GBA (GBA1) encodes lysosomal acid glucosylceramidase (glucocerebrosidase, GCase; EC 3.2.1.45), a glycoside hydrolase that carries out the penultimate step of glycosphingolipid degradation. Within the lysosome it hydrolyses glucosylceramide (glucocerebroside) to ceramide and glucose, and also hydrolyses glucosylsphingosine. Full activity requires the sphingolipid activator protein saposin C (produced from prosaposin/PSAP) together with negatively charged phospholipids, which promote the enzyme's association with the substrate-bearing membrane. Because it lacks mannose-6-phosphate, GCase reaches the lysosome by a mannose-6-phosphate-independent route: it binds the lysosomal integral membrane protein LIMP-2 (SCARB2) in the endoplasmic reticulum and is co-transported through the Golgi and trans-Golgi network to the lysosome. As a retaining beta-glucosidase it can also catalyse transglucosylation side reactions in vitro, transferring glucose between glucosylceramide and cholesterol (forming/degrading cholesteryl-glucoside) and acting weakly on galactosylceramide. Deficiency of GCase causes Gaucher disease, the most common lysosomal storage disorder, and heterozygous GBA1 variants are the numerically greatest genetic risk factor for Parkinson disease and dementia with Lewy bodies.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006680 glucosylceramide catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the core biological process of GBA1: lysosomal degradation of glucosylceramide. This is the central, best-supported function of the gene and is corroborated by multiple experimental annotations. Reason: GBA hydrolyses glucosylceramide to ceramide and glucose in the lysosome; this is the defining catabolic role of the enzyme and its deficiency causes lysosomal GlcCer accumulation (Gaucher disease). The IBA term is at the correct level of specificity. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides |
| GO:0004348 glucosylceramidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the core molecular function: glucosylceramidase (glucocerebrosidase, EC 3.2.1.45). This is the exact molecular activity that defines GBA1 and is supported by numerous IDA/IMP annotations. Reason: This is the primary catalytic activity of GBA and matches the enzyme's defining EC number 3.2.1.45. Correct term, correct specificity. Selected as the core molecular function. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides |
| GO:0004336 galactosylceramidase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic annotation (RHEA/EC 3.2.1.46 mapping) to galactosylceramidase activity. GBA can hydrolyse galactosylceramides in vitro, but with substantially lower activity than glucosylceramides. Reason: This is a genuine but minor/secondary in-vitro activity of GBA, not its physiological role (that is glucosylceramide hydrolysis). The IEA mapping is biologically defensible; retain as a non-core secondary activity rather than remove. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Catalyzes the hydrolysis of galactosylceramides/GalCers |
| GO:0004348 glucosylceramidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (ARBA/InterPro/RHEA, EC 3.2.1.45) to the core glucosylceramidase activity. Redundant with the experimental and IBA annotations to the same term. Reason: Correct core molecular function, independently derived from sequence/reaction mappings; consistent with the experimental evidence. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation to lysosomal membrane. GBA is a peripheral (lumenal-side) lysosomal membrane-associated protein; its membrane association is promoted by saposin C and by binding to LIMP-2. Reason: Consistent with UniProt subcellular location (Lysosome membrane; peripheral membrane protein, lumenal side) and with experimental (IDA/HDA) annotations to the same term. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Lysosome membrane |
| GO:0006665 sphingolipid metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based electronic annotation to the broad parent process sphingolipid metabolic process. GBA's GlcCer catabolism is a step of sphingolipid/glycosphingolipid metabolism. Reason: Biologically correct but general; the more specific glucosylceramide catabolic process (GO:0006680) is the core annotation. Retain this broader IEA as non-core. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Sphingolipid metabolism. |
| GO:0008422 beta-glucosidase activity | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation to the broad parent activity beta-glucosidase. GBA is a retaining beta-glucosidase; it also hydrolyses other beta-glucosides such as bile-acid-3-O-beta-glucoside and cholesteryl-beta-glucoside. Reason: Correct but broad relative to the specific glucosylceramidase activity. Supported experimentally (e.g. bile acid beta-glucosidase activity, PMID:22659419). Retain as a non-core parent-level activity. Supporting Evidence: PMID:22659419 Here we show that GBA1 also hydrolyses BG. |
| GO:0016241 regulation of macroautophagy | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA electronic annotation to regulation of macroautophagy. Effects of GBA on autophagy are downstream consequences of loss of GCase activity (impaired autophagy-lysosome pathway), not a distinct molecular action of the enzyme. Reason: GCase deficiency compromises autophagic lysosome reformation and macroautophagy (PMID:27378698), but this is an indirect, disease-state consequence of losing the catabolic enzyme rather than a direct regulatory role of GBA. Over-annotation of the causal chain. Supporting Evidence: PMID:27378698 ALR dysfunction was accompanied by impairment of macroautophagy and chaperone-mediated autophagy |
