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.
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.
Parent term: lysosome organization
Supporting Evidence:
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.
Parent term: glucosylceramide catabolic process
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006680 glucosylceramide catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. Reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0004348 glucosylceramidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0004336 galactosylceramidase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: GBA1 can hydrolyze galactosylceramide, but UniProt describes this as lower activity than glucosylceramide hydrolysis. Reason: This is a direct side activity rather than the core lysosomal glucosylceramide catabolic function. Supporting Evidence: file:human/GBA1/GBA1-uniprot.txt Catalyzes the hydrolysis of galactosylceramides/GalCers file:human/GBA1/GBA1-uniprot.txt with lower activity than with GlcCers |
| GO:0004348 glucosylceramidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000120 | ACCEPT | Summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. Reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0006665 sphingolipid metabolic process | IEA GO_REF:0000002 | MODIFY | Summary: The broad sphingolipid metabolic process annotation captures the general lipid class but loses the specific GBA1 function. Reason: Replace with glucosylceramide catabolic process, the specific sphingolipid process directly catalyzed by GBA1. Proposed replacements: glucosylceramide catabolic process Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0016241 regulation of macroautophagy | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: GCase deficiency affects autophagy readouts and ALR after starvation/refeeding, but macroautophagy regulation is downstream of lysosomal lipid catabolism. Reason: The evidence supports a non-core proteostasis effect rather than a primary regulatory molecular function. Supporting Evidence: PMID:27378698 autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase PMID:27378698 GCase deficiency affects lysosomal recycling PMID:27378698 Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes |
| GO:0030163 protein catabolic process | IEA GO_REF:0000117 | MODIFY | Summary: Generic protein catabolic process is too broad for GBA1; the relevant evidence concerns lysosomal proteolysis/alpha-synuclein handling when GCase activity is deficient. Reason: Use regulation of lysosomal protein catabolic process to reflect the indirect lysosomal proteostasis role. Proposed replacements: regulation of lysosomal protein catabolic process Supporting Evidence: PMID:21700325 GCase depletion causes a decline in lysosomal proteolysis that preferentially affects alpha-syn PMID:26392287 Glucocerebrosidase gene therapy prevents alpha-synucleinopathy of midbrain dopamine neurons |
| GO:0042176 regulation of protein catabolic process | IEA GO_REF:0000117 | MODIFY | Summary: Regulation of protein catabolic process is too broad for the observed GBA1-linked lysosomal proteostasis effects. Reason: Use regulation of lysosomal protein catabolic process, which matches the alpha-synuclein/lysosomal degradation context more closely. Proposed replacements: regulation of lysosomal protein catabolic process Supporting Evidence: PMID:21700325 GCase depletion causes a decline in lysosomal proteolysis that preferentially affects alpha-syn PMID:26392287 Glucocerebrosidase gene therapy prevents alpha-synucleinopathy of midbrain dopamine neurons |
| GO:0042391 regulation of membrane potential | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Regulation of membrane potential is not a well-supported direct GBA1 function in the reviewed evidence. Reason: Mitochondrial and neuronal electrophysiology phenotypes are downstream disease contexts and should not be propagated as a GBA1 core GO process. Supporting Evidence: PMID:25456120 mitochondria ... displayed normal morphology and regular distribution |
| GO:0050295 steryl-beta-glucosidase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: GBA1 can hydrolyze glucosylated cholesterol/steryl beta-glucosides, but this is a side activity relative to glucosylceramide hydrolysis. Reason: Retain as a direct non-core catalytic activity supported by cholesterol-glucoside metabolism studies. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:0005515 protein binding | IPI PMID:21098288 Decreased glucocerebrosidase activity in Gaucher disease par... | MARK AS OVER ANNOTATED | Summary: The cited interaction is real, but generic protein binding is not an informative GBA1 molecular function. Reason: The underlying evidence concerns folding, degradation, chaperone recruitment, or trafficking rather than a reusable binding function term for GBA1. Supporting Evidence: PMID:21098288 reduced binding of GCase to TCP1 ring complex (TRiC), a regulator of correct protein folding |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000120 | MODIFY | Summary: Signaling receptor binding is misleading for GBA1 because the receptor evidence concerns LIMP-2/SCARB2-dependent lysosomal trafficking, not signal transduction. Reason: Replace with scavenger receptor binding for the LIMP-2/SCARB2 interaction, or curate the interaction as lysosomal targeting context rather than signaling. Proposed replacements: scavenger receptor binding Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:25202012 LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome PMID:40159502 GCase reaches the lysosome exclusively in complex with its proprietary transport protein lysosomal integral membrane protein type-2 (LIMP-2) |
