON_CORE
    reason: The process is true in specific substrate/pathway contexts, but the core function
      is the upstream deubiquitinase activity and endosomal cargo regulation.
    supported_by:
    - reference_id: PMID:27302062
      supporting_text: regulates the ubiquitination, trafficking, and lysosomal degradation of
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4641236
  qualifier: enables
  review:
    summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity
      on K48- and K63-linked ubiquitin chains where tested.
    action: ACCEPT
    reason: This is the core molecular function of USP8 and is supported by direct biochemical
      and cellular evidence.
    supported_by:
    - *id001
    - *id002
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains.
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8875443
  qualifier: enables
  review:
    summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity
      on K48- and K63-linked ubiquitin chains where tested.
    action: ACCEPT
    reason: This is the core molecular function of USP8 and is supported by direct biochemical
      and cellular evidence.
    supported_by:
    - *id001
    - *id002
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:16520378
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:17711858
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:19427866
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:28505279
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:16520378
  qualifier: located_in
  review:
    summary: USP8 can associate peripherally with cell/endosomal membranes, but this is not the
      principal location term.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core localization; endosome membrane/cytosol are more informative for
      normal USP8 function.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Cell membrane
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: EXP
  original_reference_id: PMID:16520378
  qualifier: located_in
  review:
    summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo
      sorting.
    action: ACCEPT
    reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY
      studies.
    supported_by:
    - *id003
    - *id004
    - reference_id: PMID:16520378
      supporting_text: UBPY function is essential for growth factor receptor down-regulation
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: EXP
  original_reference_id: PMID:17711858
  qualifier: located_in
  review:
    summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo
      sorting.
    action: ACCEPT
    reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY
      studies.
    supported_by:
    - *id003
    - *id004
    - reference_id: PMID:16520378
      supporting_text: UBPY function is essential for growth factor receptor down-regulation
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IDA
  original_reference_id: PMID:16520378
  qualifier: located_in
  review:
    summary: USP8 functions at endosomes, regulating endosomal ubiquitin dynamics and receptor/cargo
      sorting.
    action: ACCEPT
    reason: Endosomal localization and endosome organization are well supported by direct USP8/UBPY
      studies.
    supported_by:
    - *id003
    - *id004
    - reference_id: PMID:16520378
      supporting_text: UBPY function is essential for growth factor receptor down-regulation
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:16520378
  qualifier: is_active_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0061578
    label: K63-linked deubiquitinase activity
  evidence_type: IDA
  original_reference_id: PMID:16520378
  qualifier: enables
  review:
    summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity
      on K48- and K63-linked ubiquitin chains where tested.
    action: ACCEPT
    reason: This is the core molecular function of USP8 and is supported by direct biochemical
      and cellular evidence.
    supported_by:
    - *id001
    - *id002
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains.
- term:
    id: GO:1990380
    label: K48-linked deubiquitinase activity
  evidence_type: IDA
  original_reference_id: PMID:16520378
  qualifier: enables
  review:
    summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity
      on K48- and K63-linked ubiquitin chains where tested.
    action: ACCEPT
    reason: This is the core molecular function of USP8 and is supported by direct biochemical
      and cellular evidence.
    supported_by:
    - *id001
    - *id002
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains.
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IDA
  original_reference_id: PMID:27444016
  qualifier: enables
  review:
    summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity
      on K48- and K63-linked ubiquitin chains where tested.
    action: ACCEPT
    reason: This is the core molecular function of USP8 and is supported by direct biochemical
      and cellular evidence.
    supported_by:
    - *id001
    - *id002
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:27444016
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:1905166
    label: negative regulation of lysosomal protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:27444016
  qualifier: involved_in
  review:
    summary: This annotation captures a substrate-specific consequence of USP8 deubiquitination
      and trafficking regulation.
    action: KEEP_AS_NON_CORE
    reason: The process is true in specific substrate/pathway contexts, but the core function
      is the upstream deubiquitinase activity and endosomal cargo regulation.