| GO:0030163 protein catabolic process | IEA GO_REF:0000117 | REMOVE | Summary: ARBA electronic annotation to protein catabolic process. GBA is a lipid-degrading glycosidase, not a protease; any effect on protein catabolism is indirect (via the autophagy-lysosome pathway). Reason: This IEA is a spurious/over-general electronic inference. GBA does not catalyse protein catabolism; it hydrolyses glucosylceramide. The apparent link runs through lysosomal/autophagic dysfunction in GCase-deficient cells, which does not justify a direct 'protein catabolic process' annotation. |
| GO:0042176 regulation of protein catabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA electronic annotation to regulation of protein catabolic process. As with protein catabolic process, this is an indirect consequence of GCase deficiency on lysosomal/autophagic degradation, not a direct function of GBA. Reason: GCase loss impairs lysosomal degradation of substrates such as alpha-synuclein, but GBA does not itself regulate protein catabolism; this electronic mapping over-annotates a downstream disease phenotype. Supporting Evidence: PMID:27378698 neurons are unable to maintain the pool of mature and functional lysosomes required for the autophagic clearance of Ξ±-synuclein |
| GO:0042391 regulation of membrane potential | IEA GO_REF:0000117 | REMOVE | Summary: ARBA electronic annotation to regulation of membrane potential. There is no direct evidence that GBA, a lysosomal lipid hydrolase, regulates membrane potential; any link is indirect (mitochondrial membrane potential changes in GCase-deficient neurons). Reason: Over-general electronic inference with no biological support for a direct role. Changes in mitochondrial membrane potential in GCase-deficient cells (PMID:26388395) are secondary consequences of enzyme loss, not a molecular function of GBA. |
| GO:0050295 steryl-beta-glucosidase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: RHEA-based electronic annotation to steryl-beta-glucosidase activity. GBA can hydrolyse cholesteryl-3-beta-D-glucoside (GlcChol) to cholesterol and glucose (RHEA:11956), a demonstrated in-vitro activity. Reason: Genuine secondary activity supported experimentally (PMID:24211208, PMID:26724485) but distinct from and much less prominent than GlcCer hydrolysis. Retain as non-core. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Can also hydrolyze cholesteryl 3-beta-D-glucoside producing glucose and cholesterol |
| GO:0005515 protein binding | IPI PMID:21098288 Decreased glucocerebrosidase activity in Gaucher disease par... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from an IntAct interaction; the partner (UniProtKB:P17987) is TCP1/CCT, a chaperonin subunit implicated in GCase folding. Reason: Bare 'protein binding' is uninformative. The underlying interaction with TCP1 (TRiC/CCT) relates to GCase maturation/quality control (PMID:21098288), but the GO term itself conveys no functional specificity and should not be treated as a core function. Supporting Evidence: PMID:21098288 reduced binding of GCase to TCP1 ring complex (TRiC), a regulator of correct protein folding, may result in defective maturation of nascent GCase in GD cells |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic annotation (ARBA + transfer from mouse ortholog) to signaling receptor binding. This most plausibly reflects GBA binding to its trafficking receptor LIMP-2/SCARB2. Reason: The biologically meaningful binding partner is LIMP-2/SCARB2 (a CD36-family scavenger-receptor protein). 'Signaling receptor binding' is imprecise but points to the real LIMP-2 interaction; retain as non-core rather than as a molecular function. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Interacts with SCARB2 |
| GO:0005764 lysosome | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic annotation (Ensembl transfer from mouse ortholog) to lysosome. GBA is a lysosomal enzyme; this is a core localization. Reason: Well established: GCase acts within the lysosome and reaches it via the LIMP-2 route. Consistent with experimental IMP annotation to lysosome (PMID:25202012). Supporting Evidence: file:human/GBA/GBA-uniprot.txt Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation to endoplasmic reticulum, a biosynthetic/transit compartment where the GCase-LIMP-2 transport complex forms. Reason: GBA transits the ER, where it associates with LIMP-2 before lysosomal delivery (PMID:40159502). Real but not the site of function; retain as non-core transit location. Supporting Evidence: PMID:40159502 The GCase/LIMP-2 transport complex forms within the endoplasmic reticulum |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation to Golgi apparatus, a transit compartment on the GCase-LIMP-2 route to the lysosome. Reason: GBA traverses the Golgi/TGN en route to the lysosome. Transit location, not the site of catalytic function; retain as non-core. Supporting Evidence: PMID:40159502 travels through the trans-Golgi network to the lysosome |
| GO:0005802 trans-Golgi network | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation to trans-Golgi network, a transit compartment on the GCase-LIMP-2 trafficking route. Reason: The GCase-LIMP-2 complex travels through the trans-Golgi network to the lysosome. Transit location; retain as non-core. Supporting Evidence: PMID:40159502 travels through the trans-Golgi network to the lysosome |
| GO:0006680 glucosylceramide catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (ARBA + mouse ortholog transfer) to the core biological process, glucosylceramide catabolism. Redundant with the IBA and experimental annotations. Reason: Correct core process, independently supported by sequence-based inference and by multiple experimental annotations to the same term. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides |
| GO:0006914 autophagy | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Electronic annotation to autophagy. GBA's connection to autophagy is indirect: loss of GCase activity impairs the autophagy-lysosome pathway. Reason: Autophagy defects are a downstream consequence of GCase deficiency (PMID:27378698), not a direct function of GBA in autophagy. Over-annotation via the disease phenotype. Supporting Evidence: PMID:27378698 autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase |
| GO:0007040 lysosome organization | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Electronic annotation to lysosome organization. Effects of GBA on lysosome biogenesis/reformation are indirect consequences of enzyme deficiency. Reason: GCase deficiency impairs autophagic lysosome reformation (PMID:27378698), but GBA is a lumenal hydrolase and does not directly organize the lysosome. Downstream phenotype, over-annotated as a direct process. Supporting Evidence: PMID:27378698 which regenerates functional lysosomes from autolysosomes formed during macroautophagy |
| GO:0008203 cholesterol metabolic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic annotation to cholesterol metabolic process. GBA can transglucosylate cholesterol (forming/degrading cholesteryl-glucoside), linking it to cholesterol metabolism. Reason: GBA participates in cholesterol glucosylation/de-glucosylation via transglucosylation (PMID:24211208, PMID:26724485), a genuine but secondary activity. Retain as non-core; the primary role is glycosphingolipid catabolism. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Catalyzes the glucosylation of cholesterol |
| GO:0009247 glycolipid biosynthetic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic annotation to glycolipid biosynthetic process, reflecting the transglucosylation reaction by which GBA can form cholesteryl-glucoside from GlcCer. Reason: GBA can synthesize glucosylated cholesterol (a glycolipid) by transglucosylation (PMID:24211208), so the annotation is defensible, but this is a minor side reaction of a fundamentally catabolic enzyme. Retain as non-core. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Catalyzes the glucosylation of cholesterol |
| GO:0009267 cellular response to starvation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from the mouse ortholog to cellular response to starvation, likely reflecting the autophagy/mTOR link in GCase-deficient cells. Reason: No direct evidence that GBA mediates a starvation response; the association runs through autophagy/TOR signalling downstream of enzyme deficiency. Over-annotation. |
| GO:0009268 response to pH | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation (rat ortholog transfer) to response to pH. GBA has an acidic pH optimum (~5.3) suited to the lysosome, but 'response to pH' as a biological process is not a documented function. Reason: The enzyme's acidic pH optimum reflects its lysosomal working environment, not participation in a 'response to pH' process. Electronic transfer over-annotation. |
| GO:0032006 regulation of TOR signaling | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Electronic annotation to regulation of TOR signaling. In GCase-deficient cells mTOR activity (phospho-S6K) is altered, but this is a downstream consequence of impaired autophagic lysosome reformation. Reason: Altered mTOR signalling in GCase-deficient cells (PMID:27378698) is an indirect effect of enzyme loss, not a direct regulatory role of GBA in TOR signalling. Supporting Evidence: PMID:27378698 A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models of GCase deficiency |
| GO:0033574 response to testosterone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from the rat ortholog to response to testosterone. This is a peripheral, expression-level physiological response with no direct mechanistic role for GBA. Reason: Hormone-response terms transferred electronically from a rodent ortholog do not describe a molecular/biological function of human GBA. Peripheral over-annotation. |
| GO:0043202 lysosomal lumen | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic annotation to lysosomal lumen. GBA acts on the lumenal side of the lysosomal membrane and is a lumenal/lumenal-side-membrane-associated hydrolase. Reason: Consistent with UniProt (lumenal side, lysosome) and with the enzyme's function acting on lumenal glucosylceramide. Appropriate core localization term. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Lumenal side |
| GO:0043627 response to estrogen | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from the rat ortholog to response to estrogen; a peripheral hormone-response term. Reason: Electronically transferred rodent hormone-response annotation; not a direct function of human GBA. Peripheral over-annotation. |
| GO:0046527 glucosyltransferase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic annotation to glucosyltransferase activity, reflecting GBA's transglucosylation side reaction (glucose transfer from GlcCer to cholesterol). Reason: As a retaining glycosidase, GBA can transfer glucose to acceptors such as cholesterol (PMID:24211208, PMID:26724485). This is a genuine but secondary transglucosylase side activity, not a canonical anabolic glucosyltransferase role. Retain as non-core. Supporting Evidence: file:human/GBA/GBA-uniprot.txt a transglucosylation reaction where glucose is transferred from GlcCer to cholesterol |
