id: P04062 gene_symbol: GBA1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 'GBA1 encodes lysosomal acid glucosylceramidase, a LIMP-2/SCARB2-trafficked lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Its core function is lysosomal glycosphingolipid catabolism at the lumenal side of the lysosomal membrane. Loss of GCase activity also impairs autophagic lysosome reformation, lysosomal recycling, and alpha-synuclein/lysosomal proteostasis in disease models, while cholesterol glucosylation, steryl-beta-glucoside hydrolysis, ceramide salvage, and inflammatory signaling are supported non-core contexts.' alternative_products: - name: Long id: P04062-1 - name: Short id: P04062-2 sequence_note: VSP_018800 - name: '3' id: P04062-3 sequence_note: VSP_025216, VSP_025217, VSP_025218 - name: '4' id: P04062-4 sequence_note: VSP_054655 - name: '5' id: P04062-5 sequence_note: VSP_054656 existing_annotations: - term: id: GO:0006680 label: glucosylceramide catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. action: ACCEPT reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0004336 label: galactosylceramidase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: GBA1 can hydrolyze galactosylceramide, but UniProt describes this as lower activity than glucosylceramide hydrolysis. action: KEEP_AS_NON_CORE reason: This is a direct side activity rather than the core lysosomal glucosylceramide catabolic function. supported_by: - reference_id: file:human/GBA1/GBA1-uniprot.txt supporting_text: Catalyzes the hydrolysis of galactosylceramides/GalCers - reference_id: file:human/GBA1/GBA1-uniprot.txt supporting_text: with lower activity than with GlcCers - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0005765 label: lysosomal membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. action: ACCEPT reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. additional_reference_ids: - PMID:40159502 - PMID:18022370 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0006665 label: sphingolipid metabolic process evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: The broad sphingolipid metabolic process annotation captures the general lipid class but loses the specific GBA1 function. action: MODIFY reason: Replace with glucosylceramide catabolic process, the specific sphingolipid process directly catalyzed by GBA1. proposed_replacement_terms: - id: GO:0006680 label: glucosylceramide catabolic process supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0016241 label: regulation of macroautophagy evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: GCase deficiency affects autophagy readouts and ALR after starvation/refeeding, but macroautophagy regulation is downstream of lysosomal lipid catabolism. action: KEEP_AS_NON_CORE reason: The evidence supports a non-core proteostasis effect rather than a primary regulatory molecular function. additional_reference_ids: - PMID:27378698 supported_by: - reference_id: PMID:27378698 supporting_text: autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase - reference_id: PMID:27378698 supporting_text: GCase deficiency affects lysosomal recycling - reference_id: PMID:27378698 supporting_text: Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes - term: id: GO:0030163 label: protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Generic protein catabolic process is too broad for GBA1; the relevant evidence concerns lysosomal proteolysis/alpha-synuclein handling when GCase activity is deficient. action: MODIFY reason: Use regulation of lysosomal protein catabolic process to reflect the indirect lysosomal proteostasis role. proposed_replacement_terms: - id: GO:1905165 label: regulation of lysosomal protein catabolic process additional_reference_ids: - PMID:21700325 - PMID:26392287 supported_by: - reference_id: PMID:21700325 supporting_text: GCase depletion causes a decline in lysosomal proteolysis that preferentially affects alpha-syn - reference_id: PMID:26392287 supporting_text: Glucocerebrosidase gene therapy prevents alpha-synucleinopathy of midbrain dopamine neurons - term: id: GO:0042176 label: regulation of protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Regulation of protein catabolic process is too broad for the observed GBA1-linked lysosomal proteostasis effects. action: MODIFY reason: Use regulation of lysosomal protein catabolic process, which matches the alpha-synuclein/lysosomal degradation context more closely. proposed_replacement_terms: - id: GO:1905165 label: regulation of lysosomal protein catabolic process additional_reference_ids: - PMID:21700325 - PMID:26392287 supported_by: - reference_id: PMID:21700325 supporting_text: GCase depletion causes a decline in lysosomal proteolysis that preferentially affects alpha-syn - reference_id: PMID:26392287 supporting_text: Glucocerebrosidase gene therapy prevents alpha-synucleinopathy of midbrain dopamine neurons - term: id: GO:0042391 label: regulation of membrane potential evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Regulation of membrane potential is not a well-supported direct GBA1 function in the reviewed evidence. action: MARK_AS_OVER_ANNOTATED reason: Mitochondrial and neuronal electrophysiology phenotypes are downstream disease contexts and should not be propagated as a GBA1 core GO process. supported_by: - reference_id: PMID:25456120 supporting_text: mitochondria ... displayed normal morphology and regular distribution - term: id: GO:0050295 label: steryl-beta-glucosidase activity evidence_type: IEA original_reference_id: GO_REF:0000116 qualifier: enables review: summary: GBA1 can hydrolyze glucosylated cholesterol/steryl beta-glucosides, but this is a side activity relative to glucosylceramide hydrolysis. action: KEEP_AS_NON_CORE reason: Retain as a direct non-core catalytic activity supported by cholesterol-glucoside metabolism studies. additional_reference_ids: - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21098288 qualifier: enables review: summary: The cited interaction is real, but generic protein binding is not an informative GBA1 molecular function. action: MARK_AS_OVER_ANNOTATED reason: The underlying evidence concerns folding, degradation, chaperone recruitment, or trafficking rather than a reusable binding function term for GBA1. supported_by: - reference_id: PMID:21098288 supporting_text: reduced binding of GCase to TCP1 ring complex (TRiC), a regulator of correct protein folding - term: id: GO:0005102 label: signaling receptor binding evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Signaling receptor binding is misleading for GBA1 because the receptor evidence concerns LIMP-2/SCARB2-dependent lysosomal trafficking, not signal transduction. action: MODIFY reason: Replace with scavenger receptor binding for the LIMP-2/SCARB2 interaction, or curate the interaction as lysosomal targeting context rather than signaling. proposed_replacement_terms: - id: GO:0005124 label: scavenger receptor