UCHL1

UniProt ID: P09936
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

UCHL1 encodes ubiquitin carboxyl-terminal hydrolase isozyme L1, a cytosolic cysteine-type deubiquitinase/omega peptidase that hydrolyzes small ubiquitin C-terminal adducts and helps maintain monoubiquitin pools for ubiquitin-dependent proteostasis. UCHL1 also has substrate- and context-specific roles in LC3/autophagy regulation, alpha-2A adrenergic receptor/MAPK signaling, HIF-1alpha stabilization, glycolysis-linked Parkinson disease models, and Parkin interaction; these are supported non-core contexts rather than replacements for the core UCH activity.

Proposed New Ontology Terms

ATG8-family protein deubiquitination

Definition: A protein deubiquitination process in which ubiquitin is removed from, or ubiquitin-dependent modification of, an ATG8-family protein is regulated to modulate autophagosome formation or autophagy flux.

Justification: The PN context and PMID:29462615 indicate that UCHL1 affects autophagosome formation through DUB activity and interaction with LC3, but current GOA can only capture broad protein deubiquitination or regulation of macroautophagy.

Parent term: protein deubiquitination

Supporting Evidence:

Existing Annotations Review

GO Term Evidence Action Reason
GO:0030163 protein catabolic process
IBA
GO_REF:0000033 		MODIFY
Summary: Protein catabolic process is too broad for UCHL1 and obscures the specific deubiquitination chemistry.
Reason: Replace with protein deubiquitination, the direct process supported by UCH enzymology and Reactome.
Proposed replacements: protein deubiquitination
Supporting Evidence:
Reactome:R-HSA-5688426
Deubiquitinating enzymes (DUBs) catalyze the removal of Ub and regulate Ub-mediated pathways
Reactome:R-HSA-5690319
UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers
PMID:9521656
Ubiquitin C-terminal hydrolases (UCH) are deubiquitinating enzymes which hydrolyze C-terminal esters and amides of ubiquitin
PMID:9521656
to generate free monomeric ubiquitin from ubiquitin proproteins
GO:0004843 cysteine-type deubiquitinase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
PMID:9521656
Ubiquitin C-terminal hydrolases (UCH) are deubiquitinating enzymes which hydrolyze C-terminal esters and amides of ubiquitin
PMID:9521656
to generate free monomeric ubiquitin from ubiquitin proproteins
PMID:8639624
Site-directed mutagenesis of UCH-L1 reveals that C90 and H161 are involved in catalytic rate enhancement
PMID:16475834
UCHs cleave Ub-X bonds (Ub is ubiquitin and X an alcohol, an amine, or a protein)
PMID:20439756
reduces ubiquitin binding and severely impairs the catalytic activity of the enzyme
PMID:23359680
near complete loss of UCHL1 hydrolase activity
Reactome:R-HSA-5690319
UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: UCHL1 is a cytoplasmic/cytosolic enzyme, and cytoplasm is an appropriate cellular location.
Reason: This location is consistent with UniProt, GOA, and receptor-interaction evidence placing UCHL1 in the cytoplasm.
Supporting Evidence:
PMID:19477270
interaction of alpha(2A)AR and Uch-L1 occurred in the cytoplasm
GO:0005789 endoplasmic reticulum membrane
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: A membrane-associated fraction of UCHL1 can localize to the endoplasmic reticulum membrane, but this is not the main site of the soluble UCH catalytic function.
Reason: Retain as a supported non-core localization while keeping cytoplasm/cytosol as the core location.
GO:0006511 ubiquitin-dependent protein catabolic process
IEA
GO_REF:0000120 		MODIFY
Summary: Ubiquitin-dependent protein catabolic process is directionally related but too broad for the direct UCHL1 role.
Reason: UCHL1 removes or processes ubiquitin adducts; protein deubiquitination is the more accurate GO process term.
Proposed replacements: protein deubiquitination
Supporting Evidence:
Reactome:R-HSA-5688426
Deubiquitinating enzymes (DUBs) catalyze the removal of Ub and regulate Ub-mediated pathways
Reactome:R-HSA-5690319
UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers
PMID:9521656
Ubiquitin C-terminal hydrolases (UCH) are deubiquitinating enzymes which hydrolyze C-terminal esters and amides of ubiquitin
PMID:9521656
to generate free monomeric ubiquitin from ubiquitin proproteins
GO:0005515 protein binding
IPI
PMID:12082530
Interaction and colocalization of PGP9.5 with JAB1 and p27(K... 		MARK AS OVER ANNOTATED
Summary: The cited interaction may be real, but generic protein binding is not an informative molecular function for UCHL1.
Reason: UCHL1 should be curated to specific activities or named binding terms where supported, not to generic protein binding from interaction screens.
GO:0005515 protein binding
IPI
PMID:16049941
A pilot proteomic study of amyloid precursor interactors in ... 		MARK AS OVER ANNOTATED
Summary: The cited interaction may be real, but generic protein binding is not an informative molecular function for UCHL1.
Reason: UCHL1 should be curated to specific activities or named binding terms where supported, not to generic protein binding from interaction screens.
GO:0005515 protein binding
IPI
PMID:16169070
A human protein-protein interaction network: a resource for ... 		MARK AS OVER ANNOTATED
Summary: The cited interaction may be real, but generic protein binding is not an informative molecular function for UCHL1.
Reason: UCHL1 should be curated to specific activities or named binding terms where supported, not to generic protein binding from interaction screens.
GO:0005515 protein binding
IPI
PMID:19615732
Defining the human deubiquitinating enzyme interaction lands... 		MARK AS OVER ANNOTATED
Summary: The cited interaction may be real, but generic protein binding is not an informative molecular function for UCHL1.
Reason: UCHL1 should be curated to specific activities or named binding terms where supported, not to generic protein binding from interaction screens.
GO:0005515 protein binding
IPI
PMID:20029029
Regulation of epidermal growth factor receptor trafficking b... 		MARK AS OVER ANNOTATED
Summary: The cited interaction may be real, but generic protein binding is not an informative molecular function for UCHL1.
Reason: UCHL1 should be curated to specific activities or named binding terms where supported, not to generic protein binding from interaction screens.
GO:0005515 protein binding
IPI
PMID:21044950
Genome-wide YFP fluorescence complementation screen identifi... 		MARK AS OVER ANNOTATED
Summary: The cited interaction may be real, but generic protein binding is not an informative molecular function for UCHL1.
Reason: UCHL1 should be curated to specific activities or named binding terms where supported, not to generic protein binding from interaction screens.
GO:0005515 protein binding
IPI
PMID:23543736
Ubiquitin C-terminal hydrolase L1 (UCH-L1) acts as a novel p... 		MARK AS OVER ANNOTATED
Summary: The cited interaction may be real, but generic protein binding is not an informative molecular function for UCHL1.
Reason: UCHL1 should be curated to specific activities or named binding terms where supported, not to generic protein binding from interaction screens.
GO:0005515 protein binding
IPI
PMID:31980649
Extensive rewiring of the EGFR network in colorectal cancer ... 		MARK AS OVER ANNOTATED
Summary: The cited interaction may be real, but generic protein binding is not an informative molecular function for UCHL1.
Reason: UCHL1 should be curated to specific activities or named binding terms where supported, not to generic protein binding from interaction screens.
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		MARK AS OVER ANNOTATED
Summary: The cited interaction may be real, but generic protein binding is not an informative molecular function for UCHL1.
Reason: UCHL1 should be curated to specific activities or named binding terms where supported, not to generic protein binding from interaction screens.
GO:0005654 nucleoplasm
IDA
GO_REF:0000052 		KEEP AS NON CORE
Summary: Nucleoplasm is a high-throughput immunofluorescence location and not the main compartment for UCHL1 catalytic function.
Reason: Retain as non-core localization context because the strongest functional evidence supports cytoplasmic/cytosolic deubiquitinase activity.
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: Cytosol is an appropriate core cellular location for soluble UCHL1 deubiquitinase activity.
Reason: UCHL1 is described as a cytoplasmic/cytosolic neuronal deubiquitinase; Reactome also places the UCHL1 reaction in this context.
Supporting Evidence:
PMID:19477270
interaction of alpha(2A)AR and Uch-L1 occurred in the cytoplasm
GO:0016579 protein deubiquitination
TAS
Reactome:R-HSA-5688426 		ACCEPT
Summary: UCHL1 participates in protein deubiquitination through hydrolysis of ubiquitin C-terminal adducts and recycling of monoubiquitin.
Reason: Protein deubiquitination is the correct biological-process framing for the core UCHL1 catalytic activity.
Supporting Evidence:
Reactome:R-HSA-5688426
Deubiquitinating enzymes (DUBs) catalyze the removal of Ub and regulate Ub-mediated pathways
Reactome:R-HSA-5690319
UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers
PMID:9521656
Ubiquitin C-terminal hydrolases (UCH) are deubiquitinating enzymes which hydrolyze C-terminal esters and amides of ubiquitin
PMID:9521656
to generate free monomeric ubiquitin from ubiquitin proproteins
GO:0004843 cysteine-type deubiquitinase activity
TAS
Reactome:R-HSA-5690319 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
Reactome:R-HSA-5690319
UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers
GO:0004843 cysteine-type deubiquitinase activity
EXP
PMID:12408865
The UCH-L1 gene encodes two opposing enzymatic activities th... 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
PMID:12408865
comparable hydrolase activity as the wild-type enzyme
GO:0004843 cysteine-type deubiquitinase activity
EXP
PMID:12705903
Alterations of structure and hydrolase activity of parkinson... 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
PMID:12705903
examined their structure (using circular dichroism) and hydrolase activities
GO:0004843 cysteine-type deubiquitinase activity
EXP
PMID:16475834
Mechanistic studies of ubiquitin C-terminal hydrolase L1. 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
PMID:16475834
UCHs cleave Ub-X bonds (Ub is ubiquitin and X an alcohol, an amine, or a protein)
GO:0004843 cysteine-type deubiquitinase activity
EXP
PMID:20439756
Ubiquitin vinyl methyl ester binding orients the misaligned ... 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
PMID:20439756
reduces ubiquitin binding and severely impairs the catalytic activity of the enzyme
GO:0004843 cysteine-type deubiquitinase activity
EXP
PMID:23359680
Recessive loss of function of the neuronal ubiquitin hydrola... 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
PMID:23359680
near complete loss of UCHL1 hydrolase activity
GO:0004843 cysteine-type deubiquitinase activity
EXP
PMID:25615526