| GO:0061436 establishment of skin barrier | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation (rat ortholog transfer) to establishment of skin barrier. GlcCer hydrolysis in the epidermis contributes to the lipid lamellae of the stratum corneum, so there is a physiological connection, but this is a tissue-level developmental outcome. Reason: Epidermal GCase activity contributes to skin permeability-barrier lipids; the link is real but tissue-specific and downstream of the core catabolic activity. Retain as non-core. |
| GO:0071548 response to dexamethasone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from the rat ortholog to response to dexamethasone; a peripheral pharmacological-response term. Reason: Rodent electronic transfer of a drug-response term; not a direct function of human GBA. Peripheral over-annotation. |
| GO:0097066 response to thyroid hormone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic annotation transferred from the rat ortholog to response to thyroid hormone; a peripheral hormone-response term. Reason: Electronically transferred rodent hormone-response annotation; not a direct function of human GBA. Peripheral over-annotation. |
| GO:0098773 skin epidermis development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation (rat ortholog transfer) to skin epidermis development, related to the role of epidermal GlcCer metabolism in skin barrier formation. Reason: Connected to epidermal glucosylceramide processing but a tissue-level developmental term, downstream of the enzyme's catabolic activity. Retain as non-core. |
| GO:1901805 beta-glucoside catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation (rat ortholog transfer) to beta-glucoside catabolic process, a parent process consistent with GBA's beta-glucosidase activity on various beta-glucosides. Reason: Correct but broad; the specific glucosylceramide catabolic process is the core BP. Retain as a non-core parent-level process. Supporting Evidence: PMID:22659419 Here we show that GBA1 also hydrolyses BG. |
| GO:0005765 lysosomal membrane | IPI PMID:40159502 Cryo-TEM structure of Ξ²-glucocerebrosidase in complex with i... | ACCEPT | Summary: ComplexPortal annotation (from the cryo-EM GCase-LIMP-2 complex study) placing GBA at the lysosomal membrane via its LIMP-2 complex. Reason: GBA associates with the lysosomal membrane, in part through its complex with the LIMP-2 membrane protein. Consistent with UniProt and other membrane-localization annotations. Supporting Evidence: PMID:40159502 the lysosomal hydrolase Ξ²-glucocerebrosidase (GCase) is a prominent example for such an M6PR-independent transport mechanism |
| GO:0019377 glycolipid catabolic process | NAS PMID:40159502 Cryo-TEM structure of Ξ²-glucocerebrosidase in complex with i... | KEEP AS NON CORE | Summary: NAS (ComplexPortal) annotation to glycolipid catabolic process. GBA hydrolyses the glycolipid glucosylceramide, so this parent-level catabolic process is correct. Reason: Correct but broader than the specific glucosylceramide catabolic process (GO:0006680) chosen as core. Retain as a non-core parent-level process. Supporting Evidence: PMID:40159502 hydrolyses the glycolipid glucosylceramide (GlcCer) into glucose and ceramide |
| GO:0009247 glycolipid biosynthetic process | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: IDA annotation: purified GBA catalyses cholesterol glucosylation (formation of the glycolipid cholesteryl-glucoside) by transglucosylation from GlcCer. Reason: Experimentally demonstrated transglucosylation forming a glycolipid (cholesteryl-glucoside), a genuine secondary/anabolic side reaction of this catabolic enzyme. Retain as non-core. Supporting Evidence: PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation reaction of |
| GO:0009247 glycolipid biosynthetic process | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: IDA annotation: recombinant GBA forms glucosylated cholesterol (GlcChol) via transglucosylation, supporting a glycolipid-biosynthetic (transglucosylase) capacity in vitro. Reason: Demonstrated transglucosylation-based synthesis of a sterol-glycolipid; a real but secondary activity of a fundamentally catabolic enzyme. Retain as non-core. Supporting Evidence: PMID:26724485 both GBA and GBA2 are able to catalyze in vitro the transfer of glucosyl-moieties from GlcCer to cholesterol |
| GO:1905146 lysosomal protein catabolic process | IDA PMID:26392287 Glucocerebrosidase gene therapy prevents Ξ±-synucleinopathy o... | MARK AS OVER ANNOTATED | Summary: IDA annotation (ParkinsonsUK-UCL) linking GBA to lysosomal protein catabolism, via GCase gene therapy reducing alpha-synuclein accumulation in PD models. Reason: Restoring GCase reduces lysosomal accumulation of alpha-synuclein (PMID:26392287), but GBA is a lipid glycosidase, not a protease; its effect on lysosomal protein catabolism is indirect (via restored lysosomal/autophagic function). Over-annotation of a downstream phenotype. Supporting Evidence: PMID:26392287 increasing GCase through AAV-GBA1 intra-cerebral gene delivery in two PD rodent models would reduce the accumulation of Ξ±-synuclein |
| GO:0050728 negative regulation of inflammatory response | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: IMP annotation: knockdown of GBA1 enhances a pro-inflammatory (p38delta/IL-6) response in MCF-7 cells, implying an anti-inflammatory role via ceramide production. Reason: Supported experimentally, but the effect is an indirect signalling consequence of GBA-generated ceramide (an anti-inflammatory lipid) rather than a direct role of GBA in inflammation. Retain as non-core downstream physiology. Supporting Evidence: PMID:19279008 possible role for ceramide as an anti-inflammatory lipid |
