USP8 is a cysteine-type deubiquitinase that removes ubiquitin from protein substrates. It regulates endosomal ubiquitin dynamics, cargo sorting and substrate stability, linking deubiquitination to receptor trafficking and protein turnover.
Summary: Recombinant human USP8 removes ubiquitin; the horse protein conserves the USP catalytic architecture.
Reason: Recombinant human USP8 removes ubiquitin; the horse protein conserves the USP catalytic architecture. This assessment transfers characterized mammalian biology to the selected horse sequence with the sequence limitations stated in the comparison.
Supporting Evidence:
file:human/USP8/USP8-uniprot.txt
CC -!- FUNCTION: Hydrolase that can remove conjugated ubiquitin from proteins CC and therefore plays an important regulatory role at the level of CC protein turnover by preventing degradation. Converts both 'Lys-48' an CC 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the CC M phase. Involved in cell proliferation. Required to enter into S phase CC in response to serum stimulation. May regulate T-cell anergy mediated CC by RNF128 via the formation of a complex containing RNF128 and OTUB1. CC Probably regulates the stability of STAM2 and RASGRF1. Regulates CC endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early CC endosomes, and maintenance of ESCRT-0 stability. The level of protein CC ubiquitination on endosomes is essential for maintaining the morphology CC of the organelle. Deubiquitinates EPS15 and controls tyrosine kinase CC stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR CC degradation and downstream MAPK signaling. Involved in acrosome CC biogenesis through interaction with the spermatid ESCRT-0 complex and CC microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. CC Deubiquitinates BACE1 which inhibits BACE1 lysosomal degradation and CC modulates BACE-mediated APP cleavage and amyloid-beta formation CC (PubMed:27302062). {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369, CC ECO:0000269|PubMed:27302062, ECO:0000269|PubMed:9628861}.
file:HORSE/USP8/USP8-bioinformatics/RESULTS.md
The horse sequence A0A9L0T7K6 (1112 residues) aligns to human P40818 (1118 residues) with 91.82% identity across 1112 paired residues. Paired coverage is 99.46% of the human sequence and 100.0% of the horse sequence.
We have identified and characterized a novel human ubiquitin isopeptidase, UBPY, which both as a recombinant protein and upon immunoprecipitation from cell extracts is able to cleave linear or isopeptide-linked ubiquitin chains.
Summary: A nuclear pool is compatible with the human record but is not the central endosomal deubiquitination function.
Reason: A nuclear pool is compatible with the human record but is not the central endosomal deubiquitination function. This assessment transfers characterized mammalian biology to the selected horse sequence with the sequence limitations stated in the comparison.
Supporting Evidence:
file:human/USP8/USP8-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}.
file:HORSE/USP8/USP8-bioinformatics/RESULTS.md
The horse sequence A0A9L0T7K6 (1112 residues) aligns to human P40818 (1118 residues) with 91.82% identity across 1112 paired residues. Paired coverage is 99.46% of the human sequence and 100.0% of the horse sequence.
Summary: USP8 acts in the cytoplasmic/endosomal compartment.
Reason: USP8 acts in the cytoplasmic/endosomal compartment. This assessment transfers characterized mammalian biology to the selected horse sequence with the sequence limitations stated in the comparison.
Supporting Evidence:
file:human/USP8/USP8-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}.
file:HORSE/USP8/USP8-bioinformatics/RESULTS.md
The horse sequence A0A9L0T7K6 (1112 residues) aligns to human P40818 (1118 residues) with 91.82% identity across 1112 paired residues. Paired coverage is 99.46% of the human sequence and 100.0% of the horse sequence.
We have identified and characterized a novel human ubiquitin isopeptidase, UBPY, which both as a recombinant protein and upon immunoprecipitation from cell extracts is able to cleave linear or isopeptide-linked ubiquitin chains.
Summary: Cytosolic localization is compatible with access to endosomal ubiquitinated substrates.
Reason: Cytosolic localization is compatible with access to endosomal ubiquitinated substrates. This assessment transfers characterized mammalian biology to the selected horse sequence with the sequence limitations stated in the comparison.
