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-1α - 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 β-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-1α. 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.