binding additional_reference_ids: - PMID:18022370 - PMID:25202012 - PMID:40159502 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:25202012 supporting_text: LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome - reference_id: PMID:40159502 supporting_text: GCase reaches the lysosome exclusively in complex with its proprietary transport protein lysosomal integral membrane protein type-2 (LIMP-2) - term: id: GO:0005576 label: extracellular region evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: GBA1 can be detected or secreted outside the lysosome in some contexts, but this is not the main catalytic compartment. action: KEEP_AS_NON_CORE reason: Retain as non-core because normal GBA1 function depends on lysosomal targeting; extracellular localization is secondary or context-dependent. supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2-deficient mouse tissues ... beta-glucocerebrosidase was secreted - term: id: GO:0005764 label: lysosome evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: lysosome is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. action: ACCEPT reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. additional_reference_ids: - PMID:40159502 - PMID:18022370 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: endoplasmic reticulum is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. action: KEEP_AS_NON_CORE reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. additional_reference_ids: - PMID:40159502 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0005794 label: Golgi apparatus evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Golgi apparatus is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. action: KEEP_AS_NON_CORE reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. additional_reference_ids: - PMID:40159502 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0005802 label: trans-Golgi network evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: trans-Golgi network is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. action: KEEP_AS_NON_CORE reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. additional_reference_ids: - PMID:40159502 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0006680 label: glucosylceramide catabolic process evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. action: ACCEPT reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0006914 label: autophagy evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Generic autophagy is too broad for the GBA1 evidence, which specifically shows impaired ALR, lysosomal recycling, and autophagosome clearance after GCase loss. action: MODIFY reason: Replace with lysosome organization and regulation of macroautophagy to capture the proteostasis effect without overclaiming a core autophagy machinery role. proposed_replacement_terms: - id: GO:0007040 label: lysosome organization - id: GO:0016241 label: regulation of macroautophagy additional_reference_ids: - PMID:27378698 supported_by: - reference_id: PMID:27378698 supporting_text: autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase - reference_id: PMID:27378698 supporting_text: GCase deficiency affects lysosomal recycling - reference_id: PMID:27378698 supporting_text: Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes - term: id: GO:0007040 label: lysosome organization evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: GBA1 deficiency impairs autophagic lysosome reformation, lysosomal recycling, and endosome maturation, supporting lysosome organization in the proteostasis context. action: ACCEPT reason: The term is broader than the ALR phenotype, but current GO lacks an autophagic lysosome reformation term and the experimental evidence directly links GCase loss to defective lysosome organization. additional_reference_ids: - PMID:27378698 supported_by: - reference_id: PMID:27378698 supporting_text: autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase - reference_id: PMID:27378698 supporting_text: GCase deficiency affects lysosomal recycling - reference_id: PMID:27378698 supporting_text: Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes - term: id: GO:0008203 label: cholesterol metabolic process evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: GBA1 participates in glucosylated cholesterol formation and degradation, but cholesterol metabolism is a side context relative to GlcCer catabolism. action: KEEP_AS_NON_CORE reason: Retain as non-core because the direct catalytic evidence is conditional/side activity rather than the main lysosomal substrate pathway. additional_reference_ids: - PMID:24211208 - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:0008422 label: beta-glucosidase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: GBA1 has beta-glucosidase activity, including bile-acid beta-glucoside hydrolysis, but this broad term is less specific than the core glucosylceramidase annotation. action: KEEP_AS_NON_CORE reason: Retain as a supported non-core/broad catalytic context while keeping glucosylceramidase activity as the core molecular function. additional_reference_ids: - PMID:22659419 supported_by: - reference_id: PMID:22659419 supporting_text: GBA1 also hydrolyses BG - reference_id: PMID:22659419 supporting_text: GBA1 as a bile acid beta-glucosidase - term: id: GO:0009247 label: glycolipid biosynthetic process evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: GBA1 can catalyze cholesterol glucosylation through transglucosylation, providing a direct but non-core glycoside biosynthetic activity. action: KEEP_AS_NON_CORE reason: Retain as non-core because the principal function is catabolism of glucosylceramide, not glycolipid biosynthesis. additional_reference_ids: - PMID:24211208 - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:0009267 label: cellular response to starvation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: The ALR evidence uses starvation/refeeding and shows defective lysosome regeneration in GCase-deficient cells. action: KEEP_AS_NON_CORE reason: This supports a non-core starvation-response context, but the molecular function remains lysosomal glucosylceramidase activity. additional_reference_ids: - PMID:27378698 supported_by: - reference_id: PMID:27378698 supporting_text: autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase - reference_id: PMID:27378698 supporting_text: GCase deficiency affects lysosomal recycling - reference_id: PMID:27378698 supporting_text: Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes - term: id: GO:0009268 label: response to pH evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: GBA1 has an acidic pH optimum, but enzyme pH dependence is not evidence that the gene product is involved in response to pH. action: MARK_AS_OVER_ANNOTATED reason: The reviewed evidence supports acid lysosomal catalysis and an enzyme pH optimum, not a regulated response-to-pH biological process. supported_by: - reference_id: file:human/GBA1/GBA1-uniprot.txt