    supported_by:
    - reference_id: PMID:27302062
      supporting_text: regulates the ubiquitination, trafficking, and lysosomal degradation of
- term:
    id: GO:1905908
    label: positive regulation of amyloid fibril formation
  evidence_type: IMP
  original_reference_id: PMID:27444016
  qualifier: involved_in
  review:
    summary: Positive regulation of amyloid fibril formation is a disease-model consequence of
      alpha-synuclein deubiquitination, not a core normal function.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:27444016
      supporting_text: it deubiquitinated K63-linked chains on alpha-synuclein
    - reference_id: PMID:27444016
      supporting_text: knockdown increased the lysosomal degradation of alpha-synuclein
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IDA
  original_reference_id: PMID:18728397
  qualifier: enables
  review:
    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.
    action: UNDECIDED
    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.
    supported_by:
    - reference_id: file:publications/PMID_18728397.md
      supporting_text: Usp39 is essential for mitotic spindle checkpoint integrity and controls
        mRNA-levels of aurora B.
- term:
    id: GO:0090263
    label: positive regulation of canonical Wnt signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:20495530
  qualifier: involved_in
  review:
    summary: USP8 regulation of Wnt signaling through Frizzled deubiquitination is supported but
      pathway-specific and non-core.
    action: KEEP_AS_NON_CORE
    reason: PMID:20495530 supports FZD deubiquitination and altered Wnt responsiveness, but this
      is one substrate/pathway context of the broader deubiquitinase role.
    supported_by:
    - reference_id: PMID:20495530
      supporting_text: cell surface level of Frizzled is regulated by deubiquitylating enzyme
        UBPY/ubiquitin-specific protease 8 (USP8)
- term:
    id: GO:0016579
    label: protein deubiquitination
  evidence_type: IMP
  original_reference_id: PMID:27302062
  qualifier: involved_in
  review:
    summary: USP8-mediated protein deubiquitination is central to its regulation of receptor and
      cargo turnover.
    action: ACCEPT
    reason: The process term correctly captures the biological consequence of the USP8 catalytic
      activity.
    supported_by:
    - *id001
    - *id002
    - reference_id: PMID:27302062
      supporting_text: USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating
        lysine 501
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: IMP
  original_reference_id: PMID:27302062
  qualifier: involved_in
  review:
    summary: This annotation captures a substrate-specific consequence of USP8 deubiquitination
      and trafficking regulation.
    action: KEEP_AS_NON_CORE
    reason: The process is true in specific substrate/pathway contexts, but the core function
      is the upstream deubiquitinase activity and endosomal cargo regulation.
    supported_by:
    - reference_id: PMID:27302062
      supporting_text: regulates the ubiquitination, trafficking, and lysosomal degradation of
- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IMP
  original_reference_id: PMID:27302062
  qualifier: involved_in
  review:
    summary: This annotation captures a substrate-specific consequence of USP8 deubiquitination
      and trafficking regulation.
    action: KEEP_AS_NON_CORE
    reason: The process is true in specific substrate/pathway contexts, but the core function
      is the upstream deubiquitinase activity and endosomal cargo regulation.
    supported_by:
    - reference_id: PMID:27302062
      supporting_text: regulates the ubiquitination, trafficking, and lysosomal degradation of
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: HDA
  original_reference_id: PMID:25468996
  qualifier: enables
  review:
    summary: Cadherin binding comes from a high-throughput E-cadherin interactome and is not a
      defining USP8 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The source can be retained as interaction context, but cadherin binding should not
      be treated as a core molecular function of USP8.
    supported_by:
    - reference_id: PMID:25468996
      supporting_text: E-cadherin interactome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1358791
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1358795
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1358797
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4641236
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690196
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6782628
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8875443
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0000281
    label: mitotic cytokinesis
  evidence_type: IMP
  original_reference_id: PMID:18388320
  qualifier: acts_upstream_of_or_within
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: The cytokinesis annotation is supported by PMID:18388320 and should be retained as
      non-core.
    supported_by:
    - reference_id: PMID:18388320
      supporting_text: UBPY was detected only in the final stage of cytokinesis at the midbody
    - reference_id: PMID:18388320
      supporting_text: Depletion of cellular UBPY or AMSH led to defects in cytokinesis.