| GO:0005576 extracellular region | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: GBA1 can be detected or secreted outside the lysosome in some contexts, but this is not the main catalytic compartment. Reason: Retain as non-core because normal GBA1 function depends on lysosomal targeting; extracellular localization is secondary or context-dependent. Supporting Evidence: PMID:18022370 LIMP-2-deficient mouse tissues ... beta-glucocerebrosidase was secreted |
| GO:0005764 lysosome | IEA GO_REF:0000107 | ACCEPT | Summary: lysosome is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. Reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: endoplasmic reticulum is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. Reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Golgi apparatus is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. Reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0005802 trans-Golgi network | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: trans-Golgi network is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. Reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0006680 glucosylceramide catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. Reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0006914 autophagy | IEA GO_REF:0000120 | MODIFY | Summary: Generic autophagy is too broad for the GBA1 evidence, which specifically shows impaired ALR, lysosomal recycling, and autophagosome clearance after GCase loss. Reason: Replace with lysosome organization and regulation of macroautophagy to capture the proteostasis effect without overclaiming a core autophagy machinery role. Proposed replacements: lysosome organization regulation of macroautophagy Supporting Evidence: PMID:27378698 autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase PMID:27378698 GCase deficiency affects lysosomal recycling PMID:27378698 Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes |
| GO:0007040 lysosome organization | IEA GO_REF:0000120 | ACCEPT | Summary: GBA1 deficiency impairs autophagic lysosome reformation, lysosomal recycling, and endosome maturation, supporting lysosome organization in the proteostasis context. 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. Supporting Evidence: PMID:27378698 autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase PMID:27378698 GCase deficiency affects lysosomal recycling PMID:27378698 Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes |
| GO:0008203 cholesterol metabolic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: GBA1 participates in glucosylated cholesterol formation and degradation, but cholesterol metabolism is a side context relative to GlcCer catabolism. Reason: Retain as non-core because the direct catalytic evidence is conditional/side activity rather than the main lysosomal substrate pathway. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:0008422 beta-glucosidase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: GBA1 has beta-glucosidase activity, including bile-acid beta-glucoside hydrolysis, but this broad term is less specific than the core glucosylceramidase annotation. Reason: Retain as a supported non-core/broad catalytic context while keeping glucosylceramidase activity as the core molecular function. Supporting Evidence: PMID:22659419 GBA1 also hydrolyses BG PMID:22659419 GBA1 as a bile acid beta-glucosidase |
| GO:0009247 glycolipid biosynthetic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: GBA1 can catalyze cholesterol glucosylation through transglucosylation, providing a direct but non-core glycoside biosynthetic activity. Reason: Retain as non-core because the principal function is catabolism of glucosylceramide, not glycolipid biosynthesis. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:0009267 cellular response to starvation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The ALR evidence uses starvation/refeeding and shows defective lysosome regeneration in GCase-deficient cells. Reason: This supports a non-core starvation-response context, but the molecular function remains lysosomal glucosylceramidase activity. Supporting Evidence: PMID:27378698 autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase PMID:27378698 GCase deficiency affects lysosomal recycling PMID:27378698 Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes |
| GO:0009268 response to pH | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: GBA1 has an acidic pH optimum, but enzyme pH dependence is not evidence that the gene product is involved in response to pH. Reason: The reviewed evidence supports acid lysosomal catalysis and an enzyme pH optimum, not a regulated response-to-pH biological process. Supporting Evidence: file:human/GBA1/GBA1-uniprot.txt pH dependence: file:human/GBA1/GBA1-uniprot.txt Optimum pH is 5.3. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000107 | MODIFY | Summary: Hydrolase activity is correct but too broad to be informative for GBA1. Reason: Replace with glucosylceramidase activity, the specific hydrolase activity of GBA1. Proposed replacements: glucosylceramidase activity Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0032006 regulation of TOR signaling | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: GCase deficiency lowers mTOR/S6K signaling during ALR recovery, and recombinant GCase can reverse that effect. Reason: This is a downstream ALR/lysosome-recycling consequence rather than the core enzymatic function. Supporting Evidence: PMID:27378698 Cerezyme treatment significantly increased phospho-S6K levels ... corroborating the direct relation between the loss of GCase activity and the decreased mTOR activity PMID:27378698 ALR is a cellular process controlled by mTOR |
| GO:0033574 response to testosterone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: response to testosterone is not supported as a direct GBA1 function by the reviewed lysosomal enzyme literature. Reason: This appears to be an automatic/contextual projection and should not be treated as a curated GBA1 functional annotation without direct evidence. Supporting Evidence: GO_REF:0000107 automatic or inferred annotation; no direct supporting GBA1 publication was identified in the cached review evidence |
| GO:0043202 lysosomal lumen | IEA GO_REF:0000107 | ACCEPT | Summary: lysosomal lumen is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. Reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0043627 response to estrogen | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: response to estrogen is not supported as a direct GBA1 function by the reviewed lysosomal enzyme literature. Reason: This appears to be an automatic/contextual projection and should not be treated as a curated GBA1 functional annotation without direct evidence. Supporting Evidence: GO_REF:0000107 automatic or inferred annotation; no direct supporting GBA1 publication was identified in the cached review evidence |
| GO:0046527 glucosyltransferase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: GBA1 can transfer glucose from GlcCer to cholesterol through a transglucosylation reaction. Reason: This direct glucosyltransferase side activity is retained as non-core because GBA1 is primarily a lysosomal glucosylceramidase. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:0061436 establishment of skin barrier | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: establishment of skin barrier is a broad organismal/developmental outcome that is not established as a direct GBA1 function in the reviewed evidence. Reason: GBA1 lipid catabolism can affect tissues, but this annotation over-propagates phenotype/development context beyond the core lysosomal enzyme role. Supporting Evidence: GO_REF:0000107 automatic annotation; direct cached evidence supports lysosomal lipid catabolism rather than this broad developmental process |
| GO:0071548 response to dexamethasone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: response to dexamethasone is not supported as a direct GBA1 function by the reviewed lysosomal enzyme literature. Reason: This appears to be an automatic/contextual projection and should not be treated as a curated GBA1 functional annotation without direct evidence. Supporting Evidence: GO_REF:0000107 automatic or inferred annotation; no direct supporting GBA1 publication was identified in the cached review evidence |
| GO:0097066 response to thyroid hormone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: response to thyroid hormone is not supported as a direct GBA1 function by the reviewed lysosomal enzyme literature. Reason: This appears to be an automatic/contextual projection and should not be treated as a curated GBA1 functional annotation without direct evidence. Supporting Evidence: GO_REF:0000107 automatic or inferred annotation; no direct supporting GBA1 publication was identified in the cached review evidence |
| GO:0098773 skin epidermis development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: skin epidermis development is a broad organismal/developmental outcome that is not established as a direct GBA1 function in the reviewed evidence. Reason: GBA1 lipid catabolism can affect tissues, but this annotation over-propagates phenotype/development context beyond the core lysosomal enzyme role. Supporting Evidence: GO_REF:0000107 automatic annotation; direct cached evidence supports lysosomal lipid catabolism rather than this broad developmental process |