supporting_text: 'pH dependence:' - reference_id: file:human/GBA1/GBA1-uniprot.txt supporting_text: Optimum pH is 5.3. - term: id: GO:0016787 label: hydrolase activity evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Hydrolase activity is correct but too broad to be informative for GBA1. action: MODIFY reason: Replace with glucosylceramidase activity, the specific hydrolase activity of GBA1. proposed_replacement_terms: - id: GO:0004348 label: glucosylceramidase activity supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0032006 label: regulation of TOR signaling evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: GCase deficiency lowers mTOR/S6K signaling during ALR recovery, and recombinant GCase can reverse that effect. action: KEEP_AS_NON_CORE reason: This is a downstream ALR/lysosome-recycling consequence rather than the core enzymatic function. supported_by: - reference_id: PMID:27378698 supporting_text: Cerezyme treatment significantly increased phospho-S6K levels ... corroborating the direct relation between the loss of GCase activity and the decreased mTOR activity - reference_id: PMID:27378698 supporting_text: ALR is a cellular process controlled by mTOR - term: id: GO:0033574 label: response to testosterone evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: response to testosterone is not supported as a direct GBA1 function by the reviewed lysosomal enzyme literature. action: MARK_AS_OVER_ANNOTATED reason: This appears to be an automatic/contextual projection and should not be treated as a curated GBA1 functional annotation without direct evidence. supported_by: - reference_id: GO_REF:0000107 supporting_text: automatic or inferred annotation; no direct supporting GBA1 publication was identified in the cached review evidence - term: id: GO:0043202 label: lysosomal lumen evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: lysosomal lumen is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. action: ACCEPT reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. additional_reference_ids: - PMID:40159502 - PMID:18022370 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0043627 label: response to estrogen evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: response to estrogen is not supported as a direct GBA1 function by the reviewed lysosomal enzyme literature. action: MARK_AS_OVER_ANNOTATED reason: This appears to be an automatic/contextual projection and should not be treated as a curated GBA1 functional annotation without direct evidence. supported_by: - reference_id: GO_REF:0000107 supporting_text: automatic or inferred annotation; no direct supporting GBA1 publication was identified in the cached review evidence - term: id: GO:0046527 label: glucosyltransferase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: GBA1 can transfer glucose from GlcCer to cholesterol through a transglucosylation reaction. action: KEEP_AS_NON_CORE reason: This direct glucosyltransferase side activity is retained as non-core because GBA1 is primarily a lysosomal glucosylceramidase. additional_reference_ids: - PMID:24211208 - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:0061436 label: establishment of skin barrier evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: establishment of skin barrier is a broad organismal/developmental outcome that is not established as a direct GBA1 function in the reviewed evidence. action: MARK_AS_OVER_ANNOTATED reason: GBA1 lipid catabolism can affect tissues, but this annotation over-propagates phenotype/development context beyond the core lysosomal enzyme role. supported_by: - reference_id: GO_REF:0000107 supporting_text: automatic annotation; direct cached evidence supports lysosomal lipid catabolism rather than this broad developmental process - term: id: GO:0071548 label: response to dexamethasone evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: response to dexamethasone is not supported as a direct GBA1 function by the reviewed lysosomal enzyme literature. action: MARK_AS_OVER_ANNOTATED reason: This appears to be an automatic/contextual projection and should not be treated as a curated GBA1 functional annotation without direct evidence. supported_by: - reference_id: GO_REF:0000107 supporting_text: automatic or inferred annotation; no direct supporting GBA1 publication was identified in the cached review evidence - term: id: GO:0097066 label: response to thyroid hormone evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: response to thyroid hormone is not supported as a direct GBA1 function by the reviewed lysosomal enzyme literature. action: MARK_AS_OVER_ANNOTATED reason: This appears to be an automatic/contextual projection and should not be treated as a curated GBA1 functional annotation without direct evidence. supported_by: - reference_id: GO_REF:0000107 supporting_text: automatic or inferred annotation; no direct supporting GBA1 publication was identified in the cached review evidence - term: id: GO:0098773 label: skin epidermis development evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: skin epidermis development is a broad organismal/developmental outcome that is not established as a direct GBA1 function in the reviewed evidence. action: MARK_AS_OVER_ANNOTATED reason: GBA1 lipid catabolism can affect tissues, but this annotation over-propagates phenotype/development context beyond the core lysosomal enzyme role. supported_by: - reference_id: GO_REF:0000107 supporting_text: automatic annotation; direct cached evidence supports lysosomal lipid catabolism rather than this broad developmental process - term: id: GO:1901805 label: beta-glucoside catabolic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Beta-glucoside catabolic process is too generic for the main GBA1 substrate context. action: MODIFY reason: Replace with glucosylceramide catabolic process, the specific lysosomal beta-glucoside catabolism catalyzed by GBA1. proposed_replacement_terms: - id: GO:0006680 label: glucosylceramide catabolic process supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0005765 label: lysosomal membrane evidence_type: IPI original_reference_id: PMID:40159502 qualifier: located_in review: summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. action: ACCEPT reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. additional_reference_ids: - PMID:40159502 - PMID:18022370 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0019377 label: glycolipid catabolic process evidence_type: NAS original_reference_id: PMID:40159502 qualifier: involved_in review: summary: Glycolipid catabolic process is directionally correct but less specific than the supported GBA1 function. action: MODIFY reason: Replace with glucosylceramide catabolic process, the specific glycolipid catabolic pathway for GBA1. proposed_replacement_terms: - id: GO:0006680 label: glucosylceramide catabolic process additional_reference_ids: - PMID:40159502 supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0009247 label: glycolipid biosynthetic process evidence_type: IDA original_reference_id: PMID:24211208 qualifier: involved_in review: summary: GBA1 can catalyze cholesterol glucosylation through transglucosylation, providing a direct but non-core glycoside biosynthetic activity. action: KEEP_AS_NON_CORE reason: Retain as non-core because the principal function is catabolism of glucosylceramide, not glycolipid biosynthesis. additional_reference_ids: - PMID:24211208 - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:0009247 label: glycolipid biosynthetic process evidence_type: IDA original_reference_id: PMID:26724485 qualifier: involved_in review: summary: GBA1 can catalyze cholesterol glucosylation through transglucosylation, providing a direct but non-core glycoside biosynthetic activity. action: KEEP_AS_NON_CORE reason: Retain as non-core because the principal function is catabolism of glucosylceramide, not glycolipid biosynthesis. additional_reference_ids: - PMID:24211208 - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:1905146 label: lysosomal protein catabolic process evidence_type: IDA original_reference_id: PMID:26392287 qualifier: involved_in review: summary: GBA1 activity can influence lysosomal protein catabolism and alpha-synuclein handling in neuronal disease models. action: KEEP_AS_NON_CORE reason: This is a supported proteostasis/disease consequence but not the enzyme core substrate pathway. additional_reference_ids: - PMID:26392287 - PMID:21700325 supported_by: - reference_id: PMID:21700325 supporting_text: GCase depletion causes a decline in lysosomal proteolysis that preferentially affects alpha-syn - reference_id: PMID:26392287 supporting_text: Glucocerebrosidase gene therapy prevents alpha-synucleinopathy of midbrain dopamine neurons - term: id: GO:0050728 label: negative regulation of inflammatory response evidence_type: IMP original_reference_id: PMID:19279008 qualifier: involved_in review: summary: GBA1-generated ceramide counteracts inflammatory signaling and IL-6 production in the cited cell model. action: KEEP_AS_NON_CORE reason: Retain as non-core because it is a downstream signaling consequence of lysosomal lipid metabolism. supported_by: - reference_id: PMID:19279008 supporting_text: GBA1-ceramide pathway ... regulating a pro-inflammatory pathway initiated by PKC and leading to activation of p38 and induction of interleukin 6 - reference_id: PMID:19279008 supporting_text: Knockdown of GBA1 also evoked the hyperproduction of IL-6 - term: id: GO:0043409 label: negative regulation of MAPK cascade evidence_type: IMP original_reference_id: PMID:19279008 qualifier: involved_in review: summary: GBA1 depletion increased p38 pathway activation in the cited inflammatory signaling model. action: KEEP_AS_NON_CORE reason: Retain as non-core because MAPK regulation is downstream of ceramide signaling rather than the conserved enzyme role. supported_by: - reference_id: PMID:19279008 supporting_text: GBA1-ceramide pathway ... regulating a pro-inflammatory pathway initiated by PKC and leading to activation of p38 and induction of interleukin 6 - reference_id: PMID:19279008 supporting_text: Knockdown of GBA1 also evoked the hyperproduction of IL-6 - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IMP original_reference_id: PMID:25584808 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0006680 label: glucosylceramide catabolic process evidence_type: IMP original_reference_id: PMID:25584808 qualifier: involved_in review: summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. action: ACCEPT reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-1605591 qualifier: located_in review: summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. action: ACCEPT reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. additional_reference_ids: - PMID:40159502 - PMID:18022370 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IDA original_reference_id: PMID:22659419 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IMP original_reference_id: PMID:22659419 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0008422 label: beta-glucosidase activity evidence_type: IDA original_reference_id: PMID:22659419 qualifier: enables review: summary: GBA1 has beta-glucosidase activity, including bile-acid beta-glucoside hydrolysis, but this broad term is less specific than the core glucosylceramidase annotation. action: KEEP_AS_NON_CORE reason: Retain as a supported non-core/broad catalytic context while keeping glucosylceramidase activity as the core molecular function. additional_reference_ids: - PMID:22659419 supported_by: - reference_id: PMID:22659419 supporting_text: GBA1 also hydrolyses BG - reference_id: PMID:22659419 supporting_text: GBA1 as a bile acid beta-glucosidase - term: id: GO:0008422 label: beta-glucosidase activity evidence_type: IMP original_reference_id: PMID:22659419 qualifier: enables review: summary: GBA1 has beta-glucosidase activity, including bile-acid beta-glucoside hydrolysis, but this broad term is less specific than the core glucosylceramidase annotation. action: KEEP_AS_NON_CORE reason: Retain as a supported non-core/broad catalytic context while keeping glucosylceramidase activity as the core molecular function. additional_reference_ids: - PMID:22659419 supported_by: - reference_id: PMID:22659419 supporting_text: GBA1 also hydrolyses BG - reference_id: PMID:22659419 supporting_text: GBA1 as a bile acid beta-glucosidase - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: endoplasmic reticulum is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. action: KEEP_AS_NON_CORE reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. additional_reference_ids: - PMID:40159502 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0005794 label: Golgi apparatus evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Golgi apparatus is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. action: KEEP_AS_NON_CORE reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. additional_reference_ids: - PMID:40159502 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0005802 label: trans-Golgi network evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: trans-Golgi network is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. action: KEEP_AS_NON_CORE reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. additional_reference_ids: - PMID:40159502 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27789271 qualifier: enables review: summary: The cited interaction is real, but generic protein binding is not an informative GBA1 molecular function. action: MARK_AS_OVER_ANNOTATED reason: The underlying evidence concerns folding, degradation, chaperone recruitment, or trafficking rather than a reusable binding function term for GBA1. supported_by: - reference_id: PMID:27789271 supporting_text: PGRN binds directly to GCase - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IDA