UCHL1 provides diagnostic and antimetastatic strategies due ... 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
PMID:25615526
UCHL1 promotes metastases as a deubiquitinating enzyme for HIF-1ฮฑ
GO:0004843 cysteine-type deubiquitinase activity
EXP
PMID:8639624
Substrate binding and catalysis by ubiquitin C-terminal hydr... 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
PMID:8639624
Site-directed mutagenesis of UCH-L1 reveals that C90 and H161 are involved in catalytic rate enhancement
GO:0004843 cysteine-type deubiquitinase activity
EXP
PMID:9774100
The ubiquitin pathway in Parkinson's disease. 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
PMID:9521656
Ubiquitin C-terminal hydrolases (UCH) are deubiquitinating enzymes which hydrolyze C-terminal esters and amides of ubiquitin
PMID:9521656
to generate free monomeric ubiquitin from ubiquitin proproteins
PMID:8639624
Site-directed mutagenesis of UCH-L1 reveals that C90 and H161 are involved in catalytic rate enhancement
PMID:16475834
UCHs cleave Ub-X bonds (Ub is ubiquitin and X an alcohol, an amine, or a protein)
PMID:20439756
reduces ubiquitin binding and severely impairs the catalytic activity of the enzyme
PMID:23359680
near complete loss of UCHL1 hydrolase activity
Reactome:R-HSA-5690319
UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers
GO:0030547 signaling receptor inhibitor activity
IDA
PMID:19477270
Interaction of the ubiquitin carboxyl terminal esterase L1 w... 		KEEP AS NON CORE
Summary: UCHL1 inhibits alpha-2 adrenergic receptor agonist-mediated p44/42 MAPK activation in the cited receptor study.
Reason: This is a specific signaling side context and not the conserved core UCH enzymatic function.
Supporting Evidence:
PMID:19477270
Uch-L1 binds preferentially to the alpha(2A)AR subtype
PMID:19477270
p44/42 MAP Kinase was drastically decreased in the presence of Uch-L1
GO:0043409 negative regulation of MAPK cascade
IDA
PMID:19477270
Interaction of the ubiquitin carboxyl terminal esterase L1 w... 		KEEP AS NON CORE
Summary: UCHL1 interaction with alpha-2A adrenergic receptor decreases agonist-mediated p44/42 MAPK activation.
Reason: Retain as a supported non-core receptor/signaling process downstream of a specific interaction.
Supporting Evidence:
PMID:19477270
Uch-L1 binds preferentially to the alpha(2A)AR subtype
PMID:19477270
p44/42 MAP Kinase was drastically decreased in the presence of Uch-L1
GO:0004843 cysteine-type deubiquitinase activity
IMP
PMID:34244144
Loss of UCHL1 rescues the defects related to Parkinson's dis... 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
PMID:34244144
The DUB activity of each UCHL1 or UCH mutant protein was measured using a DUB activity assay kit
GO:0045821 positive regulation of glycolytic process
IMP
PMID:34244144
Loss of UCHL1 rescues the defects related to Parkinson's dis... 		KEEP AS NON CORE
Summary: UCHL1 loss reduces glycolytic metabolites and destabilizes PKM in Parkinson disease models, implying that UCHL1 can support glycolysis in that context.
Reason: This is a supported disease/metabolic context, but not the core UCHL1 deubiquitinase function.
Supporting Evidence:
PMID:34244144
loss of UCHL1 destabilizes pyruvate kinase (PKM)
PMID:34244144
specific glycolytic metabolites are decreased
GO:0004843 cysteine-type deubiquitinase activity
IDA
PMID:9521656
Substrate specificity of deubiquitinating enzymes: ubiquitin... 		ACCEPT
Summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin C-terminal hydrolase activity.
Reason: This is the conserved catalytic function of UCHL1 and is supported by enzymology, variant, structural, Reactome, and substrate-specific studies.
Supporting Evidence:
PMID:9521656
Ubiquitin C-terminal hydrolases (UCH) are deubiquitinating enzymes which hydrolyze C-terminal esters and amides of ubiquitin
GO:0005829 cytosol
TAS
Reactome:R-HSA-5690319 		ACCEPT
Summary: Cytosol is an appropriate core cellular location for soluble UCHL1 deubiquitinase activity.
Reason: UCHL1 is described as a cytoplasmic/cytosolic neuronal deubiquitinase; Reactome also places the UCHL1 reaction in this context.
Supporting Evidence:
PMID:19477270
interaction of alpha(2A)AR and Uch-L1 occurred in the cytoplasm
GO:0016241 regulation of macroautophagy
TAS
PMID:24879150
UCHL1 deficiency exacerbates human islet amyloid polypeptide... 		KEEP AS NON CORE
Summary: UCHL1 affects autophagosome formation and autophagy/lysosomal pathway readouts, including LC3 puncta and beta-cell proteotoxicity models.
Reason: This is a real proteostasis context, but the direct function is deubiquitination rather than core autophagy machinery activity.
Supporting Evidence:
PMID:29462615
UCHL1 overexpression inhibits LC3 puncta formation and is dependent on its DUB activity
PMID:29462615
UCHL1 may affect autophagy by interacting with LC3
PMID:24879150
UCHL1 dysfunction aggravated the hIAPP-induced defect in the autophagy/lysosomal pathway
GO:0031625 ubiquitin protein ligase binding
IPI
PMID:19725078
Proteomic analysis of increased Parkin expression and its in... 		KEEP AS NON CORE
Summary: UCHL1 was identified as a potential Parkin interactor in a Parkin proteomic study.
Reason: Retain as non-core interaction context; UCHL1 is not itself an E3 ligase, and the core activity remains deubiquitinase/UCH activity.
Supporting Evidence:
PMID:19725078
Tandem affinity purification/MS revealed 14 potential interactants of Parkin; CKB, DBT, HSPD1, HSPA9, LRPPRC, NDUFS2, PRDX6, SLC25A5, TPI1, UCHL1, UQCRC1, VCL, YWHAZ, YWHAE
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
NAS
PMID:24252804
The role of oxidative stress in Parkinson's disease. 		KEEP AS NON CORE
Summary: UCHL1 participates in ubiquitin homeostasis that can influence proteasome-mediated protein catabolism.
Reason: Retain as non-core pathway context because the direct mechanism is ubiquitin adduct hydrolysis/protein deubiquitination, and the cited PMID is a broad Parkinson oxidative-stress review.
Supporting Evidence:
Reactome:R-HSA-5688426
Deubiquitinating enzymes (DUBs) catalyze the removal of Ub and regulate Ub-mediated pathways
Reactome:R-HSA-5690319
UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers
PMID:24252804
cellular homeostatic processes including the ubiquitin-proteasome system and mitophagy are impacted by oxidative stress
GO:0005737 cytoplasm
IDA
PMID:19477270
Interaction of the ubiquitin carboxyl terminal esterase L1 w... 		ACCEPT
Summary: UCHL1 is a cytoplasmic/cytosolic enzyme, and cytoplasm is an appropriate cellular location.
Reason: This location is consistent with UniProt, GOA, and receptor-interaction evidence placing UCHL1 in the cytoplasm.
Supporting Evidence:
PMID:19477270
interaction of alpha(2A)AR and Uch-L1 occurred in the cytoplasm
GO:0005886 plasma membrane
IDA
PMID:19477270
Interaction of the ubiquitin carboxyl terminal esterase L1 w... 		KEEP AS NON CORE
Summary: UCHL1 colocalization with plasma membrane in the receptor study reflects alpha-2A adrenergic receptor interaction context rather than the main UCHL1 compartment.
Reason: Retain as non-core localization; cytoplasm/cytosol are the better supported core locations.
Supporting Evidence:
PMID:19477270
Uch-L1 binds preferentially to the alpha(2A)AR subtype
PMID:19477270
p44/42 MAP Kinase was drastically decreased in the presence of Uch-L1
GO:0031694 alpha-2A adrenergic receptor binding
IPI
PMID:19477270
Interaction of the ubiquitin carboxyl terminal esterase L1 w... 		KEEP AS NON CORE
Summary: UCHL1 binds preferentially to the alpha-2A adrenergic receptor subtype in the cited study.
Reason: This is a specific, supported binding function but is a non-core receptor/signaling context relative to UCHL1 deubiquitinase activity.
Supporting Evidence:
PMID:19477270
Uch-L1 binds preferentially to the alpha(2A)AR subtype
PMID:19477270
p44/42 MAP Kinase was drastically decreased in the presence of Uch-L1
GO:0005737 cytoplasm
TAS
PMID:16130169
Proteomics of human umbilical vein endothelial cells applied... 		ACCEPT
Summary: UCHL1 is a cytoplasmic/cytosolic enzyme, and cytoplasm is an appropriate cellular location.
Reason: This location is consistent with UniProt, GOA, and receptor-interaction evidence placing UCHL1 in the cytoplasm.
Supporting Evidence:
PMID:19477270
interaction of alpha(2A)AR and Uch-L1 occurred in the cytoplasm
GO:0005737 cytoplasm
ISS
GO_REF:0000024 		ACCEPT
Summary: UCHL1 is a cytoplasmic/cytosolic enzyme, and cytoplasm is an appropriate cellular location.
Reason: This location is consistent with UniProt, GOA, and receptor-interaction evidence placing UCHL1 in the cytoplasm.
Supporting Evidence:
PMID:19477270
interaction of alpha(2A)AR and Uch-L1 occurred in the cytoplasm
GO:0004197 cysteine-type endopeptidase activity
IDA
PMID:8639624
Substrate binding and catalysis by ubiquitin C-terminal hydr... 		MODIFY
Summary: Cysteine-type endopeptidase activity is too broad for UCHL1 and does not capture the ubiquitin C-terminal specificity.
Reason: Replace with cysteine-type deubiquitinase activity, the specific cysteine protease activity supported by the same active-site evidence.
Supporting Evidence:
PMID:8639624
Site-directed mutagenesis of UCH-L1 reveals that C90 and H161 are involved in catalytic rate enhancement
GO:0008242 omega peptidase activity
IDA
PMID:9521656
Substrate specificity of deubiquitinating enzymes: ubiquitin... 		ACCEPT
Summary: UCHL1 has omega peptidase / ubiquitin C-terminal hydrolase activity, cleaving small adducts from the C-terminus of ubiquitin.
Reason: This term captures the C-terminal peptidase chemistry of the core UCHL1 enzymatic function.
Supporting Evidence:
PMID:9521656
cleave small leaving groups such as amino acids and oligopeptides from the C-terminus of ubiquitin
GO:0016579 protein deubiquitination
IDA
PMID:9521656
Substrate specificity of deubiquitinating enzymes: ubiquitin... 		ACCEPT
Summary: UCHL1 participates in protein deubiquitination through hydrolysis of ubiquitin C-terminal adducts and recycling of monoubiquitin.
Reason: Protein deubiquitination is the correct biological-process framing for the core UCHL1 catalytic activity.
Supporting Evidence:
Reactome:R-HSA-5688426
Deubiquitinating enzymes (DUBs) catalyze the removal of Ub and regulate Ub-mediated pathways
Reactome:R-HSA-5690319
UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers
PMID:9521656
Ubiquitin C-terminal hydrolases (UCH) are deubiquitinating enzymes which hydrolyze C-terminal esters and amides of ubiquitin
PMID:9521656
to generate free monomeric ubiquitin from ubiquitin proproteins
GO:0043130 ubiquitin binding
IDA
PMID:9521656
Substrate specificity of deubiquitinating enzymes: ubiquitin... 		KEEP AS NON CORE
Summary: UCHL1 binds ubiquitin as the substrate for its C-terminal hydrolase reaction.
Reason: Retain as a substrate-binding context, but the core molecular function should be deubiquitinase/UCH catalytic activity rather than binding alone.
Supporting Evidence:
PMID:8639624
indicates the existence of a specific and extensive binding site for ubiquitin on the surface of the enzyme