Supporting Evidence:
file:human/USP8/USP8-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}.
file:HORSE/USP8/USP8-bioinformatics/RESULTS.md
The horse sequence A0A9L0T7K6 (1112 residues) aligns to human P40818 (1118 residues) with 91.82% identity across 1112 paired residues. Paired coverage is 99.46% of the human sequence and 100.0% of the horse sequence.
We have identified and characterized a novel human ubiquitin isopeptidase, UBPY, which both as a recombinant protein and upon immunoprecipitation from cell extracts is able to cleave linear or isopeptide-linked ubiquitin chains.
Summary: Plasma-membrane association is a trafficking-related location, secondary to the central deubiquitination mechanism.
Reason: Plasma-membrane association is a trafficking-related location, secondary to the central deubiquitination mechanism. This assessment transfers characterized mammalian biology to the selected horse sequence with the sequence limitations stated in the comparison.
Supporting Evidence:
file:human/USP8/USP8-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}.
file:HORSE/USP8/USP8-bioinformatics/RESULTS.md
The horse sequence A0A9L0T7K6 (1112 residues) aligns to human P40818 (1118 residues) with 91.82% identity across 1112 paired residues. Paired coverage is 99.46% of the human sequence and 100.0% of the horse sequence.
GO:0006511 ubiquitin-dependent protein catabolic process
IEA GO_REF:0000104
ACCEPT
Summary: Deubiquitination regulates ubiquitin-dependent cargo degradation and can participate in catabolism; the term does not assert that USP8 itself proteolyzes the cargo.
Reason: Deubiquitination regulates ubiquitin-dependent cargo degradation and can participate in catabolism; the term does not assert that USP8 itself proteolyzes the cargo. This assessment transfers characterized mammalian biology to the selected horse sequence with the sequence limitations stated in the comparison.
Supporting Evidence:
file:human/USP8/USP8-uniprot.txt
CC -!- FUNCTION: Hydrolase that can remove conjugated ubiquitin from proteins CC and therefore plays an important regulatory role at the level of CC protein turnover by preventing degradation. Converts both 'Lys-48' an CC 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the CC M phase. Involved in cell proliferation. Required to enter into S phase CC in response to serum stimulation. May regulate T-cell anergy mediated CC by RNF128 via the formation of a complex containing RNF128 and OTUB1. CC Probably regulates the stability of STAM2 and RASGRF1. Regulates CC endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early CC endosomes, and maintenance of ESCRT-0 stability. The level of protein CC ubiquitination on endosomes is essential for maintaining the morphology CC of the organelle. Deubiquitinates EPS15 and controls tyrosine kinase CC stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR CC degradation and downstream MAPK signaling. Involved in acrosome CC biogenesis through interaction with the spermatid ESCRT-0 complex and CC microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. CC Deubiquitinates BACE1 which inhibits BACE1 lysosomal degradation and CC modulates BACE-mediated APP cleavage and amyloid-beta formation CC (PubMed:27302062). {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369, CC ECO:0000269|PubMed:27302062, ECO:0000269|PubMed:9628861}.
file:HORSE/USP8/USP8-bioinformatics/RESULTS.md
The horse sequence A0A9L0T7K6 (1112 residues) aligns to human P40818 (1118 residues) with 91.82% identity across 1112 paired residues. Paired coverage is 99.46% of the human sequence and 100.0% of the horse sequence.
We have identified and characterized a novel human ubiquitin isopeptidase, UBPY, which both as a recombinant protein and upon immunoprecipitation from cell extracts is able to cleave linear or isopeptide-linked ubiquitin chains.
Summary: USP8 regulates ubiquitin dynamics and cargo sorting on endosomes.
Reason: USP8 regulates ubiquitin dynamics and cargo sorting on endosomes. This assessment transfers characterized mammalian biology to the selected horse sequence with the sequence limitations stated in the comparison.
Supporting Evidence:
file:human/USP8/USP8-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}.
file:HORSE/USP8/USP8-bioinformatics/RESULTS.md
The horse sequence A0A9L0T7K6 (1112 residues) aligns to human P40818 (1118 residues) with 91.82% identity across 1112 paired residues. Paired coverage is 99.46% of the human sequence and 100.0% of the horse sequence.