original_reference_id: PMID:16293621 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0005765 label: lysosomal membrane evidence_type: IDA original_reference_id: PMID:17187079 qualifier: located_in review: summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. action: ACCEPT reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. additional_reference_ids: - PMID:40159502 - PMID:18022370 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0006680 label: glucosylceramide catabolic process evidence_type: IDA original_reference_id: PMID:16293621 qualifier: involved_in review: summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. action: ACCEPT reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0006914 label: autophagy evidence_type: IMP original_reference_id: PMID:27378698 qualifier: involved_in review: summary: Generic autophagy is too broad for the GBA1 evidence, which specifically shows impaired ALR, lysosomal recycling, and autophagosome clearance after GCase loss. action: MODIFY reason: Replace with lysosome organization and regulation of macroautophagy to capture the proteostasis effect without overclaiming a core autophagy machinery role. proposed_replacement_terms: - id: GO:0007040 label: lysosome organization - id: GO:0016241 label: regulation of macroautophagy additional_reference_ids: - PMID:27378698 supported_by: - reference_id: PMID:27378698 supporting_text: autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase - reference_id: PMID:27378698 supporting_text: GCase deficiency affects lysosomal recycling - reference_id: PMID:27378698 supporting_text: Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes - term: id: GO:0007040 label: lysosome organization evidence_type: IMP original_reference_id: PMID:27378698 qualifier: involved_in review: summary: GBA1 deficiency impairs autophagic lysosome reformation, lysosomal recycling, and endosome maturation, supporting lysosome organization in the proteostasis context. action: ACCEPT reason: The term is broader than the ALR phenotype, but current GO lacks an autophagic lysosome reformation term and the experimental evidence directly links GCase loss to defective lysosome organization. additional_reference_ids: - PMID:27378698 supported_by: - reference_id: PMID:27378698 supporting_text: autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase - reference_id: PMID:27378698 supporting_text: GCase deficiency affects lysosomal recycling - reference_id: PMID:27378698 supporting_text: Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes - term: id: GO:0008203 label: cholesterol metabolic process evidence_type: IDA original_reference_id: PMID:26724485 qualifier: involved_in review: summary: GBA1 participates in glucosylated cholesterol formation and degradation, but cholesterol metabolism is a side context relative to GlcCer catabolism. action: KEEP_AS_NON_CORE reason: Retain as non-core because the direct catalytic evidence is conditional/side activity rather than the main lysosomal substrate pathway. additional_reference_ids: - PMID:24211208 - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:0032006 label: regulation of TOR signaling evidence_type: IMP original_reference_id: PMID:27378698 qualifier: involved_in review: summary: GCase deficiency lowers mTOR/S6K signaling during ALR recovery, and recombinant GCase can reverse that effect. action: KEEP_AS_NON_CORE reason: This is a downstream ALR/lysosome-recycling consequence rather than the core enzymatic function. supported_by: - reference_id: PMID:27378698 supporting_text: Cerezyme treatment significantly increased phospho-S6K levels ... corroborating the direct relation between the loss of GCase activity and the decreased mTOR activity - reference_id: PMID:27378698 supporting_text: ALR is a cellular process controlled by mTOR - term: id: GO:0046527 label: glucosyltransferase activity evidence_type: IDA original_reference_id: PMID:26724485 qualifier: enables review: summary: GBA1 can transfer glucose from GlcCer to cholesterol through a transglucosylation reaction. action: KEEP_AS_NON_CORE reason: This direct glucosyltransferase side activity is retained as non-core because GBA1 is primarily a lysosomal glucosylceramidase. additional_reference_ids: - PMID:24211208 - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:0050295 label: steryl-beta-glucosidase activity evidence_type: IDA original_reference_id: PMID:26724485 qualifier: enables review: summary: GBA1 can hydrolyze glucosylated cholesterol/steryl beta-glucosides, but this is a side activity relative to glucosylceramide hydrolysis. action: KEEP_AS_NON_CORE reason: Retain as a direct non-core catalytic activity supported by cholesterol-glucoside metabolism studies. additional_reference_ids: - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IDA original_reference_id: PMID:24211208 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0006680 label: glucosylceramide catabolic process evidence_type: IDA original_reference_id: PMID:24211208 qualifier: involved_in review: summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. action: ACCEPT reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0008203 label: cholesterol metabolic process evidence_type: IDA original_reference_id: PMID:24211208 qualifier: involved_in review: summary: GBA1 participates in glucosylated cholesterol formation and degradation, but cholesterol metabolism is a side context relative to GlcCer catabolism. action: KEEP_AS_NON_CORE reason: Retain as non-core because the direct catalytic evidence is conditional/side activity rather than the main lysosomal substrate pathway. additional_reference_ids: - PMID:24211208 - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:0046527 label: glucosyltransferase activity evidence_type: IDA original_reference_id: PMID:24211208 qualifier: enables review: summary: GBA1 can transfer glucose from GlcCer to cholesterol through a transglucosylation reaction. action: KEEP_AS_NON_CORE reason: This direct glucosyltransferase side activity is retained as non-core because GBA1 is primarily a lysosomal glucosylceramidase. additional_reference_ids: - PMID:24211208 - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:0050295 label: steryl-beta-glucosidase activity evidence_type: IDA original_reference_id: PMID:24211208 qualifier: enables review: summary: GBA1 can hydrolyze glucosylated cholesterol/steryl beta-glucosides, but this is a side activity relative to glucosylceramide hydrolysis. action: KEEP_AS_NON_CORE reason: Retain as a direct non-core catalytic activity supported by cholesterol-glucoside metabolism studies. additional_reference_ids: - PMID:26724485 supported_by: - reference_id: PMID:24211208 supporting_text: purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity - reference_id: PMID:26724485 supporting_text: GBA is able to form GlcChol by transglucosylation of cholesterol - reference_id: PMID:26724485 supporting_text: GlcChol is ... also an