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.
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:
| 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-1Ξ± |
| 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. Proposed replacements: cysteine-type deubiquitinase activity 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 |
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Download this section (compressed HTML)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
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
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