Existing Annotations Review

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 β-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 β-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 α-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 β-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 β-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 β-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 β-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 β-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 β-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 β-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 β-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 α-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 α-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 β-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

Core Functions

Lysosomal acid glucosylceramidase activity that hydrolyzes glucosylceramide to ceramide and glucose, maintaining glycosphingolipid turnover and lysosomal lipid homeostasis.

Molecular Function:

glucosylceramidase activity

Directly Involved In:

glucosylceramide catabolic process lysosome organization

Cellular Locations:

lysosome lysosomal lumen lysosomal membrane

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
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
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

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:15916907

Use of fluorescent substrates for characterization of Gaucher disease mutations.

PMID:16293621

Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.

PMID:17187079

Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease.

PMID:17897319

Integral and associated lysosomal membrane proteins.

PMID:18022370

LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase.

PMID:19279008

Acid beta-glucosidase 1 counteracts p38delta-dependent induction of interleukin-6: possible role for ceramide as an anti-inflammatory lipid.

PMID:19279011

Involvement of acid beta-glucosidase 1 in the salvage pathway of ceramide formation.

PMID:21098288

Decreased glucocerebrosidase activity in Gaucher disease parallels quantitative enzyme loss due to abnormal interaction with TCP1 and c-Cbl.

PMID:21700325

Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.

PMID:22659419

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.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

PMID:23580063

Loss of β-glucocerebrosidase activity does not affect alpha-synuclein levels or lysosomal function in neuronal cells.

PMID:24022302

Functional analysis of 11 novel GBA alleles.

PMID:24162852

Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36.

PMID:24211208

Cholesterol glucosylation is catalyzed by transglucosylation reaction of β-glucosidase 1.

PMID:25202012

The LIMP-2/SCARB2 binding motif on acid β-glucosidase: basic and applied implications for Gaucher disease and associated neurodegenerative diseases.

PMID:25456120

iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease.

PMID:25584808

Identification of miRNAs that modulate glucocerebrosidase activity in Gaucher disease cells.

PMID:26388395

Mitochondrial dysfunction associated with glucocerebrosidase deficiency.

PMID:26392287

Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons.

PMID:26724485

Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular β-glucosidases.

PMID:27378698

Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease.

PMID:27789271

Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease.

PMID:40159502

Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2.

PMID:9201993

Effect of saposins A and C on the enzymatic hydrolysis of liposomal glucosylceramide.

Reactome:R-HSA-1605591

GBA1:SAPC hydrolyzes GlcCer

Suggested Experiments

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

📚 Additional Documentation

Notes

(GBA1-notes.md)

GBA1 review notes

Review context

GBA1 is in the proteostasis network under lysosomal lipid catabolism and a no-mapping
autophagic lysosome reformation context. The PN ALR row is useful for literature
triage, but the review decisions below are based on GOA, UniProt, cached publications,
and Reactome rather than PN taxonomy alone.

Falcon deep research: just deep-research-falcon human GBA1 timed out after 600s
with Provider falcon timed out after 600s; no Falcon findings were available to
incorporate into this review.

Core function synthesis

GBA1 encodes lysosomal acid glucosylceramidase. The UniProt record summarizes the
core activity as lysosomal hydrolysis of glucosylceramides to ceramides and glucose,
with a pH optimum in the acidic lysosomal range and activation by saposins A/C
[UniProt:P04062 "Glucosylceramidase that catalyzes, within the lysosomal compartment,
the hydrolysis of glucosylceramides/GlcCers ... into free ceramides ... and glucose"].

The glucosylceramide catabolic role is repeatedly supported by experimental papers:
saposin A/C assays state that glucosylceramide degradation in lysosomes is accomplished
by glucosylceramidase and that saposin C promotes membrane binding of GCase
[PMID:9201993 "The degradation of glucosylceramide in lysosomes is accomplished by
glucosylceramidase"; PMID:9201993 "saposin C is responsible for the membrane binding
of glucosylceramidase"]. Disease-variant and substrate assays also support
glucosylceramidase activity and glucosylceramide catabolism [PMID:16293621
"Analyses of variant acid beta-glucosidases"; PMID:15916907 "Use of fluorescent
substrates for characterization of Gaucher disease mutations"; PMID:24022302
"Functional analysis of 11 novel GBA alleles"].