excellent substrate for hydrolysis by GBA - term: id: GO:0006680 label: glucosylceramide catabolic process evidence_type: IMP original_reference_id: PMID:24022302 qualifier: involved_in review: summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. action: ACCEPT reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IDA original_reference_id: PMID:9201993 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0006680 label: glucosylceramide catabolic process evidence_type: IDA original_reference_id: PMID:9201993 qualifier: involved_in review: summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. action: ACCEPT reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IMP original_reference_id: PMID:15916907 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0005124 label: scavenger receptor binding evidence_type: IPI original_reference_id: PMID:25202012 qualifier: enables review: summary: GBA1 directly binds LIMP-2/SCARB2, the lysosomal trafficking receptor for GCase. action: KEEP_AS_NON_CORE reason: This binding is mechanistically important for localization but is not the core catalytic activity. additional_reference_ids: - PMID:25202012 - PMID:18022370 - PMID:40159502 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:25202012 supporting_text: LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome - reference_id: PMID:40159502 supporting_text: GCase reaches the lysosome exclusively in complex with its proprietary transport protein lysosomal integral membrane protein type-2 (LIMP-2) - term: id: GO:0005764 label: lysosome evidence_type: IMP original_reference_id: PMID:25202012 qualifier: located_in review: summary: lysosome is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. action: ACCEPT reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. additional_reference_ids: - PMID:40159502 - PMID:18022370 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IMP original_reference_id: PMID:23580063 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0007005 label: mitochondrion organization evidence_type: IMP original_reference_id: PMID:25456120 qualifier: involved_in negated: true review: summary: Mitochondrion organization is not supported as a direct GBA1 process by the cited iPSC twin study. action: MARK_AS_OVER_ANNOTATED reason: The paper reports normal mitochondrial morphology/distribution, and broader mitochondrial dysfunction is a downstream disease context rather than core GBA1 function. supported_by: - reference_id: PMID:25456120 supporting_text: mitochondria ... displayed normal morphology and regular distribution - term: id: GO:0031175 label: neuron projection development evidence_type: IMP original_reference_id: PMID:25456120 qualifier: involved_in negated: true review: summary: Neuron projection development is too broad and indirect for the GBA1 iPSC disease-model evidence. action: MARK_AS_OVER_ANNOTATED reason: The cited study supports disease phenotypes in dopaminergic neurons, not a direct developmental function for GBA1. supported_by: - reference_id: PMID:25456120 supporting_text: mDA neurons from both twins had ~50% GBA enzymatic activity, ~3-fold elevated alpha-synuclein protein levels, and a reduced capacity to synthesize and release dopamine - term: id: GO:1904457 label: positive regulation of neuronal action potential evidence_type: IMP original_reference_id: PMID:25456120 qualifier: involved_in review: summary: Positive regulation of neuronal action potential is an over-specific neuronal phenotype annotation for GBA1. action: MARK_AS_OVER_ANNOTATED reason: The cited iPSC study observed electrophysiology differences in a disease model, but the evidence does not establish this as a direct GBA1 biological process. supported_by: - reference_id: PMID:25456120 supporting_text: delay in the emergence of spontaneous action potentials - term: id: GO:1905165 label: regulation of lysosomal protein catabolic process evidence_type: TAS original_reference_id: PMID:25456120 qualifier: involved_in review: summary: GBA1 activity can affect lysosomal protein catabolism/alpha-synuclein clearance in neuronal disease models. action: KEEP_AS_NON_CORE reason: This is a supported non-core proteostasis consequence of lysosomal lipid catabolism. additional_reference_ids: - PMID:21700325 - PMID:26392287 supported_by: - reference_id: PMID:21700325 supporting_text: GCase depletion causes a decline in lysosomal proteolysis that preferentially affects alpha-syn - reference_id: PMID:26392287 supporting_text: Glucocerebrosidase gene therapy prevents alpha-synucleinopathy of midbrain dopamine neurons - term: id: GO:0016241 label: regulation of macroautophagy evidence_type: TAS original_reference_id: PMID:26388395 qualifier: involved_in review: summary: GCase deficiency affects autophagy readouts and ALR after starvation/refeeding, but macroautophagy regulation is downstream of lysosomal lipid catabolism. action: KEEP_AS_NON_CORE reason: The evidence supports a non-core proteostasis effect rather than a primary regulatory molecular function. additional_reference_ids: - PMID:27378698 supported_by: - reference_id: PMID:27378698 supporting_text: autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase - reference_id: PMID:27378698 supporting_text: GCase deficiency affects lysosomal recycling - reference_id: PMID:27378698 supporting_text: Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IMP original_reference_id: PMID:21700325 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0006680 label: glucosylceramide catabolic process evidence_type: IMP original_reference_id: PMID:21700325 qualifier: involved_in review: summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. action: ACCEPT reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:23533145 qualifier: located_in review: summary: GBA1 was detected in extracellular exosome proteomics, but this is not the main functional compartment. action: KEEP_AS_NON_CORE reason: Retain as non-core high-throughput localization context while keeping lysosome/lysosomal membrane as the core location. supported_by: - reference_id: PMID:23533145 supporting_text: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24162852 qualifier: enables review: summary: The cited interaction is real, but generic protein binding is not an informative GBA1 molecular function. action: MARK_AS_OVER_ANNOTATED reason: The underlying evidence concerns folding, degradation, chaperone recruitment, or trafficking rather than a reusable binding function term for GBA1. supported_by: - reference_id: PMID:24162852 supporting_text: LIMP-2 shows a helical bundle where β-glucocerebrosidase binds - term: id: GO:0005765 label: lysosomal membrane evidence_type: HDA original_reference_id: PMID:17897319 qualifier: located_in review: summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. action: ACCEPT reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. additional_reference_ids: - PMID:40159502 - PMID:18022370 