| GO:1901805 beta-glucoside catabolic process | IEA GO_REF:0000107 | MODIFY | Summary: Beta-glucoside catabolic process is too generic for the main GBA1 substrate context. Reason: Replace with glucosylceramide catabolic process, the specific lysosomal beta-glucoside catabolism catalyzed by GBA1. Proposed replacements: glucosylceramide catabolic process Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0005765 lysosomal membrane | IPI PMID:40159502 Cryo-TEM structure of Ξ²-glucocerebrosidase in complex with i... | ACCEPT | Summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. Reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0019377 glycolipid catabolic process | NAS PMID:40159502 Cryo-TEM structure of Ξ²-glucocerebrosidase in complex with i... | MODIFY | Summary: Glycolipid catabolic process is directionally correct but less specific than the supported GBA1 function. Reason: Replace with glucosylceramide catabolic process, the specific glycolipid catabolic pathway for GBA1. Proposed replacements: glucosylceramide catabolic process Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0009247 glycolipid biosynthetic process | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: GBA1 can catalyze cholesterol glucosylation through transglucosylation, providing a direct but non-core glycoside biosynthetic activity. Reason: Retain as non-core because the principal function is catabolism of glucosylceramide, not glycolipid biosynthesis. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:0009247 glycolipid biosynthetic process | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: GBA1 can catalyze cholesterol glucosylation through transglucosylation, providing a direct but non-core glycoside biosynthetic activity. Reason: Retain as non-core because the principal function is catabolism of glucosylceramide, not glycolipid biosynthesis. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:1905146 lysosomal protein catabolic process | IDA PMID:26392287 Glucocerebrosidase gene therapy prevents Ξ±-synucleinopathy o... | KEEP AS NON CORE | Summary: GBA1 activity can influence lysosomal protein catabolism and alpha-synuclein handling in neuronal disease models. Reason: This is a supported proteostasis/disease consequence but not the enzyme core substrate pathway. Supporting Evidence: PMID:21700325 GCase depletion causes a decline in lysosomal proteolysis that preferentially affects alpha-syn PMID:26392287 Glucocerebrosidase gene therapy prevents alpha-synucleinopathy of midbrain dopamine neurons |
| GO:0050728 negative regulation of inflammatory response | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: GBA1-generated ceramide counteracts inflammatory signaling and IL-6 production in the cited cell model. Reason: Retain as non-core because it is a downstream signaling consequence of lysosomal lipid metabolism. Supporting Evidence: PMID:19279008 GBA1-ceramide pathway ... regulating a pro-inflammatory pathway initiated by PKC and leading to activation of p38 and induction of interleukin 6 PMID:19279008 Knockdown of GBA1 also evoked the hyperproduction of IL-6 |
| GO:0043409 negative regulation of MAPK cascade | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: GBA1 depletion increased p38 pathway activation in the cited inflammatory signaling model. Reason: Retain as non-core because MAPK regulation is downstream of ceramide signaling rather than the conserved enzyme role. Supporting Evidence: PMID:19279008 GBA1-ceramide pathway ... regulating a pro-inflammatory pathway initiated by PKC and leading to activation of p38 and induction of interleukin 6 PMID:19279008 Knockdown of GBA1 also evoked the hyperproduction of IL-6 |
| GO:0004348 glucosylceramidase activity | IMP PMID:25584808 Identification of miRNAs that modulate glucocerebrosidase ac... | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:25584808 Identification of miRNAs that modulate glucocerebrosidase ac... | ACCEPT | Summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. Reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-1605591 | ACCEPT | Summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. Reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0004348 glucosylceramidase activity | IDA PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0004348 glucosylceramidase activity | IMP PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0008422 beta-glucosidase activity | IDA PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | KEEP AS NON CORE | Summary: GBA1 has beta-glucosidase activity, including bile-acid beta-glucoside hydrolysis, but this broad term is less specific than the core glucosylceramidase annotation. Reason: Retain as a supported non-core/broad catalytic context while keeping glucosylceramidase activity as the core molecular function. Supporting Evidence: PMID:22659419 GBA1 also hydrolyses BG PMID:22659419 GBA1 as a bile acid beta-glucosidase |