GBA1 localizes to the lysosomal lumenal side of the lysosomal membrane. LIMP-2/SCARB2
is the trafficking receptor for M6P-independent lysosomal delivery of GCase
[PMID:18022370 "LIMP-2 is a specific binding partner of beta-glucocerebrosidase";
PMID:18022370 "LIMP-2-deficient mouse tissues ... beta-glucocerebrosidase was
secreted"]. The 2025 cryo-TEM structure supports an ER-to-TGN-to-lysosome transport
complex with LIMP-2 and confirms that GCase remains enzymatically active in that
complex [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"].

Proteostasis and ALR context

The key proteostasis-relevant paper reports that GCase deficiency compromises
autophagic lysosome reformation (ALR), lysosomal recycling, endosome maturation, and
mTOR reactivation after starvation/refeeding [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"]. This supports keeping
lysosome organization as a real GBA1 process annotation, but it does not make
generic autophagy or all protein catabolic process terms core molecular functions.

Alpha-synuclein/GCase papers support non-core disease and lysosomal protein-catabolism
contexts. GCase depletion can reduce lysosomal proteolysis affecting alpha-synuclein
and establish a bidirectional pathogenic loop PMID:21700325, while a
contrasting neuronal-cell study found that strong GCase inhibition was not sufficient
to raise alpha-synuclein or impair lysosomal degradation PMID:23580063. These data justify non-core or cautious treatment of
lysosomal protein catabolism annotations.

Side activities and downstream processes

GBA1 has direct but non-core side activities. It can hydrolyze bile-acid glucosides
and therefore has a beta-glucosidase side activity [PMID:22659419 "GBA1 also
hydrolyses BG"; PMID:22659419 "GBA1 as a bile acid beta-glucosidase"]. It can also
catalyze cholesterol glucosylation by transglucosylation and hydrolyze glucosylated
cholesterol [PMID:24211208 "GBA1 was found to be the responsible enzyme for
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"]. These support non-core cholesterol metabolism,
glycolipid biosynthesis, glucosyltransferase, and steryl-beta-glucosidase annotations.

Ceramide, sphingosine, inflammatory, MAPK, and IL-6 annotations are downstream
cellular consequences of GBA1-generated ceramide rather than the core conserved
activity [PMID:19279011 "GBA1 activation can generate the source (sphingosine) for
PMA-induced formation of ceramide through the salvage pathway"; PMID:19279008
"GBA1-ceramide pathway ... regulating a pro-inflammatory pathway initiated by PKC and
leading to activation of p38 and induction of interleukin 6"].

Generic protein binding annotations are not informative GBA1 molecular functions.
The underlying interactions are real in folding, trafficking, or chaperone contexts
[PMID:21098288 "reduced binding of GCase to TCP1 ring complex"; PMID:27789271 "PGRN
binds directly to GCase"; PMID:24162852 "LIMP-2 shows a helical bundle where
beta-glucocerebrosidase binds"], but the more meaningful curation target for the
LIMP-2 interaction is scavenger receptor binding / lysosomal targeting rather than
generic protein binding.

Pn Notes

(GBA1-pn-notes.md)

GBA1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P04062
AIGR review status: COMPLETE
Review batch: proteostasis-pr-1217 (PR 1217)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/GBA1/GBA1-ai-review.yaml
AIGR review HTML: present - genes/human/GBA1/GBA1-ai-review.html
Gene notes: present - genes/human/GBA1/GBA1-notes.md
GOA TSV: present - genes/human/GBA1/GBA1-goa.tsv
UniProt record: present - genes/human/GBA1/GBA1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/GBA1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/GBA1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