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0005102 label: signaling receptor binding evidence_type: ISS original_reference_id: PMID:18022370 qualifier: enables review: summary: Signaling receptor binding is misleading for GBA1 because the receptor evidence concerns LIMP-2/SCARB2-dependent lysosomal trafficking, not signal transduction. action: MODIFY reason: Replace with scavenger receptor binding for the LIMP-2/SCARB2 interaction, or curate the interaction as lysosomal targeting context rather than signaling. proposed_replacement_terms: - id: GO:0005124 label: scavenger receptor binding additional_reference_ids: - PMID:18022370 - PMID:25202012 - PMID:40159502 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:25202012 supporting_text: LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome - reference_id: PMID:40159502 supporting_text: GCase reaches the lysosome exclusively in complex with its proprietary transport protein lysosomal integral membrane protein type-2 (LIMP-2) - term: id: GO:0005765 label: lysosomal membrane evidence_type: ISS original_reference_id: PMID:18022370 qualifier: located_in review: summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. action: ACCEPT reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. additional_reference_ids: - PMID:40159502 - PMID:18022370 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0043202 label: lysosomal lumen evidence_type: ISS original_reference_id: PMID:18022370 qualifier: located_in review: summary: lysosomal lumen is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. action: ACCEPT reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. additional_reference_ids: - PMID:40159502 - PMID:18022370 supported_by: - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - term: id: GO:0023021 label: termination of signal transduction evidence_type: IMP original_reference_id: PMID:19279008 qualifier: involved_in review: summary: The cited inflammatory signaling study supports a role for GBA1-derived ceramide in terminating p38/IL-6 signaling. action: KEEP_AS_NON_CORE reason: Retain as a non-core signaling consequence rather than a primary GBA1 molecular function. supported_by: - reference_id: PMID:19279008 supporting_text: GBA1-ceramide pathway ... regulating a pro-inflammatory pathway initiated by PKC and leading to activation of p38 and induction of interleukin 6 - reference_id: PMID:19279008 supporting_text: Knockdown of GBA1 also evoked the hyperproduction of IL-6 - term: id: GO:0032715 label: negative regulation of interleukin-6 production evidence_type: IDA original_reference_id: PMID:19279008 qualifier: involved_in review: summary: GBA1-derived ceramide negatively regulates IL-6 production in the cited inflammatory signaling model. action: KEEP_AS_NON_CORE reason: Retain as non-core because cytokine regulation is downstream of lysosomal lipid metabolism. supported_by: - reference_id: PMID:19279008 supporting_text: GBA1-ceramide pathway ... regulating a pro-inflammatory pathway initiated by PKC and leading to activation of p38 and induction of interleukin 6 - reference_id: PMID:19279008 supporting_text: Knockdown of GBA1 also evoked the hyperproduction of IL-6 - term: id: GO:0071356 label: cellular response to tumor necrosis factor evidence_type: IMP original_reference_id: PMID:19279008 qualifier: involved_in review: summary: The cited PMID supports PKC/p38/IL-6 signaling effects, but not a specific cellular response to tumor necrosis factor annotation for GBA1. action: MARK_AS_OVER_ANNOTATED reason: This term overstates the evidence and should not be retained without direct TNF-response support. supported_by: - reference_id: PMID:19279008 supporting_text: GBA1-ceramide pathway ... regulating a pro-inflammatory pathway initiated by PKC and leading to activation of p38 and induction of interleukin 6 - reference_id: PMID:19279008 supporting_text: Knockdown of GBA1 also evoked the hyperproduction of IL-6 - term: id: GO:0004348 label: glucosylceramidase activity evidence_type: IDA original_reference_id: PMID:19279011 qualifier: enables review: summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. action: ACCEPT reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0006680 label: glucosylceramide catabolic process evidence_type: IMP original_reference_id: PMID:19279011 qualifier: involved_in review: summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. action: ACCEPT reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - term: id: GO:0046512 label: sphingosine biosynthetic process evidence_type: IMP original_reference_id: PMID:19279011 qualifier: involved_in review: summary: GBA1 hydrolysis of glucosylceramide can feed sphingosine generation in the ceramide salvage pathway. action: KEEP_AS_NON_CORE reason: This is a downstream lipid-metabolic context, not the core GBA1 catalytic annotation. supported_by: - reference_id: PMID:19279011 supporting_text: GBA1 activation can generate the source (sphingosine) for PMA-induced formation of ceramide through the salvage pathway - term: id: GO:0046513 label: ceramide biosynthetic process evidence_type: IMP original_reference_id: PMID:19279011 qualifier: involved_in review: summary: GBA1-generated sphingosine can support ceramide formation through the salvage pathway in the cited PKC model. action: KEEP_AS_NON_CORE reason: Retain as non-core because ceramide biosynthesis is an indirect pathway output of glucosylceramide hydrolysis. supported_by: - reference_id: PMID:19279011 supporting_text: GBA1 activation can generate the source (sphingosine) for PMA-induced formation of ceramide through the salvage pathway references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - 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:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000116 title: Automatic Gene Ontology annotation based on Rhea mapping findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:15916907 title: Use of fluorescent substrates for characterization of Gaucher disease mutations. findings: [] - id: PMID:16293621 title: 'Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.' findings: [] - id: PMID:17187079 title: Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease. findings: [] - id: PMID:17897319 title: Integral and associated lysosomal membrane proteins. findings: [] - id: PMID:18022370 title: LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. findings: [] - id: PMID:19279008 title: 'Acid beta-glucosidase 1 counteracts p38delta-dependent induction of interleukin-6: possible role for ceramide as an anti-inflammatory lipid.' findings: [] - id: PMID:19279011 title: Involvement of acid beta-glucosidase 1 in the salvage pathway of ceramide formation. findings: [] - id: PMID:21098288 title: Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl. findings: [] - id: PMID:21700325 title: Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. findings: [] - id: PMID:22659419 title: Beta-glucosidase 1 (GBA1) is a