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IDA
  original_reference_id: PMID:18388320
  qualifier: enables
  review:
    summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity
      on K48- and K63-linked ubiquitin chains where tested.
    action: ACCEPT
    reason: This is the core molecular function of USP8 and is supported by direct biochemical
      and cellular evidence.
    supported_by:
    - *id001
    - *id002
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:18388320
  qualifier: located_in
  review:
    summary: Cytosol/cytoplasm localization is consistent with USP8 function as a cytosolic enzyme
      recruited to endosomal membranes and other cytoplasmic structures.
    action: ACCEPT
    reason: The broad cytosolic/cytoplasmic localization is supported by UniProt and direct localization
      studies.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:28505279
      supporting_text: USP8 was exclusively expressed in the cytoplasm of the nonmutant tumors
- term:
    id: GO:0016579
    label: protein deubiquitination
  evidence_type: IMP
  original_reference_id: PMID:18388320
  qualifier: acts_upstream_of_or_within
  review:
    summary: USP8-mediated protein deubiquitination is central to its regulation of receptor and
      cargo turnover.
    action: ACCEPT
    reason: The process term correctly captures the biological consequence of the USP8 catalytic
      activity.
    supported_by:
    - *id001
    - *id002
    - reference_id: PMID:27302062
      supporting_text: USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating
        lysine 501
- term:
    id: GO:0030496
    label: midbody
  evidence_type: IDA
  original_reference_id: PMID:18388320
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: The cytokinesis annotation is supported by PMID:18388320 and should be retained as
      non-core.
    supported_by:
    - reference_id: PMID:18388320
      supporting_text: UBPY was detected only in the final stage of cytokinesis at the midbody
    - reference_id: PMID:18388320
      supporting_text: Depletion of cellular UBPY or AMSH led to defects in cytokinesis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18329369
  qualifier: enables
  review:
    summary: The interaction is retained as context, but generic protein binding is too vague
      for USP8 functional curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Interacts with NBR1, RASGRF1, RNF41 and IST1.
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IDA
  original_reference_id: PMID:16520378
  qualifier: enables
  review:
    summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity
      on K48- and K63-linked ubiquitin chains where tested.
    action: ACCEPT
    reason: This is the core molecular function of USP8 and is supported by direct biochemical
      and cellular evidence.
    supported_by:
    - *id001
    - *id002
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains.
- term:
    id: GO:0070536
    label: protein K63-linked deubiquitination
  evidence_type: IDA
  original_reference_id: PMID:16520378
  qualifier: involved_in
  review:
    summary: USP8-mediated protein deubiquitination is central to its regulation of receptor and
      cargo turnover.
    action: ACCEPT
    reason: The process term correctly captures the biological consequence of the USP8 catalytic
      activity.
    supported_by:
    - *id001
    - *id002
    - reference_id: PMID:27302062
      supporting_text: USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating
        lysine 501
- term:
    id: GO:0071108
    label: protein K48-linked deubiquitination
  evidence_type: IDA
  original_reference_id: PMID:16520378
  qualifier: involved_in
  review:
    summary: USP8-mediated protein deubiquitination is central to its regulation of receptor and
      cargo turnover.
    action: ACCEPT
    reason: The process term correctly captures the biological consequence of the USP8 catalytic
      activity.
    supported_by:
    - *id001
    - *id002
    - reference_id: PMID:27302062
      supporting_text: USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating
        lysine 501
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: TAS
  original_reference_id: PMID:9827704
  qualifier: enables
  review:
    summary: Cysteine-type endopeptidase activity is too broad for USP8; the specific deubiquitinase
      activity term should be used.
    action: MODIFY
    reason: USP8 is a cysteine protease in the deubiquitinating enzyme family, but GO:0004843
      captures the biologically relevant activity.
    proposed_replacement_terms:
    - id: GO:0004843
      label: cysteine-type deubiquitinase activity
    supported_by:
    - reference_id: PMID:9827704
      supporting_text: Deubiquitinating enzymes are cysteine proteases that specifically cleave
        ubiquitin from ubiquitin-conjugated protein substrates.