Core Functions

Cytosolic ubiquitin C-terminal hydrolase activity that cleaves small ubiquitin C-terminal adducts/proproteins to recycle monomeric ubiquitin and support ubiquitin-dependent proteostasis.

Molecular Function:
cysteine-type deubiquitinase activity
Directly Involved In:
protein deubiquitination
Cellular Locations:
cytosol cytoplasm
Supporting Evidence:
  • PMID:9521656
    Ubiquitin C-terminal hydrolases (UCH) are deubiquitinating enzymes which hydrolyze C-terminal esters and amides of ubiquitin
  • PMID:9521656
    to generate free monomeric ubiquitin from ubiquitin proproteins
  • PMID:8639624
    Site-directed mutagenesis of UCH-L1 reveals that C90 and H161 are involved in catalytic rate enhancement
  • PMID:16475834
    UCHs cleave Ub-X bonds (Ub is ubiquitin and X an alcohol, an amine, or a protein)
  • PMID:20439756
    reduces ubiquitin binding and severely impairs the catalytic activity of the enzyme
  • PMID:23359680
    near complete loss of UCHL1 hydrolase activity
  • Reactome:R-HSA-5690319
    UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers
  • Reactome:R-HSA-5688426
    Deubiquitinating enzymes (DUBs) catalyze the removal of Ub and regulate Ub-mediated pathways
  • Reactome:R-HSA-5690319
    UCHL1 and UCHL3 can hydrolyze several short C-terminal ubiquitin adducts to generate ubiquitin monomers

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
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:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:12082530
Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1).
PMID:12408865
The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility.
PMID:12705903
Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants.
PMID:16049941
A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease.
PMID:16130169
Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.
PMID:16169070
A human protein-protein interaction network: a resource for annotating the proteome.
PMID:16475834
Mechanistic studies of ubiquitin C-terminal hydrolase L1.
PMID:19477270
Interaction of the ubiquitin carboxyl terminal esterase L1 with alpha(2)-adrenergic receptors inhibits agonist-mediated p44/42 MAP kinase activation.
PMID:19615732
Defining the human deubiquitinating enzyme interaction landscape.
PMID:19725078
Proteomic analysis of increased Parkin expression and its interactants provides evidence for a role in modulation of mitochondrial function.
PMID:20029029
Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
PMID:20439756
Ubiquitin vinyl methyl ester binding orients the misaligned active site of the ubiquitin hydrolase UCHL1 into productive conformation.
PMID:21044950
Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.
PMID:23359680
Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.
PMID:23543736
Ubiquitin C-terminal hydrolase L1 (UCH-L1) acts as a novel potentiator of cyclin-dependent kinases to enhance cell proliferation independently of its hydrolase activity.
PMID:24252804
The role of oxidative stress in Parkinson's disease.
PMID:24879150
UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in ฮฒ-cells: evidence of interplay between the ubiquitin/proteasome system and autophagy.
PMID:25615526
UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1ฮฑ.
PMID:31980649
Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:34244144
Loss of UCHL1 rescues the defects related to Parkinson's disease by suppressing glycolysis.
PMID:8639624
Substrate binding and catalysis by ubiquitin C-terminal hydrolases: identification of two active site residues.
PMID:9521656
Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases.
PMID:9774100
The ubiquitin pathway in Parkinson's disease.
Reactome:R-HSA-5688426
Deubiquitination
Reactome:R-HSA-5690319
UCHL1, UCHL3 cleave ubiquitin adducts
PMID:29462615
Ubiquitin C-Terminal Hydrolase L1 regulates autophagy by inhibiting autophagosome formation through its deubiquitinating enzyme activity.

Suggested Questions for Experts

Q: Should UCHL1 be annotated to a new ATG8-family protein deubiquitination term when the substrate/context is LC3-dependent autophagosome formation?

Suggested experts: Yanfen Liu, Cong Yan, GO autophagy editors

Q: Should UCHL1 catalytic activity be represented primarily by cysteine-type deubiquitinase activity, omega peptidase activity, or a more specific ubiquitin C-terminal hydrolase term?

Suggested experts: Keith D. Wilkinson, Catherine Larsen, GO molecular function editors

Q: Which UCHL1 substrate-specific contexts, such as HIF-1alpha, EGFR/BACE1, alpha-2A adrenergic receptor signaling, or PKM/glycolysis, should remain gene-level non-core annotations?

Suggested experts: Harada Hiraoka, Brendie Weber, GO proteostasis editors

Suggested Experiments

Experiment: Map LC3 ubiquitination sites and test whether catalytically inactive UCHL1, I93M UCHL1, and substrate-binding mutants alter LC3 ubiquitination, LC3 puncta, and autophagy flux in matched rescue cells.

Hypothesis: UCHL1 regulates autophagosome formation by deubiquitinating LC3/ATG8-family proteins or an LC3-proximal substrate.

Type: substrate mapping and autophagy flux rescue assay

Experiment: Compare Ub-AMC, ubiquitin proprotein, small ubiquitin adduct, and ubiquitinated protein substrates across UCHL1 variants to separate omega-peptidase/proprotein processing from protein deubiquitination.

Hypothesis: UCHL1 core activity is optimized for small ubiquitin C-terminal adducts, while substrate-specific protein deubiquitination depends on cellular context or binding partners.