| GO:0043409 negative regulation of MAPK cascade | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: IMP annotation: the GBA1-ceramide pathway terminates p38 (MAPK) activation; GBA knockdown potentiates p38 activation in MCF-7 cells. Reason: Real but indirect: GBA affects MAPK (p38) signalling through the ceramide it produces, not by acting on the MAPK cascade directly. Retain as non-core downstream signalling role. Supporting Evidence: PMID:19279008 implicating the GBA1-ceramide pathway in the termination of p38 activation |
| GO:0004348 glucosylceramidase activity | IMP PMID:25584808 Identification of miRNAs that modulate glucocerebrosidase ac... | ACCEPT | Summary: IMP annotation: miRNAs that modulate GBA1 change glucocerebrosidase activity in Gaucher cells, confirming the enzyme's glucosylceramidase (GCase) activity as the assayed readout. Reason: Supports the core molecular function via functional modulation experiments in patient cells. Correct core activity. Supporting Evidence: PMID:25584808 To determine whether miRNAs can affect glucocerebrosidase activity |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:25584808 Identification of miRNAs that modulate glucocerebrosidase ac... | ACCEPT | Summary: IMP annotation linking GBA1 modulation to glucosylceramide catabolism, the enzyme's core process, in Gaucher disease cells. Reason: Consistent with the core catabolic role; modulating GBA1 activity affects GlcCer degradation. Supporting Evidence: PMID:25584808 miRNAs that modulate glucocerebrosidase activity in Gaucher |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-1605591 | ACCEPT | Summary: TAS annotation from Reactome (GBA1:SAPC hydrolyzes GlcCer) placing GBA at the lysosomal membrane, where it acts together with saposin C on membrane-inserted glucosylceramide. Reason: Consistent with UniProt subcellular location and with the saposin-C-dependent, membrane-associated mode of action. Appropriate localization. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Lysosome membrane |
| GO:0004348 glucosylceramidase activity | IDA PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | ACCEPT | Summary: IDA annotation: recombinant GBA1 (lysosomal glucocerebrosidase) hydrolyses glucosylceramide and also bile-acid-beta-glucoside, confirming its glucosylceramidase activity. Reason: Direct assay of GBA1 glucosylceramidase activity; supports the core molecular function. Supporting Evidence: PMID:22659419 Beta-glucosidase 1 (GBA1; lysosomal glucocerebrosidase) and Ξ²-glucosidase 2 (GBA2, non-lysosomal glucocerebrosidase) both have glucosylceramide as a main natural substrate |
| GO:0004348 glucosylceramidase activity | IMP PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | ACCEPT | Summary: IMP annotation: comparison of GBA1-deficient and wild-type material (mice/humans) demonstrates GBA1's glucosylceramidase activity as the natural role. Reason: Loss-of-function comparison confirms the core glucosylceramidase activity of GBA1. Supporting Evidence: PMID:22659419 both have glucosylceramide as a main natural substrate |
| GO:0008422 beta-glucosidase activity | IDA PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | KEEP AS NON CORE | Summary: IDA annotation: GBA1 directly hydrolyses bile-acid-3-O-beta-glucoside, demonstrating broad beta-glucosidase activity beyond glucosylceramide. Reason: Correct broad activity supported by direct assay, but general relative to the specific glucosylceramidase activity. Retain as non-core parent-level activity. Supporting Evidence: PMID:22659419 Here we show that GBA1 also hydrolyses BG. |
| GO:0008422 beta-glucosidase activity | IMP PMID:22659419 Beta-glucosidase 1 (GBA1) is a second bile acid Ξ²-glucosidas... | KEEP AS NON CORE | Summary: IMP annotation: residual bile-acid-beta-glucoside hydrolysis in GBA1-deficient vs wild-type material supports GBA1's beta-glucosidase activity. Reason: Supports broad beta-glucosidase activity via loss-of-function comparison; general relative to the core glucosylceramidase term. Retain as non-core. Supporting Evidence: PMID:22659419 GBA1 and GBA2 activities had characteristic differences between the studied fibroblast, liver and brain samples |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation (from mouse ortholog) to endoplasmic reticulum, the biosynthetic/transit compartment where GCase associates with LIMP-2. Reason: ER is a transit/complex-formation compartment (PMID:40159502), not the site of function. Retain as non-core, consistent with the IEA ER annotation. Supporting Evidence: PMID:40159502 The GCase/LIMP-2 transport complex forms within the endoplasmic reticulum |
| GO:0005794 Golgi apparatus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation (from mouse ortholog) to Golgi apparatus, a transit compartment on the GCase-LIMP-2 route to the lysosome. Reason: Transit location; not the site of catalytic function. Retain as non-core. Supporting Evidence: PMID:40159502 travels through the trans-Golgi network to the lysosome |
| GO:0005802 trans-Golgi network | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation (from mouse ortholog) to trans-Golgi network, a transit compartment on the GCase-LIMP-2 trafficking route. Reason: Transit location; retain as non-core. Supporting Evidence: PMID:40159502 travels through the trans-Golgi network to the lysosome |
| GO:0005515 protein binding | IPI PMID:27789271 Progranulin Recruits HSP70 to Ξ²-Glucocerebrosidase and Is Th... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation; partner UniProtKB:P28799 is progranulin (GRN/PGRN), which binds GCase and recruits HSP70 as a co-chaperone. Reason: Bare 'protein binding' is uninformative. The underlying GRN/HSP70 chaperone interaction is real (PMID:27789271) but the GO term conveys no functional specificity; do not treat as a core function. Supporting Evidence: PMID:27789271 we report that PGRN binds directly to GCase |