| GO:0008422 beta-glucosidase activity | IMP PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | KEEP AS NON CORE | Summary: GBA1 has beta-glucosidase activity, including bile-acid beta-glucoside hydrolysis, but this broad term is less specific than the core glucosylceramidase annotation. Reason: Retain as a supported non-core/broad catalytic context while keeping glucosylceramidase activity as the core molecular function. Supporting Evidence: PMID:22659419 GBA1 also hydrolyses BG PMID:22659419 GBA1 as a bile acid beta-glucosidase |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: endoplasmic reticulum is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. Reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0005794 Golgi apparatus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Golgi apparatus is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. Reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0005802 trans-Golgi network | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: trans-Golgi network is part of the GCase-LIMP-2 biosynthetic/trafficking itinerary rather than the site of mature GBA1 catalysis. Reason: The 2025 structure supports ER-to-TGN-to-lysosome transport, but the core location remains the lysosomal lumenal/membrane interface. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0005515 protein binding | IPI PMID:27789271 Progranulin Recruits HSP70 to Ξ²-Glucocerebrosidase and Is Th... | MARK AS OVER ANNOTATED | Summary: The cited interaction is real, but generic protein binding is not an informative GBA1 molecular function. Reason: The underlying evidence concerns folding, degradation, chaperone recruitment, or trafficking rather than a reusable binding function term for GBA1. Supporting Evidence: PMID:27789271 PGRN binds directly to GCase |
| GO:0004348 glucosylceramidase activity | IDA PMID:16293621 Analyses of variant acid beta-glucosidases: effects of Gauch... | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0005765 lysosomal membrane | IDA PMID:17187079 Structure of acid beta-glucosidase with pharmacological chap... | ACCEPT | Summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. Reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0006680 glucosylceramide catabolic process | IDA PMID:16293621 Analyses of variant acid beta-glucosidases: effects of Gauch... | ACCEPT | Summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. Reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0006914 autophagy | IMP PMID:27378698 Autophagic lysosome reformation dysfunction in glucocerebros... | MODIFY | Summary: Generic autophagy is too broad for the GBA1 evidence, which specifically shows impaired ALR, lysosomal recycling, and autophagosome clearance after GCase loss. Reason: Replace with lysosome organization and regulation of macroautophagy to capture the proteostasis effect without overclaiming a core autophagy machinery role. Proposed replacements: lysosome organization regulation of macroautophagy Supporting Evidence: PMID:27378698 autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase PMID:27378698 GCase deficiency affects lysosomal recycling PMID:27378698 Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes |
| GO:0007040 lysosome organization | IMP PMID:27378698 Autophagic lysosome reformation dysfunction in glucocerebros... | ACCEPT | Summary: GBA1 deficiency impairs autophagic lysosome reformation, lysosomal recycling, and endosome maturation, supporting lysosome organization in the proteostasis context. 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. Supporting Evidence: PMID:27378698 autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase PMID:27378698 GCase deficiency affects lysosomal recycling PMID:27378698 Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes |
| GO:0008203 cholesterol metabolic process | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: GBA1 participates in glucosylated cholesterol formation and degradation, but cholesterol metabolism is a side context relative to GlcCer catabolism. Reason: Retain as non-core because the direct catalytic evidence is conditional/side activity rather than the main lysosomal substrate pathway. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:0032006 regulation of TOR signaling | IMP PMID:27378698 Autophagic lysosome reformation dysfunction in glucocerebros... | KEEP AS NON CORE | Summary: GCase deficiency lowers mTOR/S6K signaling during ALR recovery, and recombinant GCase can reverse that effect. Reason: This is a downstream ALR/lysosome-recycling consequence rather than the core enzymatic function. Supporting Evidence: PMID:27378698 Cerezyme treatment significantly increased phospho-S6K levels ... corroborating the direct relation between the loss of GCase activity and the decreased mTOR activity PMID:27378698 ALR is a cellular process controlled by mTOR |