Type: comparative enzymology

Experiment: Use substrate-selective UCHL1 mutants in neuronal and cancer-cell models to test whether LC3/autophagy, HIF-1alpha stabilization, PKM/glycolysis, and alpha-2A receptor/MAPK effects can be separated genetically.

Hypothesis: UCHL1 non-core pathway annotations reflect separable substrate contexts built on the same core deubiquitinase activity.

Type: domain-function and substrate-specific rescue

๐Ÿ“š Additional Documentation

Notes

(UCHL1-notes.md)

UCHL1 review notes

Review context

UCHL1 appears in the proteostasis network under direct ATG8-homolog processing
and under the broader UPS UCH deubiquitinase class. The workbook row was used as
triage context; the LC3/autophagy source was resolved to PMID:29462615 and
cached before being used as evidence.

Falcon deep research: just deep-research-falcon human UCHL1 timed out after
600s with Provider falcon timed out after 600s; no Falcon findings were
available to incorporate into this review.

Core function synthesis

UCHL1 encodes ubiquitin carboxyl-terminal hydrolase isozyme L1, a cysteine-type
deubiquitinase / ubiquitin C-terminal hydrolase. UniProt summarizes the core
reaction as thiol-dependent hydrolysis of bonds formed by the C-terminal glycine
of ubiquitin and notes that UCHL1 maintains a monoubiquitin pool important for
UPS and autophagy-lysosome pathways [UniProt:P09936 "recognizes and hydrolyzes
a peptide bond at the C-terminal glycine of ubiquitin"; UniProt:P09936 "to
maintain a stable pool of monoubiquitin"].

Classic enzymology supports this core function. UCH proteins are described as
deubiquitinating enzymes that hydrolyze C-terminal esters and amides of ubiquitin
PMID:9521656. The same study
concludes that UCH enzymes preferentially cleave small leaving groups from
ubiquitin and generate free monomeric ubiquitin from ubiquitin proproteins
PMID:9521656.
Active-site work on UCH-L1 identified catalytic C90 and H161, supporting the
cysteine protease mechanism PMID:8639624. Variant,
mechanistic, and structure papers further support hydrolase activity and ubiquitin
binding [PMID:12705903 "examined their structure (using circular dichroism) and
hydrolase activities"; PMID:16475834 "UCHs cleave Ub-X bonds"; PMID:20439756
"Mutation of the distal-site, surface-exposed phenylalanine to alanine reduces
ubiquitin binding and severely impairs the catalytic activity of the enzyme";
PMID:23359680 "near complete loss of UCHL1 hydrolase activity"].

Proteostasis and autophagy context

UCHL1 has a direct autophagy-related context through LC3. The 2018 BBRC paper
reports that UCHL1 overexpression inhibits LC3 puncta/autophagosome formation,
that this depends on DUB activity, and that UCHL1 affects autophagy by interacting
with LC3 [PMID:29462615 "UCHL1 overexpression inhibits LC3 puncta formation and
is dependent on its DUB activity"; PMID:29462615 "UCHL1 may affect autophagy by
interacting with LC3"]. This supports regulation of macroautophagy as a real but
context-specific non-core process and supports a possible future ATG8-family
protein deubiquitination term.

Another cached autophagy paper shows that UCHL1 deficiency worsens hIAPP-induced
autophagy/lysosomal defects in beta cells PMID:24879150. This
supports keeping autophagy/lysosome pathway effects as non-core proteostasis
context rather than treating UCHL1 as a core autophagy machinery component.

Protein catabolism and proteasome-mediated catabolism annotations should be
interpreted through the more specific protein deubiquitination and monoubiquitin
maintenance functions. Broad protein catabolic process annotations are too vague
for the direct UCH enzymology.

Side contexts

UCHL1 interacts with alpha-2A adrenergic receptor and inhibits agonist-mediated
p44/42 MAPK activation [PMID:19477270 "Uch-L1 binds preferentially to the
alpha(2A)AR subtype"; PMID:19477270 "alpha(2)AR agonist mediated activation of
p44/42 MAP Kinase was drastically decreased in the presence of Uch-L1"]. These
specific receptor binding / signaling inhibitor annotations are supported but
non-core.

UCHL1 also has cancer/metabolism and Parkinson disease model contexts, including
HIF-1alpha deubiquitination and glycolysis-linked PD phenotypes [PMID:25615526
"UCHL1 promotes metastases as a deubiquitinating enzyme for HIF-1ฮฑ"; PMID:34244144
"loss of UCHL1 destabilizes pyruvate kinase (PKM)"]. These are direct substrate
or pathway contexts but not the conserved core function.

The many protein binding rows should not be retained as core molecular
functions. The evidence points to specific interactions such as COPS5/JAB1,
Parkin, alpha-2A adrenergic receptor, EGFR-network proteins, and large
neurodegeneration interactomes, but generic protein binding does not describe
UCHL1's biochemical role.

Pn Notes

(UCHL1-pn-notes.md)

UCHL1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: P09936
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-pr-1217 (PR 1217)
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: UCHL1 encodes ubiquitin carboxyl-terminal hydrolase isozyme L1, a cytosolic cysteine-type deubiquitinase/omega peptidase that hydrolyzes small ubiquitin C-terminal adducts and helps maintain monoubiquitin pools for ubiquitin-dependent proteostasis. UCHL1 also has substrate- and context-specific roles in LC3/autophagy regulation, alpha-2A adrenergic receptor/MAPK signaling, HIF-1alpha stabilization, glycolysis-linked Parkinson disease models, and Parkin interaction; these are supported non-core contexts rather than replacements for the core UCH activity.
  • Existing/core annotation action counts: ACCEPT: 21; KEEP_AS_NON_CORE: 11; MARK_AS_OVER_ANNOTATED: 9; MODIFY: 3

PN Consistency Summary

  • Consistency: Consistent. Deep research, review, and PN agree the core function is cysteine-type DUB / ubiquitin C-terminal hydrolase activity (GO:0004843) acting in protein deubiquitination (GO:0016579), with a substrate/context-specific LC3/autophagy branch. The review treats LC3/autophagy (GO:0016241 regulation of macroautophagy) as KEEP_AS_NON_CORE, matching the PN's "inhibits autophagosome formation through DUB activity" framing.
  • PN story / NEW pressure: The ALP node "Deubiquitination of ATG8 homologs" describes a function GO cannot express specifically โ€” the review proposes a NEW term "ATG8-family protein deubiquitination" (parent GO:0016579), justified by PMID:29462615. OLS search returns no existing GO term for ATG8/LC3 deubiquitination, so this is a genuine candidate (verified absent). Verdict: the ATG8-DUB story is real but only loosely captured by broad GO:0016579 today; defensible NEW candidate (unverified as an existing term, correctly proposed not asserted).
  • Evidence alignment: PN ALP cites PMID:29462615 (UCHL1 inhibits autophagosome formation via DUB) โ€” present in the review supporting the autophagy non-core annotation. PN UPS row is domain-based (IPR001578), matched by the review's deep enzymology set (PMID:9521656, 8639624, 16475834, 20439756, 23359680). Good overlap.
  • Verdict: Consistent; the only actionable item is the proposed ATG8-family-deubiquitination NEW term (candidate, no existing GO equivalent) and the GO:0101005-vs-GO:0004843 granularity note.

Full Consistency Review

  • UniProt: P09936 ยท batch: proteostasis-pr-1217 ยท review status: COMPLETE
  • PN placement: ALP โ€ฆ|ATG8 homolog processing, direct|Deubiquitination of ATG8 homologs + UPS DUBs and UBL demodifiers|UCH ; PN-node mapping: ALP type mapped GO:0016579 protein deubiquitination (already_in_goa_exact); UPS group mapped GO:0101005 deubiquitinase activity (entailed_by_goa_closure).
  • Consistency: Consistent. Deep research, review, and PN agree the core function is cysteine-type DUB / ubiquitin C-terminal hydrolase activity (GO:0004843) acting in protein deubiquitination (GO:0016579), with a substrate/context-specific LC3/autophagy branch. The review treats LC3/autophagy (GO:0016241 regulation of macroautophagy) as KEEP_AS_NON_CORE, matching the PN's "inhibits autophagosome formation through DUB activity" framing.
  • PN story / NEW pressure: The ALP node "Deubiquitination of ATG8 homologs" describes a function GO cannot express specifically โ€” the review proposes a NEW term "ATG8-family protein deubiquitination" (parent GO:0016579), justified by PMID:29462615. OLS search returns no existing GO term for ATG8/LC3 deubiquitination, so this is a genuine candidate (verified absent). Verdict: the ATG8-DUB story is real but only loosely captured by broad GO:0016579 today; defensible NEW candidate (unverified as an existing term, correctly proposed not asserted).
  • Mapping strategy: This gene does not change the node scope. PN maps the ALP type to the broad parent GO:0016579 because no ATG8-specific term exists โ€” consistent with the review. Minor mismatch: PN's UPS group projects GO:0101005 deubiquitinase activity, whereas GOA/review use the child GO:0004843 cysteine-type deubiquitinase activity; entailed_by_goa_closure correctly reflects that GO:0004843 entails GO:0101005, so no conflict.
  • Evidence alignment: PN ALP cites PMID:29462615 (UCHL1 inhibits autophagosome formation via DUB) โ€” present in the review supporting the autophagy non-core annotation. PN UPS row is domain-based (IPR001578), matched by the review's deep enzymology set (PMID:9521656, 8639624, 16475834, 20439756, 23359680). Good overlap.
  • Verdict: Consistent; the only actionable item is the proposed ATG8-family-deubiquitination NEW term (candidate, no existing GO equivalent) and the GO:0101005-vs-GO:0004843 granularity note.