| GO:0004348 glucosylceramidase activity | IDA PMID:16293621 Analyses of variant acid beta-glucosidases: effects of Gauch... | ACCEPT | Summary: IDA annotation: purified wild-type and variant GCases assayed for glucosylceramidase (acid beta-glucosidase) activity and kinetics. Reason: Direct enzymatic characterization of the core glucosylceramidase activity across Gaucher disease variants. Correct core molecular function. Supporting Evidence: PMID:16293621 Acid beta-glucosidase (GCase) is a 497-amino acid, membrane-associated lysosomal exo-beta-glucosidase whose defective activity leads to the Gaucher disease phenotypes |
| GO:0005765 lysosomal membrane | IDA PMID:17187079 Structure of acid beta-glucosidase with pharmacological chap... | ACCEPT | Summary: IDA/structural annotation to lysosomal membrane from the GCase crystal structure work; GCase is a membrane-associated lysosomal enzyme. Reason: Consistent with the enzyme's peripheral lysosomal-membrane association and UniProt subcellular location. Appropriate localization. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Lysosome membrane |
| GO:0006680 glucosylceramide catabolic process | IDA PMID:16293621 Analyses of variant acid beta-glucosidases: effects of Gauch... | ACCEPT | Summary: IDA annotation to glucosylceramide catabolism, from direct enzymatic assay of GCase and its Gaucher-disease variants. Reason: Directly supports the core catabolic process; assays measure GlcCer/substrate hydrolysis by GCase. Supporting Evidence: PMID:16293621 whose defective activity leads to the Gaucher disease phenotypes |
| GO:0006914 autophagy | IMP PMID:27378698 Autophagic lysosome reformation dysfunction in glucocerebros... | MARK AS OVER ANNOTATED | Summary: IMP annotation: GCase-deficient cells show compromised autophagic lysosome reformation and impaired macroautophagy. Reason: Autophagy impairment is a downstream consequence of losing GCase activity (PMID:27378698), not a direct function of GBA in autophagy. Over-annotation of a disease-state phenotype. Supporting Evidence: PMID:27378698 autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase |
| GO:0007040 lysosome organization | IMP PMID:27378698 Autophagic lysosome reformation dysfunction in glucocerebros... | MARK AS OVER ANNOTATED | Summary: IMP annotation: GCase deficiency impairs regeneration of functional lysosomes from autolysosomes (autophagic lysosome reformation). Reason: Effect on lysosome reformation is indirect (consequence of enzyme loss), not a direct organizing role of the lumenal hydrolase GBA. Over-annotation of a downstream phenotype. Supporting Evidence: PMID:27378698 which regenerates functional lysosomes from autolysosomes formed during macroautophagy |
| GO:0008203 cholesterol metabolic process | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: IDA annotation: GBA participates in cholesterol metabolism by forming and degrading glucosylated cholesterol (GlcChol) through transglucosylation. Reason: Genuine but secondary activity (GlcChol formation/degradation via transglucosylation); the primary role is glycosphingolipid catabolism. Retain as non-core. Supporting Evidence: PMID:26724485 we document the ability of both GBA and GBA2 to degrade, as well as synthesize, GlcChol |
| GO:0032006 regulation of TOR signaling | IMP PMID:27378698 Autophagic lysosome reformation dysfunction in glucocerebros... | MARK AS OVER ANNOTATED | Summary: IMP annotation: mTOR activity (phospho-S6K) is decreased in GCase-deficient cells, reflecting impaired autophagic lysosome reformation. Reason: Altered TOR signalling is an indirect downstream effect of enzyme deficiency (PMID:27378698), not a direct role of GBA in regulating TOR. Over-annotation. Supporting Evidence: PMID:27378698 A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models of GCase deficiency |
| GO:0046527 glucosyltransferase activity | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: IDA annotation: GBA transfers glucosyl moieties from GlcCer to cholesterol in vitro (transglucosylation), forming glucosylated cholesterol. Reason: Demonstrated transglucosylase side activity of the retaining glycosidase; genuine but secondary to the core glucosylceramidase (hydrolase) role. Retain as non-core. Supporting Evidence: PMID:26724485 both GBA and GBA2 are able to catalyze in vitro the transfer of glucosyl-moieties from GlcCer to cholesterol |
| GO:0050295 steryl-beta-glucosidase activity | IDA PMID:26724485 Glucosylated cholesterol in mammalian cells and tissues: for... | KEEP AS NON CORE | Summary: IDA annotation: GBA hydrolyses glucosylated cholesterol (cholesteryl-beta-glucoside, GlcChol), demonstrating steryl-beta-glucosidase activity. Reason: Genuine secondary hydrolase activity on a sterol-glucoside; distinct from and minor relative to GlcCer hydrolysis. Retain as non-core. Supporting Evidence: PMID:26724485 we document the ability of both GBA and GBA2 to degrade, as well as synthesize, GlcChol |
| GO:0004348 glucosylceramidase activity | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | ACCEPT | Summary: IDA annotation: purified recombinant GBA1 assayed for glucosylceramide-related (glucocerebrosidase) activity as part of characterizing its cholesterol-glucosylation transglucosylation. Reason: Supports the core glucosylceramidase activity of GBA1 (used as the glucose donor system for the transglucosylation assays). Correct core molecular function. Supporting Evidence: PMID:24211208 purified recombinant GBA1 exhibits conduritol B-epoxide-sensitive cholesterol glucosylation activity |