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: TAS
  original_reference_id: PMID:9628861
  qualifier: enables
  review:
    summary: USP8 is a bona fide ubiquitin-specific cysteine deubiquitinase, including activity
      on K48- and K63-linked ubiquitin chains where tested.
    action: ACCEPT
    reason: This is the core molecular function of USP8 and is supported by direct biochemical
      and cellular evidence.
    supported_by:
    - *id001
    - *id002
    - reference_id: file:human/USP8/USP8-uniprot.txt
      supporting_text: Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
    mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs
    using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15161933
  title: Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.
  findings: []
- id: PMID:15778465
  title: Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer.
  findings: []
- id: PMID:16520378
  title: The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential
    for receptor down-regulation.
  findings: []
- id: PMID:17711858
  title: The MIT domain of UBPY constitutes a CHMP binding and endosomal localization signal required
    for efficient epidermal growth factor receptor degradation.
  findings: []
- id: PMID:18329369
  title: Final stages of cytokinesis and midbody ring formation are controlled by BRUCE.
  findings: []
- id: PMID:18388320
  title: Dynamic regulation of ubiquitylation and deubiquitylation at the central spindle during
    cytokinesis.
  findings: []
- id: PMID:18728397
  title: "Usp39 is essential for mitotic spindle checkpoint integrity and controls mRNA-levels of aurora B."
  findings: []
- id: PMID:19302785
  title: Ab initio protein modelling reveals novel human MIT domains.
  findings: []
- id: PMID:19427866
  title: Interactions with LC3 and polyubiquitin chains link nbr1 to autophagic protein turnover.
  findings: []
- id: PMID:20495530
  title: "Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt."
  findings: []
- id: PMID:24378640
  title: "HIF1α deubiquitination by USP8 is essential for ciliogenesis in normoxia."
  findings: []
- id: PMID:25468996
  title: E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
  findings: []
- id: PMID:27302062
  title: "The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation."
  findings: []
- id: PMID:27444016
  title: "Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease."
  findings: []
- id: PMID:28505279
  title: "Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease."
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:36931259
  title: A central chaperone-like role for 14-3-3 proteins in human cells.
  findings: []
- id: PMID:9628861
  title: "UBPY: a growth-regulated human ubiquitin isopeptidase."
  findings: []
- id: PMID:9827704
  title: 'Deubiquitinating enzymes: a new class of biological regulators.'
  findings: []
- id: Reactome:R-HSA-1358791
  title: Phosphorylation of USP8 by P-AKT
  findings: []
- id: Reactome:R-HSA-1358795
  title: Deubiquitination of RNF41 by P-USP8
  findings: []
- id: Reactome:R-HSA-1358797
  title: Ubiquitinated RNF41 binds P-USP8
  findings: []
- id: Reactome:R-HSA-4641236
  title: USP8 deubiquitinates FZD to potentiate WNT signaling
  findings: []
- id: Reactome:R-HSA-5690196
  title: USP8 deubiquitinates RNF128
  findings: []
- id: Reactome:R-HSA-6782628
  title: USP8 deubiquitinates STAM2:HGS
  findings: []
- id: Reactome:R-HSA-8875443
  title: USP8 deubiquitinates LRIG1
  findings: []
- id: file:human/USP8/USP8-uniprot.txt
  title: UniProt record for USP8
  findings: []
core_functions:
- molecular_function:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  description: USP8 removes ubiquitin from protein substrates, including K48- and K63-linked ubiquitin
    chains, to regulate endosomal ubiquitin dynamics, receptor/cargo sorting, and substrate stability.
  directly_involved_in:
  - id: GO:0016579
    label: protein deubiquitination
  - id: GO:0007032
    label: endosome organization
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0010008
    label: endosome membrane
  - id: GO:0005769
    label: early endosome
  supported_by:
  - reference_id: file:human/USP8/USP8-uniprot.txt
    supporting_text: Hydrolase that can remove conjugated ubiquitin from proteins
  - reference_id: PMID:16520378
    supporting_text: UBPY is a ubiquitin-specific protease
  - reference_id: PMID:17711858
    supporting_text: The UBPY MIT domain is dispensable for its catalytic activity but is essential
      for its localization to endosomes.
proposed_new_terms: []
suggested_questions:
- question: Which normal pituitary USP8 substrates best explain why activating USP8 mutations
    drive corticotroph adenoma biology?
- question: Should USP8 substrate-specific pathway annotations be represented as non-core contexts
    unless direct substrate deubiquitination is shown?
suggested_experiments:
- description: 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.
- description: 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.