PN Dossier Context

  • review_batch: proteostasis-pr-1217
  • review_yaml: genes/human/UCHL1/UCHL1-ai-review.yaml
  • PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Autophagophore initiation and elongation | ATG8 homolog processing, direct | Deubiquitination of ATG8 homologs

  • UniProt: P09936
  • In branches: ALP, UPS
  • Notes: Deubiquitinase that interacts with LC3 proteins to inhibit autophagosome formation
  • PN references (titles):
    • Ubiquitin C-Terminal Hydrolase L1 regulates autophagy by inhibiting autophagosome formation through its deubiquitinating enzyme activity - ScienceDirect
  • PN-node mapping records (path + ancestors):
    • [type] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|ATG8 homolog processing, direct|Deubiquitination of ATG8 homologs
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0016579 protein deubiquitination]
      rationale: This PN type denotes deubiquitination of ATG8-family proteins within the autophagy pathway. GO does not currently provide an ATG8-specific deubiquitination term, so the defensible target is the broader parent process protein deubiquitination.
    • [group] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|ATG8 homolog processing, direct
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Autophagophore initiation and elongation
      status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
      rationale: This class is a real macroautophagy context, but its descendants include core factors, component buckets, upstream modulators, localization roles, and residual categories. Projecting generic macroautophagy from this ancestor creates TRAPP-like overpropagation, so candidate GO annotations must come from narrower curated nodes.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Ubiquitin Proteasome System | DUBs and UBL demodifiers | UCH

  • UniProt: P09936
  • In branches: ALP, UPS
  • Signature domains: IPR001578
  • Auxiliary domains: (none)
  • PN-node mapping records (path + ancestors):
    • [group] Ubiquitin Proteasome System|DUBs and UBL demodifiers|UCH
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0101005 deubiquitinase activity]
      rationale: This PN group is an active deubiquitinase family bucket. The shared molecular-function assertion is deubiquitinase activity.
    • [class] Ubiquitin Proteasome System|DUBs and UBL demodifiers
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (2)

  • GO:0016579 protein deubiquitination | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Autophagophore initiation and elongation|ATG8 homolog processing, direct|Deubiquitination of ATG8 homologs
  • GO:0101005 deubiquitinase activity | scope=ok_for_propagation_to_go | goa_status=entailed_by_goa_closure | from=Ubiquitin Proteasome System|DUBs and UBL demodifiers|UCH