| GO:0046527 glucosyltransferase activity | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: GBA1 can transfer glucose from GlcCer to cholesterol through a transglucosylation reaction. Reason: This direct glucosyltransferase side activity is retained as non-core because GBA1 is primarily a lysosomal glucosylceramidase. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:0050295 steryl-beta-glucosidase activity | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: GBA1 can hydrolyze glucosylated cholesterol/steryl beta-glucosides, but this is a side activity relative to glucosylceramide hydrolysis. Reason: Retain as a direct non-core catalytic activity supported by cholesterol-glucoside metabolism studies. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:0004348 glucosylceramidase activity | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0006680 glucosylceramide catabolic process | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | ACCEPT | Summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. Reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0008203 cholesterol metabolic process | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: GBA1 participates in glucosylated cholesterol formation and degradation, but cholesterol metabolism is a side context relative to GlcCer catabolism. Reason: Retain as non-core because the direct catalytic evidence is conditional/side activity rather than the main lysosomal substrate pathway. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:0046527 glucosyltransferase activity | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: GBA1 can transfer glucose from GlcCer to cholesterol through a transglucosylation reaction. Reason: This direct glucosyltransferase side activity is retained as non-core because GBA1 is primarily a lysosomal glucosylceramidase. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:0050295 steryl-beta-glucosidase activity | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: GBA1 can hydrolyze glucosylated cholesterol/steryl beta-glucosides, but this is a side activity relative to glucosylceramide hydrolysis. Reason: Retain as a direct non-core catalytic activity supported by cholesterol-glucoside metabolism studies. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity PMID:26724485 GBA is able to form GlcChol by transglucosylation of cholesterol PMID:26724485 GlcChol is ... also an excellent substrate for hydrolysis by GBA |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:24022302 Functional analysis of 11 novel GBA alleles. | ACCEPT | Summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. Reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0004348 glucosylceramidase activity | IDA PMID:9201993 Effect of saposins A and C on the enzymatic hydrolysis of li... | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0006680 glucosylceramide catabolic process | IDA PMID:9201993 Effect of saposins A and C on the enzymatic hydrolysis of li... | ACCEPT | Summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. Reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0004348 glucosylceramidase activity | IMP PMID:15916907 Use of fluorescent substrates for characterization of Gauche... | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0005124 scavenger receptor binding | IPI PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | KEEP AS NON CORE | Summary: GBA1 directly binds LIMP-2/SCARB2, the lysosomal trafficking receptor for GCase. Reason: This binding is mechanistically important for localization but is not the core catalytic activity. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:25202012 LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome PMID:40159502 GCase reaches the lysosome exclusively in complex with its proprietary transport protein lysosomal integral membrane protein type-2 (LIMP-2) |
| GO:0005764 lysosome | IMP PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | ACCEPT | Summary: lysosome is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. Reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0004348 glucosylceramidase activity | IMP PMID:23580063 Loss of Ξ²-glucocerebrosidase activity does not affect alpha-... | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0007005 mitochondrion organization | IMP NOT PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | MARK AS OVER ANNOTATED | Summary: Mitochondrion organization is not supported as a direct GBA1 process by the cited iPSC twin study. Reason: The paper reports normal mitochondrial morphology/distribution, and broader mitochondrial dysfunction is a downstream disease context rather than core GBA1 function. Supporting Evidence: PMID:25456120 mitochondria ... displayed normal morphology and regular distribution |
| GO:0031175 neuron projection development | IMP NOT PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | MARK AS OVER ANNOTATED | Summary: Neuron projection development is too broad and indirect for the GBA1 iPSC disease-model evidence. Reason: The cited study supports disease phenotypes in dopaminergic neurons, not a direct developmental function for GBA1. Supporting Evidence: PMID:25456120 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 |
| GO:1904457 positive regulation of neuronal action potential | IMP PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | MARK AS OVER ANNOTATED | Summary: Positive regulation of neuronal action potential is an over-specific neuronal phenotype annotation for GBA1. 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. Supporting Evidence: PMID:25456120 delay in the emergence of spontaneous action potentials |