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

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 33; KEEP_AS_NON_CORE: 38; MARK_AS_OVER_ANNOTATED: 15; MODIFY: 10

PN Consistency Summary

Consistency: Excellent — the best-aligned of the set. Deep-research, review, PN, and mapping converge: core function is lysosomal acid glucosylceramidase (GO:0004348; LIMP-2/SCARB2-trafficked), and the ALR/Parkinson axis is a genuine but downstream/mechanism-unknown consequence of GCase loss. The review's handling (GO:0007040 lysosome organization; regulation of macroautophagy; "current GO lacks an autophagic lysosome reformation term") mirrors the PN node's context_only→GO:0007040 + "function unknown"→no_mapping exactly. No contradictions.
PN story / NEW pressure: The PN's ALR placement asserts a role not captured by an exact GO term — and the review correctly recognizes this. OLS confirms there is NO existing GO term "autophagic lysosome reformation" (only GO:0061739 = "protein lipidation involved in autophagosome assembly", unrelated). The review already mints the right response: proposed_new_terms includes "autophagic lysosome reformation" (parent GO:0007040) — candidate, correctly unverified/new — plus "lysosomal glucosylceramide catabolic process" (parent GO:0006680). No fabricated existing term used. Already captured (proposed_new_terms + suggested_questions); no further ADD warranted.
Evidence alignment: Strong overlap. PN cites the ALR paper (Magalhaes et al., HMG 2016) = PMID:27378698 (verified via PubMed, DOI 10.1093/hmg/ddw185), and the review cites the SAME PMID:27378698 for ALR (in core_functions, the GO:0007040 annotation, and the proposed ALR term). PN's other refs (Schröder lysosome proteome; hLGDB) are localization/database context not needed by the review.
Verdict: Fully consistent; exemplary handling of a "GO-gap" PN node (proposed NEW term instead of forcing an existing one), with matching primary evidence. Recommended edits: none.

Full Consistency Review

UniProt: P04062 · batch: proteostasis-pr-1217 · review status: COMPLETE
PN placement: ALP → Lysosomal catabolism → Lysosomal lipid catabolism → Lysosomal sphingomyelin/ceramide metabolism → Lysosomal ceramidase AND ALP → Autophagic lysosome reformation → Specific function in autophagic lysosome reformation unknown (2 rows)
PN-node mapping: ceramidase subtype/type = no_mapping (mixed ASAH1/GALC/GBA1 bucket; no safe shared ceramidase term); lipid-catabolism group = context_only → GO:0016042; catabolism class = no_mapping; ALR class = context_only/too_broad → GO:0007040 lysosome organization; ALR group ("function unknown") = no_mapping; branch no_mapping.
Consistency: Excellent — the best-aligned of the set. Deep-research, review, PN, and mapping converge: core function is lysosomal acid glucosylceramidase (GO:0004348; LIMP-2/SCARB2-trafficked), and the ALR/Parkinson axis is a genuine but downstream/mechanism-unknown consequence of GCase loss. The review's handling (GO:0007040 lysosome organization; regulation of macroautophagy; "current GO lacks an autophagic lysosome reformation term") mirrors the PN node's context_only→GO:0007040 + "function unknown"→no_mapping exactly. No contradictions.
PN story / NEW pressure: The PN's ALR placement asserts a role not captured by an exact GO term — and the review correctly recognizes this. OLS confirms there is NO existing GO term "autophagic lysosome reformation" (only GO:0061739 = "protein lipidation involved in autophagosome assembly", unrelated). The review already mints the right response: proposed_new_terms includes "autophagic lysosome reformation" (parent GO:0007040) — candidate, correctly unverified/new — plus "lysosomal glucosylceramide catabolic process" (parent GO:0006680). No fabricated existing term used. Already captured (proposed_new_terms + suggested_questions); no further ADD warranted.
Mapping strategy: No change. Including GBA1 does not alter the node: the ALR group is rightly no_mapping ("function unknown"), the class rightly context_only→GO:0007040 (broader than GBA1's enzymatic core), and the ceramidase bucket rightly no_mapping (GBA1 is a glucosylceramidase, not a ceramidase — the PN's mixed ASAH1/GALC/GBA1 grouping is appropriately not propagated). PN-projected GO:0007040 is broader than the review's enzyme-level core, so non-propagation is the right call (cf. rejected broader projections).
Evidence alignment: Strong overlap. PN cites the ALR paper (Magalhaes et al., HMG 2016) = PMID:27378698 (verified via PubMed, DOI 10.1093/hmg/ddw185), and the review cites the SAME PMID:27378698 for ALR (in core_functions, the GO:0007040 annotation, and the proposed ALR term). PN's other refs (Schröder lysosome proteome; hLGDB) are localization/database context not needed by the review.
Verdict: Fully consistent; exemplary handling of a "GO-gap" PN node (proposed NEW term instead of forcing an existing one), with matching primary evidence. Recommended edits: none.