We have identified and characterized a novel human ubiquitin isopeptidase, UBPY, which both as a recombinant protein and upon immunoprecipitation from cell extracts is able to cleave linear or isopeptide-linked ubiquitin chains.
Summary: Removal of conjugated ubiquitin is the direct USP8 reaction.
Reason: Removal of conjugated ubiquitin is the direct USP8 reaction. This assessment transfers characterized mammalian biology to the selected horse sequence with the sequence limitations stated in the comparison.
Supporting Evidence:
file:human/USP8/USP8-uniprot.txt
CC -!- FUNCTION: Hydrolase that can remove conjugated ubiquitin from proteins CC and therefore plays an important regulatory role at the level of CC protein turnover by preventing degradation. Converts both 'Lys-48' an CC 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the CC M phase. Involved in cell proliferation. Required to enter into S phase CC in response to serum stimulation. May regulate T-cell anergy mediated CC by RNF128 via the formation of a complex containing RNF128 and OTUB1. CC Probably regulates the stability of STAM2 and RASGRF1. Regulates CC endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early CC endosomes, and maintenance of ESCRT-0 stability. The level of protein CC ubiquitination on endosomes is essential for maintaining the morphology CC of the organelle. Deubiquitinates EPS15 and controls tyrosine kinase CC stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR CC degradation and downstream MAPK signaling. Involved in acrosome CC biogenesis through interaction with the spermatid ESCRT-0 complex and CC microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. CC Deubiquitinates BACE1 which inhibits BACE1 lysosomal degradation and CC modulates BACE-mediated APP cleavage and amyloid-beta formation CC (PubMed:27302062). {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369, CC ECO:0000269|PubMed:27302062, ECO:0000269|PubMed:9628861}.
file:HORSE/USP8/USP8-bioinformatics/RESULTS.md
The horse sequence A0A9L0T7K6 (1112 residues) aligns to human P40818 (1118 residues) with 91.82% identity across 1112 paired residues. Paired coverage is 99.46% of the human sequence and 100.0% of the horse sequence.
We have identified and characterized a novel human ubiquitin isopeptidase, UBPY, which both as a recombinant protein and upon immunoprecipitation from cell extracts is able to cleave linear or isopeptide-linked ubiquitin chains.
Summary: The midbody is a context-specific localization associated with cytokinesis substrates, rather than the main molecular function.
Reason: The midbody is a context-specific localization associated with cytokinesis substrates, rather than the main molecular function. This assessment transfers characterized mammalian biology to the selected horse sequence with the sequence limitations stated in the comparison.
Supporting Evidence:
file:human/USP8/USP8-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866, CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}. CC Endosome membrane {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral CC membrane protein {ECO:0000305}.
file:HORSE/USP8/USP8-bioinformatics/RESULTS.md
The horse sequence A0A9L0T7K6 (1112 residues) aligns to human P40818 (1118 residues) with 91.82% identity across 1112 paired residues. Paired coverage is 99.46% of the human sequence and 100.0% of the horse sequence.
Core Functions
USP8 is a cysteine-type deubiquitinase that removes ubiquitin from protein substrates. It regulates endosomal ubiquitin dynamics, cargo sorting and substrate stability, linking deubiquitination to receptor trafficking and protein turnover.
CC -!- FUNCTION: Hydrolase that can remove conjugated ubiquitin from proteins CC and therefore plays an important regulatory role at the level of CC protein turnover by preventing degradation. Converts both 'Lys-48' an CC 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the CC M phase. Involved in cell proliferation. Required to enter into S phase CC in response to serum stimulation. May regulate T-cell anergy mediated CC by RNF128 via the formation of a complex containing RNF128 and OTUB1. CC Probably regulates the stability of STAM2 and RASGRF1. Regulates CC endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early CC endosomes, and maintenance of ESCRT-0 stability. The level of protein CC ubiquitination on endosomes is essential for maintaining the morphology CC of the organelle. Deubiquitinates EPS15 and controls tyrosine kinase CC stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR CC degradation and downstream MAPK signaling. Involved in acrosome CC biogenesis through interaction with the spermatid ESCRT-0 complex and CC microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. CC Deubiquitinates BACE1 which inhibits BACE1 lysosomal degradation and CC modulates BACE-mediated APP cleavage and amyloid-beta formation CC (PubMed:27302062). {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369, CC ECO:0000269|PubMed:27302062, ECO:0000269|PubMed:9628861}.