| GO:0006680 glucosylceramide catabolic process | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | ACCEPT | Summary: IDA annotation to glucosylceramide catabolism, based on characterization of GBA1's GlcCer-dependent activities in fibroblasts and Gaucher patient cells. Reason: Consistent with the core catabolic role; GBA1 uses GlcCer as substrate/donor and its deficiency reduces GlcCer-dependent activity in patient cells. Core process. Supporting Evidence: PMID:24211208 Using a cell line generated from type 2 Gaucher disease patients with severe defects in GBA1 activity |
| GO:0008203 cholesterol metabolic process | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: IDA annotation: GBA1 glucosylates cholesterol by transglucosylation, linking it to cholesterol metabolism. Reason: Genuine but secondary transglucosylation activity toward cholesterol; primary role is glycosphingolipid catabolism. Retain as non-core. Supporting Evidence: PMID:24211208 Overexpression of Ξ²-glucosidase 1 (GBA1, lysosomal acid Ξ²-glucocerebrosidase) led to an increase in cholesterol glucosylation activity |
| GO:0046527 glucosyltransferase activity | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: IDA annotation: GBA1 catalyses cholesterol glucosylation by a transglucosylation reaction, transferring glucose from GlcCer to cholesterol. Reason: Demonstrated transglucosylase side reaction of the retaining glycosidase; genuine but secondary to the core hydrolase role. Retain as non-core. Supporting Evidence: PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation reaction of |
| GO:0050295 steryl-beta-glucosidase activity | IDA PMID:24211208 Cholesterol glucosylation is catalyzed by transglucosylation... | KEEP AS NON CORE | Summary: IDA annotation: GBA1 can hydrolyse cholesteryl-beta-glucoside to cholesterol and glucose, a steryl- beta-glucosidase activity. Reason: Genuine secondary hydrolase activity on a sterol-glucoside; minor relative to GlcCer hydrolysis. Retain as non-core. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Can also hydrolyze cholesteryl 3-beta-D-glucoside producing glucose and cholesterol |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:24022302 Functional analysis of 11 novel GBA alleles. | ACCEPT | Summary: IMP annotation: functional analysis of novel GBA disease alleles shows loss of acid beta-glucosidase activity, confirming GBA1's role in glucosylceramide catabolism. Reason: Loss-of-function variant analysis confirms the enzyme's core catabolic activity (deficiency causes Gaucher disease / GlcCer accumulation). Core process. Supporting Evidence: PMID:24022302 Gaucher disease is the most frequent lysosomal storage disorder due to the deficiency of the acid Ξ²-glucosidase, encoded by the GBA gene |
| GO:0004348 glucosylceramidase activity | IDA PMID:9201993 Effect of saposins A and C on the enzymatic hydrolysis of li... | ACCEPT | Summary: IDA annotation: glucosylceramidase hydrolyses liposomal glucosylceramide, an activity stimulated synergistically by saposins A and C. Reason: Direct assay of glucosylceramidase activity on the physiological substrate (liposomal GlcCer) with its saposin activators. Core molecular function. Supporting Evidence: PMID:9201993 The degradation of glucosylceramide in lysosomes is accomplished by glucosylceramidase with the assistance of, at least, another protein, saposin C |
| GO:0006680 glucosylceramide catabolic process | IDA PMID:9201993 Effect of saposins A and C on the enzymatic hydrolysis of li... | ACCEPT | Summary: IDA annotation to lysosomal glucosylceramide catabolism, demonstrated by saposin-assisted hydrolysis of liposomal GlcCer. Reason: Directly supports the core catabolic process, including the saposin-C dependence and requirement for anionic phospholipids. Core process. Supporting Evidence: PMID:9201993 both Sap A and Sap C are required for maximal hydrolysis of glucosylceramide inserted in PS-containing LUV |
| GO:0004348 glucosylceramidase activity | IMP PMID:15916907 Use of fluorescent substrates for characterization of Gauche... | ACCEPT | Summary: IMP annotation: Gaucher-disease mutations reduce beta-glucocerebrosidase activity toward fluorescent glucosylceramide substrates, confirming the core glucosylceramidase activity. Reason: Variant-based functional analysis confirms the enzyme's core glucosylceramidase activity. Correct term. Supporting Evidence: PMID:15916907 Gaucher disease results from impaired activity of the lysosomal enzyme beta-glucocerebrosidase |
| GO:0005124 scavenger receptor binding | IPI PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | KEEP AS NON CORE | Summary: IPI annotation: GBA binds LIMP-2/SCARB2 (UniProtKB:Q14108), a CD36-family scavenger-receptor protein, via a defined 11-residue motif; this mediates lysosomal trafficking. Reason: Informative binding annotation capturing the physiologically important GBA-LIMP-2 interaction required for lysosomal targeting, but this is a trafficking interaction rather than the enzyme's core catalytic function. Retain as non-core. Supporting Evidence: PMID:25202012 The acid Ξ²-glucosidase (glucocerbrosidase (GCase)) binding sequence to LIMP-2 (lysosomal integral membrane protein 2), the receptor for intracellular GCase trafficking to the lysosome, has been identified |
| GO:0005764 lysosome | IMP PMID:25202012 The LIMP-2/SCARB2 binding motif on acid Ξ²-glucosidase: basic... | ACCEPT | Summary: IMP annotation: disrupting the LIMP-2-binding motif diminishes trafficking of GCase to the lysosome and increases its secretion, confirming lysosomal localization depends on LIMP-2. Reason: Supports the core lysosomal localization of GBA (and its LIMP-2-dependent delivery). Correct localization. Supporting Evidence: PMID:25202012 diminishing the trafficking of GCase to the lysosome and significantly increasing GCase secretion |