PN Dossier Context

review_batch: proteostasis-pr-1217
review_yaml: genes/human/GBA1/GBA1-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Lysosomal catabolism | Lysosomal lipid catabolism | Lysosomal sphingomyelin/ceramide metabolism | Lysosomal ceramidase

UniProt: P04062
In branches: ALP
Notes: Catabolic enzyme of the lysosome, per Gene ontology. Also autophagic lysosomal reformation is impaired in GBA1 mutants, potentially increasing susceptibility to Parkinson's Disease.
PN references (titles):
- Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease | Human Molecular Genetics | Oxford Academic (oup.com)
- The proteome of lysosomes - Schröder - 2010 - PROTEOMICS - Wiley Online Library
- hLGDB: a database of human lysosomal genes and their regulation | Database | Oxford Academic (oup.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Lysosomal catabolism|Lysosomal lipid catabolism|Lysosomal sphingomyelin/ceramide metabolism|Lysosomal ceramidase
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a mixed lysosomal ceramide/glycosylceramide hydrolase bucket containing ASAH1, GALC, and GBA1. The current GO cache lacks a non-obsolete ceramidase term that safely covers all members, so no direct universal mapping is made.
- [type] Autophagy-Lysosome Pathway|Lysosomal catabolism|Lysosomal lipid catabolism|Lysosomal sphingomyelin/ceramide metabolism
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a mixed sphingomyelin/ceramide metabolism container. The child leaves include enzymes and activators with different molecular functions, so direct propagation from the container would lose specificity.
- [group] Autophagy-Lysosome Pathway|Lysosomal catabolism|Lysosomal lipid catabolism
  status=context_only scope=too_broad_to_propagate GO=[GO:0016042 lipid catabolic process]
  rationale: This group is a lysosomal lipid-catabolism context, but it mixes lipases, phospholipases, sphingolipid enzymes, and activators. Specific molecular functions are mapped at narrower leaves.
- [class] Autophagy-Lysosome Pathway|Lysosomal catabolism
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad lysosomal-degradation container. The subtree includes carbohydrate, lipid, protein, nuclease, phosphatase, sulfatase, and environment-regulation roles, so mapping should occur at the enzyme or process subtype level.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Autophagic lysosome reformation | Specific function in autophagic lysosome reformation unknown

UniProt: P04062
In branches: ALP
Notes: Catabolic enzyme of the lysosome, per Gene ontology. Also autophagic lysosomal reformation is impaired in GBA1 mutants, potentially increasing susceptibility to Parkinson's Disease.
PN references (titles):
- Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease | Human Molecular Genetics | Oxford Academic (oup.com)
- The proteome of lysosomes - Schröder - 2010 - PROTEOMICS - Wiley Online Library
- hLGDB: a database of human lysosomal genes and their regulation | Database | Oxford Academic (oup.com)
PN-node mapping records (path + ancestors):
- [group] Autophagy-Lysosome Pathway|Autophagic lysosome reformation|Specific function in autophagic lysosome reformation unknown
  status=no_mapping scope= GO=[]
  rationale: This PN group explicitly states that the specific role within autophagic lysosome reformation is unknown. That makes GO propagation unsafe until a narrower mechanistic interpretation is available.
- [class] Autophagy-Lysosome Pathway|Autophagic lysosome reformation
  status=context_only scope=too_broad_to_propagate GO=[GO:0007040 lysosome organization]
  rationale: Autophagic lysosome reformation is the lysosome-regeneration phase that follows autolysosome formation and cargo degradation. As a class, it is better aligned to lysosome organization than to generic autophagy, but the PN members are mechanistically mixed across membrane remodeling, tubulation, product efflux, and unknown late-stage roles, so class-level propagation would still over-annotate.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Note

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

📄 View Raw YAML

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.

GBA1

Gene Description

Proposed New Ontology Terms

autophagic lysosome reformation

lysosomal glucosylceramide catabolic process