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

๐Ÿ“„ View Raw YAML

 
id: P09936
gene_symbol: UCHL1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'UCHL1 encodes ubiquitin carboxyl-terminal hydrolase isozyme L1, a cytosolic
  cysteine-type deubiquitinase/omega peptidase that hydrolyzes small ubiquitin C-terminal
  adducts and helps maintain monoubiquitin pools for ubiquitin-dependent proteostasis.
  UCHL1 also has substrate- and context-specific roles in LC3/autophagy regulation,
  alpha-2A adrenergic receptor/MAPK signaling, HIF-1alpha stabilization, glycolysis-linked
  Parkinson disease models, and Parkin interaction; these are supported non-core contexts
  rather than replacements for the core UCH activity.'
alternative_products:
- name: '1'
  id: P09936-1
- name: '2'
  id: P09936-2
  sequence_note: VSP_062524
- name: '3'
  id: P09936-3
  sequence_note: VSP_062523
existing_annotations:
- term:
    id: GO:0030163
    label: protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Protein catabolic process is too broad for UCHL1 and obscures the 
      specific deubiquitination chemistry.
    action: MODIFY
    reason: Replace with protein deubiquitination, the direct process supported 
      by UCH enzymology and Reactome.
    proposed_replacement_terms:
    - id: GO:0016579
      label: protein deubiquitination
    additional_reference_ids:
    - PMID:9521656
    - Reactome:R-HSA-5688426
    supported_by:
    - reference_id: Reactome:R-HSA-5688426
      supporting_text: Deubiquitinating enzymes (DUBs) catalyze the removal of 
        Ub and regulate Ub-mediated pathways
    - reference_id: Reactome:R-HSA-5690319
      supporting_text: UCHL1 and UCHL3 can hydrolyze several short C-terminal 
        ubiquitin adducts to generate ubiquitin monomers
    - reference_id: PMID:9521656
      supporting_text: Ubiquitin C-terminal hydrolases (UCH) are 
        deubiquitinating enzymes which hydrolyze C-terminal esters and amides of
        ubiquitin
    - reference_id: PMID:9521656
      supporting_text: to generate free monomeric ubiquitin from ubiquitin 
        proproteins
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: PMID:9521656
      supporting_text: Ubiquitin C-terminal hydrolases (UCH) are 
        deubiquitinating enzymes which hydrolyze C-terminal esters and amides of
        ubiquitin
    - reference_id: PMID:9521656
      supporting_text: to generate free monomeric ubiquitin from ubiquitin 
        proproteins
    - reference_id: PMID:8639624
      supporting_text: Site-directed mutagenesis of UCH-L1 reveals that C90 and 
        H161 are involved in catalytic rate enhancement
    - reference_id: PMID:16475834
      supporting_text: UCHs cleave Ub-X bonds (Ub is ubiquitin and X an alcohol,
        an amine, or a protein)
    - reference_id: PMID:20439756
      supporting_text: reduces ubiquitin binding and severely impairs the 
        catalytic activity of the enzyme
    - reference_id: PMID:23359680
      supporting_text: near complete loss of UCHL1 hydrolase activity
    - reference_id: Reactome:R-HSA-5690319
      supporting_text: UCHL1 and UCHL3 can hydrolyze several short C-terminal 
        ubiquitin adducts to generate ubiquitin monomers
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UCHL1 is a cytoplasmic/cytosolic enzyme, and cytoplasm is an 
      appropriate cellular location.
    action: ACCEPT
    reason: This location is consistent with UniProt, GOA, and 
      receptor-interaction evidence placing UCHL1 in the cytoplasm.
    additional_reference_ids:
    - PMID:19477270
    supported_by:
    - reference_id: PMID:19477270
      supporting_text: interaction of alpha(2A)AR and Uch-L1 occurred in the 
        cytoplasm
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: A membrane-associated fraction of UCHL1 can localize to the 
      endoplasmic reticulum membrane, but this is not the main site of the 
      soluble UCH catalytic function.
    action: KEEP_AS_NON_CORE
    reason: Retain as a supported non-core localization while keeping 
      cytoplasm/cytosol as the core location.
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Ubiquitin-dependent protein catabolic process is directionally 
      related but too broad for the direct UCHL1 role.
    action: MODIFY
    reason: UCHL1 removes or processes ubiquitin adducts; protein 
      deubiquitination is the more accurate GO process term.
    proposed_replacement_terms:
    - id: GO:0016579
      label: protein deubiquitination
    additional_reference_ids:
    - PMID:9521656
    - Reactome:R-HSA-5688426
    supported_by:
    - reference_id: Reactome:R-HSA-5688426
      supporting_text: Deubiquitinating enzymes (DUBs) catalyze the removal of 
        Ub and regulate Ub-mediated pathways
    - reference_id: Reactome:R-HSA-5690319
      supporting_text: UCHL1 and UCHL3 can hydrolyze several short C-terminal 
        ubiquitin adducts to generate ubiquitin monomers
    - reference_id: PMID:9521656
      supporting_text: Ubiquitin C-terminal hydrolases (UCH) are 
        deubiquitinating enzymes which hydrolyze C-terminal esters and amides of
        ubiquitin
    - reference_id: PMID:9521656
      supporting_text: to generate free monomeric ubiquitin from ubiquitin 
        proproteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12082530
  qualifier: enables
  review:
    summary: The cited interaction may be real, but generic protein binding is 
      not an informative molecular function for UCHL1.
    action: MARK_AS_OVER_ANNOTATED
    reason: UCHL1 should be curated to specific activities or named binding 
      terms where supported, not to generic protein binding from interaction 
      screens.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16049941
  qualifier: enables
  review:
    summary: The cited interaction may be real, but generic protein binding is 
      not an informative molecular function for UCHL1.
    action: MARK_AS_OVER_ANNOTATED
    reason: UCHL1 should be curated to specific activities or named binding 
      terms where supported, not to generic protein binding from interaction 
      screens.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16169070
  qualifier: enables
  review:
    summary: The cited interaction may be real, but generic protein binding is 
      not an informative molecular function for UCHL1.
    action: MARK_AS_OVER_ANNOTATED
    reason: UCHL1 should be curated to specific activities or named binding 
      terms where supported, not to generic protein binding from interaction 
      screens.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19615732
  qualifier: enables
  review:
    summary: The cited interaction may be real, but generic protein binding is 
      not an informative molecular function for UCHL1.
    action: MARK_AS_OVER_ANNOTATED
    reason: UCHL1 should be curated to specific activities or named binding 
      terms where supported, not to generic protein binding from interaction 
      screens.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20029029
  qualifier: enables
  review:
    summary: The cited interaction may be real, but generic protein binding is 
      not an informative molecular function for UCHL1.
    action: MARK_AS_OVER_ANNOTATED
    reason: UCHL1 should be curated to specific activities or named binding 
      terms where supported, not to generic protein binding from interaction 
      screens.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  qualifier: enables
  review:
    summary: The cited interaction may be real, but generic protein binding is 
      not an informative molecular function for UCHL1.
    action: MARK_AS_OVER_ANNOTATED
    reason: UCHL1 should be curated to specific activities or named binding 
      terms where supported, not to generic protein binding from interaction 
      screens.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23543736
  qualifier: enables
  review:
    summary: The cited interaction may be real, but generic protein binding is 
      not an informative molecular function for UCHL1.
    action: MARK_AS_OVER_ANNOTATED
    reason: UCHL1 should be curated to specific activities or named binding 
      terms where supported, not to generic protein binding from interaction 
      screens.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  qualifier: enables
  review:
    summary: The cited interaction may be real, but generic protein binding is 
      not an informative molecular function for UCHL1.
    action: MARK_AS_OVER_ANNOTATED
    reason: UCHL1 should be curated to specific activities or named binding 
      terms where supported, not to generic protein binding from interaction 
      screens.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: The cited interaction may be real, but generic protein binding is 
      not an informative molecular function for UCHL1.
    action: MARK_AS_OVER_ANNOTATED
    reason: UCHL1 should be curated to specific activities or named binding 
      terms where supported, not to generic protein binding from interaction 
      screens.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Nucleoplasm is a high-throughput immunofluorescence location and 
      not the main compartment for UCHL1 catalytic function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core localization context because the strongest 
      functional evidence supports cytoplasmic/cytosolic deubiquitinase 
      activity.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Cytosol is an appropriate core cellular location for soluble UCHL1 
      deubiquitinase activity.
    action: ACCEPT
    reason: UCHL1 is described as a cytoplasmic/cytosolic neuronal 
      deubiquitinase; Reactome also places the UCHL1 reaction in this context.
    additional_reference_ids:
    - PMID:19477270
    supported_by:
    - reference_id: PMID:19477270
      supporting_text: interaction of alpha(2A)AR and Uch-L1 occurred in the 
        cytoplasm
- term:
    id: GO:0016579
    label: protein deubiquitination
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5688426
  qualifier: involved_in
  review:
    summary: UCHL1 participates in protein deubiquitination through hydrolysis 
      of ubiquitin C-terminal adducts and recycling of monoubiquitin.
    action: ACCEPT
    reason: Protein deubiquitination is the correct biological-process framing 
      for the core UCHL1 catalytic activity.
    additional_reference_ids:
    - PMID:9521656
    - Reactome:R-HSA-5690319
    supported_by:
    - reference_id: Reactome:R-HSA-5688426
      supporting_text: Deubiquitinating enzymes (DUBs) catalyze the removal of 
        Ub and regulate Ub-mediated pathways
    - reference_id: Reactome:R-HSA-5690319
      supporting_text: UCHL1 and UCHL3 can hydrolyze several short C-terminal 
        ubiquitin adducts to generate ubiquitin monomers
    - reference_id: PMID:9521656
      supporting_text: Ubiquitin C-terminal hydrolases (UCH) are 
        deubiquitinating enzymes which hydrolyze C-terminal esters and amides of
        ubiquitin
    - reference_id: PMID:9521656
      supporting_text: to generate free monomeric ubiquitin from ubiquitin 
        proproteins
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690319
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: Reactome:R-HSA-5690319
      supporting_text: UCHL1 and UCHL3 can hydrolyze several short C-terminal 
        ubiquitin adducts to generate ubiquitin monomers
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: EXP
  original_reference_id: PMID:12408865
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: PMID:12408865
      supporting_text: comparable hydrolase activity as the wild-type enzyme
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: EXP
  original_reference_id: PMID:12705903
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: PMID:12705903
      supporting_text: examined their structure (using circular dichroism) and 
        hydrolase activities
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: EXP
  original_reference_id: PMID:16475834
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: PMID:16475834
      supporting_text: UCHs cleave Ub-X bonds (Ub is ubiquitin and X an alcohol,