file:HORSE/USP8/USP8-bioinformatics/RESULTS.md
The horse sequence A0A9L0T7K6 (1112 residues) aligns to human P40818 (1118 residues) with 91.82% identity across 1112 paired residues. Paired coverage is 99.46% of the human sequence and 100.0% of the horse sequence.
We have identified and characterized a novel human ubiquitin isopeptidase, UBPY, which both as a recombinant protein and upon immunoprecipitation from cell extracts is able to cleave linear or isopeptide-linked ubiquitin chains.
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Assessment of 1 ProtNLM GO predictions for the selected horse USP8 protein, using mammalian experimental findings and an explicit comparison of the horse sequence.
Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.
GO:0006511 ubiquitin-dependent protein catabolic processGO_BP
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: USP8 is a deubiquitinase, but deubiquitination is not incompatible with participation in ubiquitin-dependent protein catabolism. Human USP8 controls endosomal ubiquitin dynamics and cargo sorting, including EGFR degradation, with substrate-specific effects on stability. The horse USP catalytic region is conserved in a sequence with 91.82% identity over 99.46% of the human protein. The existing target GOA term is biologically defensible as pathway participation, not an assertion that USP8 is a protease that directly destroys ubiquitinated substrates. Training-set membership is unknown.
Supporting Evidence:
file:human/USP8/USP8-uniprot.txt: "CC -!- FUNCTION: Hydrolase that can remove conjugated ubiquitin from proteins CC and therefore plays an important regulatory role at the level of CC protein turnover by preventing degradation. Converts both 'Lys-48' an CC 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the CC M phase. Involved in cell proliferation. Required to enter into S phase CC in response to serum stimulation. May regulate T-cell anergy mediated CC by RNF128 via the formation of a complex containing RNF128 and OTUB1. CC Probably regulates the stability of STAM2 and RASGRF1. Regulates CC endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early CC endosomes, and maintenance of ESCRT-0 stability. The level of protein CC ubiquitination on endosomes is essential for maintaining the morphology CC of the organelle. Deubiquitinates EPS15 and controls tyrosine kinase CC stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR CC degradation and downstream MAPK signaling. Involved in acrosome CC biogenesis through interaction with the spermatid ESCRT-0 complex and CC microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1. CC Deubiquitinates BACE1 which inhibits BACE1 lysosomal degradation and CC modulates BACE-mediated APP cleavage and amyloid-beta formation CC (PubMed:27302062). {ECO:0000269|PubMed:16520378, CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369, CC ECO:0000269|PubMed:27302062, ECO:0000269|PubMed:9628861}."
file:HORSE/USP8/USP8-bioinformatics/RESULTS.md: "The horse sequence A0A9L0T7K6 (1112 residues) aligns to human P40818 (1118 residues) with 91.82% identity across 1112 paired residues. Paired coverage is 99.46% of the human sequence and 100.0% of the horse sequence."
PMID:9628861: "We have identified and characterized a novel human ubiquitin isopeptidase, UBPY, which both as a recombinant protein and upon immunoprecipitation from cell extracts is able to cleave linear or isopeptide-linked ubiquitin chains."
📚 Additional Documentation
Notes
(USP8-notes.md)
USP8: paired evidence notes
Human reference: https://www.uniprot.org/uniprotkb/P40818/entry
We have identified and characterized a novel human ubiquitin isopeptidase, UBPY, which both as a recombinant protein and upon immunoprecipitation from cell extracts is able to cleave linear or isopeptide-linked ubiquitin chains.
The horse sequence comparison is in USP8-bioinformatics/RESULTS.md. Transfer is assessed for this exact accession; human biochemical evidence is not equine experimental validation.