second bile acid β-glucosidase in addition to β-glucosidase 2 (GBA2). Study in β-glucosidase deficient mice and humans. findings: [] - id: PMID:23533145 title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. findings: [] - id: PMID:23580063 title: Loss of β-glucocerebrosidase activity does not affect alpha-synuclein levels or lysosomal function in neuronal cells. findings: [] - id: PMID:24022302 title: Functional analysis of 11 novel GBA alleles. findings: [] - id: PMID:24162852 title: Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. findings: [] - id: PMID:24211208 title: Cholesterol glucosylation is catalyzed by transglucosylation reaction of β-glucosidase 1. findings: [] - id: PMID:25202012 title: 'The LIMP-2/SCARB2 binding motif on acid β-glucosidase: basic and applied implications for Gaucher disease and associated neurodegenerative diseases.' findings: [] - id: PMID:25456120 title: iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease. findings: [] - id: PMID:25584808 title: Identification of miRNAs that modulate glucocerebrosidase activity in Gaucher disease cells. findings: [] - id: PMID:26388395 title: Mitochondrial dysfunction associated with glucocerebrosidase deficiency. findings: [] - id: PMID:26392287 title: Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons. findings: [] - id: PMID:26724485 title: 'Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular β-glucosidases.' findings: [] - id: PMID:27378698 title: 'Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease.' findings: [] - id: PMID:27789271 title: Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease. findings: [] - id: PMID:40159502 title: Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2. findings: [] - id: PMID:9201993 title: Effect of saposins A and C on the enzymatic hydrolysis of liposomal glucosylceramide. findings: [] - id: Reactome:R-HSA-1605591 title: GBA1:SAPC hydrolyzes GlcCer findings: [] core_functions: - molecular_function: id: GO:0004348 label: glucosylceramidase activity description: Lysosomal acid glucosylceramidase activity that hydrolyzes glucosylceramide to ceramide and glucose, maintaining glycosphingolipid turnover and lysosomal lipid homeostasis. directly_involved_in: - id: GO:0006680 label: glucosylceramide catabolic process - id: GO:0007040 label: lysosome organization locations: - id: GO:0005764 label: lysosome - id: GO:0043202 label: lysosomal lumen - id: GO:0005765 label: lysosomal membrane supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer - reference_id: PMID:18022370 supporting_text: LIMP-2 is a specific binding partner of beta-glucocerebrosidase - reference_id: PMID:40159502 supporting_text: GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome - reference_id: PMID:40159502 supporting_text: GCase remained enzymatically active when in complex with LIMP-2 - reference_id: PMID:27378698 supporting_text: autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase - reference_id: PMID:27378698 supporting_text: GCase deficiency affects lysosomal recycling - reference_id: PMID:27378698 supporting_text: Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes proposed_new_terms: - proposed_name: autophagic lysosome reformation proposed_definition: A lysosome organization process in which autolysosomal membranes and contents are recycled to regenerate functional lysosomes after autophagic cargo degradation. justification: GBA1 deficiency, SPG11/ZFYVE26 loss, PIP5K1B activity, and KIF5B-mediated tubulation all point to ALR as a distinct lysosome regeneration process, but current reviews must use broader lysosome organization or regulation of macroautophagy terms. proposed_parent: id: GO:0007040 label: lysosome organization supported_by: - reference_id: PMID:27378698 supporting_text: autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase - reference_id: PMID:27378698 supporting_text: GCase deficiency affects lysosomal recycling - reference_id: PMID:27378698 supporting_text: Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes - proposed_name: lysosomal glucosylceramide catabolic process proposed_definition: The chemical reactions and pathways occurring in the lysosome that break down glucosylceramide into ceramide and glucose. justification: Existing GO:0006680 captures glucosylceramide catabolism but not the lysosomal compartment that is central to GBA1/GCase biology and Gaucher disease pathogenesis. proposed_parent: id: GO:0006680 label: glucosylceramide catabolic process supported_by: - reference_id: PMID:9201993 supporting_text: The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase - reference_id: PMID:9201993 supporting_text: Sap C is responsible for the membrane binding of glucosylceramidase - reference_id: PMID:40159502 supporting_text: GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide - reference_id: Reactome:R-HSA-1605591 supporting_text: GBA1:SAPC hydrolyzes GlcCer suggested_questions: - question: Should GBA1 be curated to a new autophagic lysosome reformation term, or is broad lysosome organization sufficient for GCase-deficiency ALR phenotypes? experts: - Li Yu - Grazia Isidoro - GO autophagy editors - question: Should GO distinguish lysosomal glucosylceramide catabolism from broader glucosylceramide catabolic process for compartment-specific enzymes such as GBA1? experts: - Johannes M. F. G. Aerts - Ellen Sidransky - GO lipid metabolism editors - question: Which GBA1 side activities, especially cholesterol transglucosylation and steryl-beta-glucoside hydrolysis, should remain non-core annotations versus separate physiological functions? experts: - Johannes M. F. G. Aerts - Ronald P. Oude Elferink - GO molecular function editors suggested_experiments: - description: Rescue GBA1-deficient cells with catalytically inactive, LIMP-2-binding-defective, and substrate-selective GBA1 variants, then quantify ALR tubulation, free lysosome regeneration, mTOR reactivation, and GlcCer accumulation after starvation/refeeding. experiment_type: genetic rescue/live-cell lysosome imaging and lipidomics hypothesis: GBA1-dependent ALR defects are driven primarily by loss of lysosomal glucosylceramide hydrolysis rather than by non-catalytic LIMP-2 binding. - description: Measure cholesterol transglucosylation, steryl-beta-glucoside hydrolysis, and GlcCer hydrolysis by matched GBA1 mutants in lysosome-like membranes across cholesterol-loading conditions. experiment_type: in vitro enzymology and lysosomal lipidomics hypothesis: Cholesterol/steryl-glucoside reactions are condition-dependent side activities separable from the core glucosylceramidase function. - description: Compare alpha-synuclein turnover, lysosomal protease activity, and GlcCer/GlcChol levels after GBA1 restoration in neuronal models with and without ALR defects. experiment_type: neuronal disease-model rescue assay hypothesis: GBA1 effects on lysosomal protein catabolism are secondary to lipid-driven lysosomal organization and ALR defects.