        an amine, or a protein)
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: EXP
  original_reference_id: PMID:20439756
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: PMID:20439756
      supporting_text: reduces ubiquitin binding and severely impairs the 
        catalytic activity of the enzyme
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: EXP
  original_reference_id: PMID:23359680
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: PMID:23359680
      supporting_text: near complete loss of UCHL1 hydrolase activity
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: EXP
  original_reference_id: PMID:25615526
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: PMID:25615526
      supporting_text: UCHL1 promotes metastases as a deubiquitinating enzyme 
        for HIF-1ฮฑ
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: EXP
  original_reference_id: PMID:8639624
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: PMID:8639624
      supporting_text: Site-directed mutagenesis of UCH-L1 reveals that C90 and 
        H161 are involved in catalytic rate enhancement
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: EXP
  original_reference_id: PMID:9774100
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: PMID:9521656
      supporting_text: Ubiquitin C-terminal hydrolases (UCH) are 
        deubiquitinating enzymes which hydrolyze C-terminal esters and amides of
        ubiquitin
    - reference_id: PMID:9521656
      supporting_text: to generate free monomeric ubiquitin from ubiquitin 
        proproteins
    - reference_id: PMID:8639624
      supporting_text: Site-directed mutagenesis of UCH-L1 reveals that C90 and 
        H161 are involved in catalytic rate enhancement
    - reference_id: PMID:16475834
      supporting_text: UCHs cleave Ub-X bonds (Ub is ubiquitin and X an alcohol,
        an amine, or a protein)
    - reference_id: PMID:20439756
      supporting_text: reduces ubiquitin binding and severely impairs the 
        catalytic activity of the enzyme
    - reference_id: PMID:23359680
      supporting_text: near complete loss of UCHL1 hydrolase activity
    - reference_id: Reactome:R-HSA-5690319
      supporting_text: UCHL1 and UCHL3 can hydrolyze several short C-terminal 
        ubiquitin adducts to generate ubiquitin monomers
- term:
    id: GO:0030547
    label: signaling receptor inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:19477270
  qualifier: enables
  review:
    summary: UCHL1 inhibits alpha-2 adrenergic receptor agonist-mediated p44/42 
      MAPK activation in the cited receptor study.
    action: KEEP_AS_NON_CORE
    reason: This is a specific signaling side context and not the conserved core
      UCH enzymatic function.
    additional_reference_ids:
    - PMID:19477270
    supported_by:
    - reference_id: PMID:19477270
      supporting_text: Uch-L1 binds preferentially to the alpha(2A)AR subtype
    - reference_id: PMID:19477270
      supporting_text: p44/42 MAP Kinase was drastically decreased in the 
        presence of Uch-L1
- term:
    id: GO:0043409
    label: negative regulation of MAPK cascade
  evidence_type: IDA
  original_reference_id: PMID:19477270
  qualifier: involved_in
  review:
    summary: UCHL1 interaction with alpha-2A adrenergic receptor decreases 
      agonist-mediated p44/42 MAPK activation.
    action: KEEP_AS_NON_CORE
    reason: Retain as a supported non-core receptor/signaling process downstream
      of a specific interaction.
    additional_reference_ids:
    - PMID:19477270
    supported_by:
    - reference_id: PMID:19477270
      supporting_text: Uch-L1 binds preferentially to the alpha(2A)AR subtype
    - reference_id: PMID:19477270
      supporting_text: p44/42 MAP Kinase was drastically decreased in the 
        presence of Uch-L1
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IMP
  original_reference_id: PMID:34244144
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: PMID:34244144
      supporting_text: The DUB activity of each UCHL1 or UCH mutant protein was 
        measured using a DUB activity assay kit
- term:
    id: GO:0045821
    label: positive regulation of glycolytic process
  evidence_type: IMP
  original_reference_id: PMID:34244144
  qualifier: involved_in
  review:
    summary: UCHL1 loss reduces glycolytic metabolites and destabilizes PKM in 
      Parkinson disease models, implying that UCHL1 can support glycolysis in 
      that context.
    action: KEEP_AS_NON_CORE
    reason: This is a supported disease/metabolic context, but not the core 
      UCHL1 deubiquitinase function.
    additional_reference_ids:
    - PMID:34244144
    supported_by:
    - reference_id: PMID:34244144
      supporting_text: loss of UCHL1 destabilizes pyruvate kinase (PKM)
    - reference_id: PMID:34244144
      supporting_text: specific glycolytic metabolites are decreased
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: IDA
  original_reference_id: PMID:9521656
  qualifier: enables
  review:
    summary: UCHL1 directly enables cysteine-type deubiquitinase / ubiquitin 
      C-terminal hydrolase activity.
    action: ACCEPT
    reason: This is the conserved catalytic function of UCHL1 and is supported 
      by enzymology, variant, structural, Reactome, and substrate-specific 
      studies.
    additional_reference_ids:
    - PMID:9521656
    - PMID:8639624
    - PMID:16475834
    - PMID:20439756
    - PMID:23359680
    supported_by:
    - reference_id: PMID:9521656
      supporting_text: Ubiquitin C-terminal hydrolases (UCH) are 
        deubiquitinating enzymes which hydrolyze C-terminal esters and amides of
        ubiquitin
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690319
  qualifier: located_in
  review:
    summary: Cytosol is an appropriate core cellular location for soluble UCHL1 
      deubiquitinase activity.
    action: ACCEPT
    reason: UCHL1 is described as a cytoplasmic/cytosolic neuronal 
      deubiquitinase; Reactome also places the UCHL1 reaction in this context.
    additional_reference_ids:
    - PMID:19477270
    supported_by:
    - reference_id: PMID:19477270
      supporting_text: interaction of alpha(2A)AR and Uch-L1 occurred in the 
        cytoplasm
- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: TAS
  original_reference_id: PMID:24879150
  qualifier: involved_in
  review:
    summary: UCHL1 affects autophagosome formation and autophagy/lysosomal 
      pathway readouts, including LC3 puncta and beta-cell proteotoxicity 
      models.
    action: KEEP_AS_NON_CORE
    reason: This is a real proteostasis context, but the direct function is 
      deubiquitination rather than core autophagy machinery activity.
    additional_reference_ids:
    - PMID:29462615
    - PMID:24879150
    supported_by:
    - reference_id: PMID:29462615
      supporting_text: UCHL1 overexpression inhibits LC3 puncta formation and is
        dependent on its DUB activity
    - reference_id: PMID:29462615
      supporting_text: UCHL1 may affect autophagy by interacting with LC3
    - reference_id: PMID:24879150
      supporting_text: UCHL1 dysfunction aggravated the hIAPP-induced defect in 
        the autophagy/lysosomal pathway
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:19725078
  qualifier: enables
  review:
    summary: UCHL1 was identified as a potential Parkin interactor in a Parkin 
      proteomic study.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core interaction context; UCHL1 is not itself an E3 
      ligase, and the core activity remains deubiquitinase/UCH activity.
    additional_reference_ids:
    - PMID:19725078
    supported_by:
    - reference_id: PMID:19725078
      supporting_text: Tandem affinity purification/MS revealed 14 potential 
        interactants of Parkin; CKB, DBT, HSPD1, HSPA9, LRPPRC, NDUFS2, PRDX6, 
        SLC25A5, TPI1, UCHL1, UQCRC1, VCL, YWHAZ, YWHAE
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:24252804
  qualifier: involved_in
  review:
    summary: UCHL1 participates in ubiquitin homeostasis that can influence 
      proteasome-mediated protein catabolism.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pathway context because the direct mechanism is 
      ubiquitin adduct hydrolysis/protein deubiquitination, and the cited PMID 
      is a broad Parkinson oxidative-stress review.
    additional_reference_ids:
    - Reactome:R-HSA-5688426
    - PMID:24252804
    supported_by:
    - reference_id: Reactome:R-HSA-5688426
      supporting_text: Deubiquitinating enzymes (DUBs) catalyze the removal of 
        Ub and regulate Ub-mediated pathways
    - reference_id: Reactome:R-HSA-5690319
      supporting_text: UCHL1 and UCHL3 can hydrolyze several short C-terminal 
        ubiquitin adducts to generate ubiquitin monomers
    - reference_id: PMID:24252804
      supporting_text: cellular homeostatic processes including the 
        ubiquitin-proteasome system and mitophagy are impacted by oxidative 
        stress
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:19477270
  qualifier: located_in
  review:
    summary: UCHL1 is a cytoplasmic/cytosolic enzyme, and cytoplasm is an 
      appropriate cellular location.
    action: ACCEPT
    reason: This location is consistent with UniProt, GOA, and 
      receptor-interaction evidence placing UCHL1 in the cytoplasm.
    additional_reference_ids:
    - PMID:19477270
    supported_by:
    - reference_id: PMID:19477270
      supporting_text: interaction of alpha(2A)AR and Uch-L1 occurred in the 
        cytoplasm
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:19477270
  qualifier: colocalizes_with
  review:
    summary: UCHL1 colocalization with plasma membrane in the receptor study 
      reflects alpha-2A adrenergic receptor interaction context rather than the 
      main UCHL1 compartment.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core localization; cytoplasm/cytosol are the better 
      supported core locations.
    additional_reference_ids:
    - PMID:19477270
    supported_by:
    - reference_id: PMID:19477270
      supporting_text: Uch-L1 binds preferentially to the alpha(2A)AR subtype
    - reference_id: PMID:19477270
      supporting_text: p44/42 MAP Kinase was drastically decreased in the 
        presence of Uch-L1
- term:
    id: GO:0031694
    label: alpha-2A adrenergic receptor binding
  evidence_type: IPI
  original_reference_id: PMID:19477270
  qualifier: enables
  review:
    summary: UCHL1 binds preferentially to the alpha-2A adrenergic receptor 
      subtype in the cited study.
    action: KEEP_AS_NON_CORE
    reason: This is a specific, supported binding function but is a non-core 
      receptor/signaling context relative to UCHL1 deubiquitinase activity.
    additional_reference_ids:
    - PMID:19477270
    supported_by:
    - reference_id: PMID:19477270
      supporting_text: Uch-L1 binds preferentially to the alpha(2A)AR subtype
    - reference_id: PMID:19477270
      supporting_text: p44/42 MAP Kinase was drastically decreased in the 
        presence of Uch-L1
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:16130169
  qualifier: located_in
  review:
    summary: UCHL1 is a cytoplasmic/cytosolic enzyme, and cytoplasm is an 
      appropriate cellular location.
    action: ACCEPT
    reason: This location is consistent with UniProt, GOA, and 
      receptor-interaction evidence placing UCHL1 in the cytoplasm.
    additional_reference_ids:
    - PMID:19477270
    supported_by:
    - reference_id: PMID:19477270
      supporting_text: interaction of alpha(2A)AR and Uch-L1 occurred in the 
        cytoplasm
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: UCHL1 is a cytoplasmic/cytosolic enzyme, and cytoplasm is an 
      appropriate cellular location.
    action: ACCEPT
    reason: This location is consistent with UniProt, GOA, and 
      receptor-interaction evidence placing UCHL1 in the cytoplasm.
    additional_reference_ids:
    - PMID:19477270
    supported_by:
    - reference_id: PMID:19477270
      supporting_text: interaction of alpha(2A)AR and Uch-L1 occurred in the 
        cytoplasm
- term:
    id: GO:0004197