| GO:1905165 regulation of lysosomal protein catabolic process | TAS PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | KEEP AS NON CORE | Summary: GBA1 activity can affect lysosomal protein catabolism/alpha-synuclein clearance in neuronal disease models. Reason: This is a supported non-core proteostasis consequence of lysosomal lipid catabolism. Supporting Evidence: PMID:21700325 GCase depletion causes a decline in lysosomal proteolysis that preferentially affects alpha-syn PMID:26392287 Glucocerebrosidase gene therapy prevents alpha-synucleinopathy of midbrain dopamine neurons |
| GO:0016241 regulation of macroautophagy | TAS PMID:26388395 Mitochondrial dysfunction associated with glucocerebrosidase... | KEEP AS NON CORE | Summary: GCase deficiency affects autophagy readouts and ALR after starvation/refeeding, but macroautophagy regulation is downstream of lysosomal lipid catabolism. Reason: The evidence supports a non-core proteostasis effect rather than a primary regulatory molecular function. Supporting Evidence: PMID:27378698 autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase PMID:27378698 GCase deficiency affects lysosomal recycling PMID:27378698 Loss of lysosomal GCase causes impairment of ALR and maturation of endosomes |
| GO:0004348 glucosylceramidase activity | IMP PMID:21700325 Gaucher disease glucocerebrosidase and Ξ±-synuclein form a bi... | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:21700325 Gaucher disease glucocerebrosidase and Ξ±-synuclein form a bi... | ACCEPT | Summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. Reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: GBA1 was detected in extracellular exosome proteomics, but this is not the main functional compartment. Reason: Retain as non-core high-throughput localization context while keeping lysosome/lysosomal membrane as the core location. Supporting Evidence: PMID:23533145 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine |
| GO:0005515 protein binding | IPI PMID:24162852 Structure of LIMP-2 provides functional insights with implic... | MARK AS OVER ANNOTATED | Summary: The cited interaction is real, but generic protein binding is not an informative GBA1 molecular function. Reason: The underlying evidence concerns folding, degradation, chaperone recruitment, or trafficking rather than a reusable binding function term for GBA1. Supporting Evidence: PMID:24162852 LIMP-2 shows a helical bundle where Ξ²-glucocerebrosidase binds |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | ACCEPT | Summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. Reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0005102 signaling receptor binding | ISS PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | MODIFY | Summary: Signaling receptor binding is misleading for GBA1 because the receptor evidence concerns LIMP-2/SCARB2-dependent lysosomal trafficking, not signal transduction. Reason: Replace with scavenger receptor binding for the LIMP-2/SCARB2 interaction, or curate the interaction as lysosomal targeting context rather than signaling. Proposed replacements: scavenger receptor binding Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:25202012 LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome PMID:40159502 GCase reaches the lysosome exclusively in complex with its proprietary transport protein lysosomal integral membrane protein type-2 (LIMP-2) |
| GO:0005765 lysosomal membrane | ISS PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | ACCEPT | Summary: lysosomal membrane is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. Reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0043202 lysosomal lumen | ISS PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | ACCEPT | Summary: lysosomal lumen is an appropriate core cellular location for GBA1 catalytic activity and/or the GCase-LIMP-2 transport complex. Reason: GBA1 acts on the lumenal side of the lysosomal membrane after LIMP-2/SCARB2-dependent lysosomal targeting. Supporting Evidence: PMID:18022370 LIMP-2 is a specific binding partner of beta-glucocerebrosidase PMID:40159502 GCase/LIMP-2 transport complex forms within the endoplasmic reticulum (ER) and travels through the trans-Golgi network to the lysosome PMID:40159502 GCase remained enzymatically active when in complex with LIMP-2 |
| GO:0023021 termination of signal transduction | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: The cited inflammatory signaling study supports a role for GBA1-derived ceramide in terminating p38/IL-6 signaling. Reason: Retain as a non-core signaling consequence rather than a primary GBA1 molecular function. Supporting Evidence: PMID:19279008 GBA1-ceramide pathway ... regulating a pro-inflammatory pathway initiated by PKC and leading to activation of p38 and induction of interleukin 6 PMID:19279008 Knockdown of GBA1 also evoked the hyperproduction of IL-6 |
| GO:0032715 negative regulation of interleukin-6 production | IDA PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: GBA1-derived ceramide negatively regulates IL-6 production in the cited inflammatory signaling model. Reason: Retain as non-core because cytokine regulation is downstream of lysosomal lipid metabolism. Supporting Evidence: PMID:19279008 GBA1-ceramide pathway ... regulating a pro-inflammatory pathway initiated by PKC and leading to activation of p38 and induction of interleukin 6 PMID:19279008 Knockdown of GBA1 also evoked the hyperproduction of IL-6 |
| GO:0071356 cellular response to tumor necrosis factor | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | MARK AS OVER ANNOTATED | Summary: The cited PMID supports PKC/p38/IL-6 signaling effects, but not a specific cellular response to tumor necrosis factor annotation for GBA1. Reason: This term overstates the evidence and should not be retained without direct TNF-response support. Supporting Evidence: PMID:19279008 GBA1-ceramide pathway ... regulating a pro-inflammatory pathway initiated by PKC and leading to activation of p38 and induction of interleukin 6 PMID:19279008 Knockdown of GBA1 also evoked the hyperproduction of IL-6 |
| GO:0004348 glucosylceramidase activity | IDA PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | ACCEPT | Summary: GBA1 directly enables lysosomal acid glucosylceramidase activity, hydrolyzing glucosylceramide to ceramide and glucose. Reason: This is the conserved catalytic function of GBA1 and is supported by biochemical, variant, Reactome, and structural/transport evidence. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | ACCEPT | Summary: GBA1 is directly involved in lysosomal glucosylceramide catabolism through its glucosylceramidase activity. Reason: Glucosylceramide catabolism is the main biological process output of the enzyme and is central to Gaucher disease and lysosomal lipid turnover. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase PMID:9201993 Sap C is responsible for the membrane binding of glucosylceramidase PMID:40159502 GCase belongs to the enzymatic family of glycosidases and hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide Reactome:R-HSA-1605591 GBA1:SAPC hydrolyzes GlcCer |
| GO:0046512 sphingosine biosynthetic process | IMP PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | KEEP AS NON CORE | Summary: GBA1 hydrolysis of glucosylceramide can feed sphingosine generation in the ceramide salvage pathway. Reason: This is a downstream lipid-metabolic context, not the core GBA1 catalytic annotation. Supporting Evidence: PMID:19279011 GBA1 activation can generate the source (sphingosine) for PMA-induced formation of ceramide through the salvage pathway |
| GO:0046513 ceramide biosynthetic process | IMP PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | KEEP AS NON CORE | Summary: GBA1-generated sphingosine can support ceramide formation through the salvage pathway in the cited PKC model. Reason: Retain as non-core because ceramide biosynthesis is an indirect pathway output of glucosylceramide hydrolysis. Supporting Evidence: PMID:19279011 GBA1 activation can generate the source (sphingosine) for PMA-induced formation of ceramide through the salvage pathway |
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Download this section (compressed HTML)Q: Should GBA1 be curated to a new autophagic lysosome reformation term, or is broad lysosome organization sufficient for GCase-deficiency ALR phenotypes?
Suggested experts: Li Yu, Grazia Isidoro, GO autophagy editors
Q: Should GO distinguish lysosomal glucosylceramide catabolism from broader glucosylceramide catabolic process for compartment-specific enzymes such as GBA1?
Suggested experts: Johannes M. F. G. Aerts, Ellen Sidransky, GO lipid metabolism editors
Q: Which GBA1 side activities, especially cholesterol transglucosylation and steryl-beta-glucoside hydrolysis, should remain non-core annotations versus separate physiological functions?
Suggested experts: Johannes M. F. G. Aerts, Ronald P. Oude Elferink, GO molecular function editors
Experiment: 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.
Hypothesis: GBA1-dependent ALR defects are driven primarily by loss of lysosomal glucosylceramide hydrolysis rather than by non-catalytic LIMP-2 binding.
Type: genetic rescue/live-cell lysosome imaging and lipidomics
Experiment: Measure cholesterol transglucosylation, steryl-beta-glucoside hydrolysis, and GlcCer hydrolysis by matched GBA1 mutants in lysosome-like membranes across cholesterol-loading conditions.
Hypothesis: Cholesterol/steryl-glucoside reactions are condition-dependent side activities separable from the core glucosylceramidase function.
Type: in vitro enzymology and lysosomal lipidomics
Experiment: Compare alpha-synuclein turnover, lysosomal protease activity, and GlcCer/GlcChol levels after GBA1 restoration in neuronal models with and without ALR defects.
Hypothesis: GBA1 effects on lysosomal protein catabolism are secondary to lipid-driven lysosomal organization and ALR defects.
Type: neuronal disease-model rescue assay
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