    label: cysteine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:8639624
  qualifier: enables
  review:
    summary: Cysteine-type endopeptidase activity is too broad for UCHL1 and 
      does not capture the ubiquitin C-terminal specificity.
    action: MODIFY
    reason: Replace with cysteine-type deubiquitinase activity, the specific 
      cysteine protease activity supported by the same active-site evidence.
    proposed_replacement_terms:
    - id: GO:0004843
      label: cysteine-type deubiquitinase activity
    additional_reference_ids:
    - PMID:8639624
    - PMID:9521656
    supported_by:
    - reference_id: PMID:8639624
      supporting_text: Site-directed mutagenesis of UCH-L1 reveals that C90 and 
        H161 are involved in catalytic rate enhancement
- term:
    id: GO:0008242
    label: omega peptidase activity
  evidence_type: IDA
  original_reference_id: PMID:9521656
  qualifier: enables
  review:
    summary: UCHL1 has omega peptidase / ubiquitin C-terminal hydrolase 
      activity, cleaving small adducts from the C-terminus of ubiquitin.
    action: ACCEPT
    reason: This term captures the C-terminal peptidase chemistry of the core 
      UCHL1 enzymatic function.
    additional_reference_ids:
    - PMID:9521656
    supported_by:
    - reference_id: PMID:9521656
      supporting_text: cleave small leaving groups such as amino acids and 
        oligopeptides from the C-terminus of ubiquitin
- term:
    id: GO:0016579
    label: protein deubiquitination
  evidence_type: IDA
  original_reference_id: PMID:9521656
  qualifier: involved_in
  review:
    summary: UCHL1 participates in protein deubiquitination through hydrolysis 
      of ubiquitin C-terminal adducts and recycling of monoubiquitin.
    action: ACCEPT
    reason: Protein deubiquitination is the correct biological-process framing 
      for the core UCHL1 catalytic activity.
    additional_reference_ids:
    - PMID:9521656
    - Reactome:R-HSA-5690319
    supported_by:
    - reference_id: Reactome:R-HSA-5688426
      supporting_text: Deubiquitinating enzymes (DUBs) catalyze the removal of 
        Ub and regulate Ub-mediated pathways
    - reference_id: Reactome:R-HSA-5690319
      supporting_text: UCHL1 and UCHL3 can hydrolyze several short C-terminal 
        ubiquitin adducts to generate ubiquitin monomers
    - reference_id: PMID:9521656
      supporting_text: Ubiquitin C-terminal hydrolases (UCH) are 
        deubiquitinating enzymes which hydrolyze C-terminal esters and amides of
        ubiquitin
    - reference_id: PMID:9521656
      supporting_text: to generate free monomeric ubiquitin from ubiquitin 
        proproteins
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IDA
  original_reference_id: PMID:9521656
  qualifier: enables
  review:
    summary: UCHL1 binds ubiquitin as the substrate for its C-terminal hydrolase
      reaction.
    action: KEEP_AS_NON_CORE
    reason: Retain as a substrate-binding context, but the core molecular 
      function should be deubiquitinase/UCH catalytic activity rather than 
      binding alone.
    additional_reference_ids:
    - PMID:8639624
    - PMID:9521656
    supported_by:
    - reference_id: PMID:8639624
      supporting_text: indicates the existence of a specific and extensive 
        binding site for ubiquitin on the surface of the enzyme
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to
    orthologs by curator judgment of sequence similarity
  findings: []
- 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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12082530
  title: Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1).
  findings: []
- id: PMID:12408865
  title: The UCH-L1 gene encodes two opposing enzymatic activities that affect 
    alpha-synuclein degradation and Parkinson's disease susceptibility.
  findings: []
- id: PMID:12705903
  title: Alterations of structure and hydrolase activity of 
    parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 
    variants.
  findings: []
- id: PMID:16049941
  title: A pilot proteomic study of amyloid precursor interactors in Alzheimer's
    disease.
  findings: []
- id: PMID:16130169
  title: Proteomics of human umbilical vein endothelial cells applied to 
    etoposide-induced apoptosis.
  findings: []
- id: PMID:16169070
  title: 'A human protein-protein interaction network: a resource for annotating the
    proteome.'
  findings: []
- id: PMID:16475834
  title: Mechanistic studies of ubiquitin C-terminal hydrolase L1.
  findings: []
- id: PMID:19477270
  title: Interaction of the ubiquitin carboxyl terminal esterase L1 with 
    alpha(2)-adrenergic receptors inhibits agonist-mediated p44/42 MAP kinase 
    activation.
  findings: []
- id: PMID:19615732
  title: Defining the human deubiquitinating enzyme interaction landscape.
  findings: []
- id: PMID:19725078
  title: Proteomic analysis of increased Parkin expression and its interactants 
    provides evidence for a role in modulation of mitochondrial function.
  findings: []
- id: PMID:20029029
  title: Regulation of epidermal growth factor receptor trafficking by lysine 
    deacetylase HDAC6.
  findings: []
- id: PMID:20439756
  title: Ubiquitin vinyl methyl ester binding orients the misaligned active site
    of the ubiquitin hydrolase UCHL1 into productive conformation.
  findings: []
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new 
    regulators for telomere signaling in human cells.
  findings: []
- id: PMID:23359680
  title: Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 
    leads to early-onset progressive neurodegeneration.
  findings: []
- id: PMID:23543736
  title: Ubiquitin C-terminal hydrolase L1 (UCH-L1) acts as a novel potentiator 
    of cyclin-dependent kinases to enhance cell proliferation independently of 
    its hydrolase activity.
  findings: []
- id: PMID:24252804
  title: The role of oxidative stress in Parkinson's disease.
  findings: []
- id: PMID:24879150
  title: 'UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in
    ฮฒ-cells: evidence of interplay between the ubiquitin/proteasome system and autophagy.'
  findings: []
- id: PMID:25615526
  title: UCHL1 provides diagnostic and antimetastatic strategies due to its 
    deubiquitinating effect on HIF-1ฮฑ.
  findings: []
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells 
    expressing transforming levels of KRAS(G13D).
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease 
    Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:34244144
  title: Loss of UCHL1 rescues the defects related to Parkinson's disease by 
    suppressing glycolysis.
  findings: []
- id: PMID:8639624
  title: 'Substrate binding and catalysis by ubiquitin C-terminal hydrolases: identification
    of two active site residues.'
  findings: []
- id: PMID:9521656
  title: 'Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal
    hydrolases.'
  findings: []
- id: PMID:9774100
  title: The ubiquitin pathway in Parkinson's disease.
  findings: []
- id: Reactome:R-HSA-5688426
  title: Deubiquitination
  findings: []
- id: Reactome:R-HSA-5690319
  title: UCHL1, UCHL3 cleave ubiquitin adducts
  findings: []
- id: PMID:29462615
  title: Ubiquitin C-Terminal Hydrolase L1 regulates autophagy by inhibiting 
    autophagosome formation through its deubiquitinating enzyme activity.
  findings: []
core_functions:
- molecular_function:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  description: Cytosolic ubiquitin C-terminal hydrolase activity that cleaves 
    small ubiquitin C-terminal adducts/proproteins to recycle monomeric 
    ubiquitin and support ubiquitin-dependent proteostasis.
  directly_involved_in:
  - id: GO:0016579
    label: protein deubiquitination
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:9521656
    supporting_text: Ubiquitin C-terminal hydrolases (UCH) are deubiquitinating 
      enzymes which hydrolyze C-terminal esters and amides of ubiquitin
  - reference_id: PMID:9521656
    supporting_text: to generate free monomeric ubiquitin from ubiquitin 
      proproteins
  - reference_id: PMID:8639624
    supporting_text: Site-directed mutagenesis of UCH-L1 reveals that C90 and 
      H161 are involved in catalytic rate enhancement
  - reference_id: PMID:16475834
    supporting_text: UCHs cleave Ub-X bonds (Ub is ubiquitin and X an alcohol, 
      an amine, or a protein)
  - reference_id: PMID:20439756
    supporting_text: reduces ubiquitin binding and severely impairs the 
      catalytic activity of the enzyme
  - reference_id: PMID:23359680
    supporting_text: near complete loss of UCHL1 hydrolase activity
  - reference_id: Reactome:R-HSA-5690319
    supporting_text: UCHL1 and UCHL3 can hydrolyze several short C-terminal 
      ubiquitin adducts to generate ubiquitin monomers
  - reference_id: Reactome:R-HSA-5688426
    supporting_text: Deubiquitinating enzymes (DUBs) catalyze the removal of Ub 
      and regulate Ub-mediated pathways
  - reference_id: Reactome:R-HSA-5690319
    supporting_text: UCHL1 and UCHL3 can hydrolyze several short C-terminal 
      ubiquitin adducts to generate ubiquitin monomers
proposed_new_terms:
- proposed_name: ATG8-family protein deubiquitination
  proposed_definition: A protein deubiquitination process in which ubiquitin is 
    removed from, or ubiquitin-dependent modification of, an ATG8-family protein
    is regulated to modulate autophagosome formation or autophagy flux.
  justification: The PN context and PMID:29462615 indicate that UCHL1 affects 
    autophagosome formation through DUB activity and interaction with LC3, but 
    current GOA can only capture broad protein deubiquitination or regulation of
    macroautophagy.
  proposed_parent:
    id: GO:0016579
    label: protein deubiquitination
  supported_by:
  - reference_id: PMID:29462615
    supporting_text: UCHL1 overexpression inhibits LC3 puncta formation and is 
      dependent on its DUB activity
  - reference_id: PMID:29462615
    supporting_text: UCHL1 may affect autophagy by interacting with LC3
suggested_questions:
- question: Should UCHL1 be annotated to a new ATG8-family protein 
    deubiquitination term when the substrate/context is LC3-dependent 
    autophagosome formation?
  experts:
  - Yanfen Liu
  - Cong Yan
  - GO autophagy editors
- question: Should UCHL1 catalytic activity be represented primarily by 
    cysteine-type deubiquitinase activity, omega peptidase activity, or a more 
    specific ubiquitin C-terminal hydrolase term?
  experts:
  - Keith D. Wilkinson
  - Catherine Larsen
  - GO molecular function editors
- question: Which UCHL1 substrate-specific contexts, such as HIF-1alpha, 
    EGFR/BACE1, alpha-2A adrenergic receptor signaling, or PKM/glycolysis, 
    should remain gene-level non-core annotations?
  experts:
  - Harada Hiraoka
  - Brendie Weber
  - GO proteostasis editors
suggested_experiments:
- description: Map LC3 ubiquitination sites and test whether catalytically 
    inactive UCHL1, I93M UCHL1, and substrate-binding mutants alter LC3 
    ubiquitination, LC3 puncta, and autophagy flux in matched rescue cells.
  experiment_type: substrate mapping and autophagy flux rescue assay
  hypothesis: UCHL1 regulates autophagosome formation by deubiquitinating 
    LC3/ATG8-family proteins or an LC3-proximal substrate.
- description: Compare Ub-AMC, ubiquitin proprotein, small ubiquitin adduct, and
    ubiquitinated protein substrates across UCHL1 variants to separate 
    omega-peptidase/proprotein processing from protein deubiquitination.
  experiment_type: comparative enzymology
  hypothesis: UCHL1 core activity is optimized for small ubiquitin C-terminal 
    adducts, while substrate-specific protein deubiquitination depends on 
    cellular context or binding partners.
- description: Use substrate-selective UCHL1 mutants in neuronal and cancer-cell
    models to test whether LC3/autophagy, HIF-1alpha stabilization, 
    PKM/glycolysis, and alpha-2A receptor/MAPK effects can be separated 
    genetically.
  experiment_type: domain-function and substrate-specific rescue
  hypothesis: UCHL1 non-core pathway annotations reflect separable substrate 
    contexts built on the same core deubiquitinase activity.