| GO:0004348 glucosylceramidase activity | IMP PMID:23580063 Loss of Ξ²-glucocerebrosidase activity does not affect alpha-... | ACCEPT | Summary: IMP annotation: pharmacological inhibition of GCase activity in neuronal cells (assayed as beta-glucocerebrosidase activity) underlies the study, supporting the core glucosylceramidase activity. Reason: Confirms the core glucosylceramidase activity as the manipulated variable (the study inhibits GCase activity). Correct core molecular function. Supporting Evidence: PMID:23580063 results from the diminished activity of the lysosomal enzyme Ξ²-glucocerebrosidase (GCase), caused by mutations in the Ξ²-glucocerebrosidase gene (GBA) |
| GO:0007005 mitochondrion organization | IMP NOT PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | ACCEPT | Summary: NOT annotation: in GBA-N370S iPSC-derived dopamine neurons, mitochondria showed normal morphology and distribution, so GBA is annotated as NOT involved in mitochondrion organization. Reason: The negation is directly supported: TEM showed normal mitochondrial morphology in GBA-N370S neurons. The NOT annotation correctly records the absence of an effect on mitochondrion organization in this model. Supporting Evidence: PMID:25456120 mitochondria in all differentiated neurons, including GBA N370S mutant mDA neurons, displayed normal morphology and regular distribution in cytoplasm and processes |
| GO:0031175 neuron projection development | IMP NOT PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | ACCEPT | Summary: NOT annotation: neurite outgrowth rates were similar between GBA-N370S and control neurons, so GBA is annotated as NOT involved in neuron projection development. Reason: The negation is supported: the study found similar neurite outgrowth rates for both twins' neurons, indicating no GBA effect on neuron projection development in this model. Supporting Evidence: PMID:25456120 the neurite outgrowth rates of both twinβs neurons were similar |
| GO:1904457 positive regulation of neuronal action potential | IMP PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | MARK AS OVER ANNOTATED | Summary: IMP annotation: GBA-N370S dopamine neurons (affected twin) showed reduced spontaneous electrical activity, interpreted as a role in neuronal action potential. Reason: The reduced spontaneous activity in affected-twin neurons is an indirect, disease-model phenotype confounded by additional factors (e.g. elevated MAO-B), not a direct role of the lysosomal enzyme GBA in generating action potentials. Over-annotation of a downstream neuronal phenotype. Supporting Evidence: PMID:25456120 Spontaneous activity in mDA neurons from the affected twin was significantly lower |
| GO:1905165 regulation of lysosomal protein catabolic process | TAS PMID:25456120 iPSC-derived dopamine neurons reveal differences between mon... | MARK AS OVER ANNOTATED | Summary: TAS annotation to regulation of lysosomal protein catabolic process, based on GBA's link to alpha-synuclein handling in the lysosome. Reason: GBA influences lysosomal clearance of alpha-synuclein indirectly (via lysosomal/autophagic function); it does not directly regulate lysosomal protein catabolism. Over-annotation of a downstream disease link. Supporting Evidence: PMID:25456120 GBA mutations lead to Ξ±-synuclein accumulation |
| GO:0016241 regulation of macroautophagy | TAS PMID:26388395 Mitochondrial dysfunction associated with glucocerebrosidase... | MARK AS OVER ANNOTATED | Summary: TAS annotation (review) to regulation of macroautophagy; loss of GCase activity impairs the autophagy-lysosome pathway, including macroautophagy. Reason: Effect on macroautophagy is a downstream consequence of GCase deficiency (PMID:26388395), not a direct regulatory function of GBA. Over-annotation of the disease-state phenotype. Supporting Evidence: PMID:26388395 The loss of GCase activity results in impairment of the autophagy-lysosome pathway (ALP) |
| GO:0004348 glucosylceramidase activity | IMP PMID:21700325 Gaucher disease glucocerebrosidase and Ξ±-synuclein form a bi... | ACCEPT | Summary: IMP annotation: functional loss of GCase in neurons/iPSC compromises lysosomal degradation, tying the glucosylceramidase activity to lysosomal function and alpha-synuclein handling. Reason: Supports the core glucosylceramidase activity via loss-of-function experiments in neurons and human iPSC. Correct core molecular function. Supporting Evidence: PMID:21700325 functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:21700325 Gaucher disease glucocerebrosidase and Ξ±-synuclein form a bi... | ACCEPT | Summary: IMP annotation: GCase cleaves the beta-glucosyl linkage of glucosylceramide; its functional loss causes GlcCer accumulation, supporting the core catabolic process. Reason: Directly supports glucosylceramide catabolism; GCase is described as the lysosomal enzyme that cleaves GlcCer, and its substrate accumulates on loss of function. Core process. Supporting Evidence: PMID:21700325 a lysosomal enzyme that cleaves the Ξ²-glucosyl linkage of GlcCer |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: HDA annotation: GBA detected by proteomics in exosomes from expressed prostatic secretions in urine. Reason: A high-throughput mass-spectrometry detection in a secreted/exosomal proteome; consistent with the known partial secretion of GCase, but not its site of function. Retain as non-core. Supporting Evidence: PMID:23533145 exosome preparations were characterized by a shotgun proteomics procedure |
| GO:0005515 protein binding | IPI PMID:24162852 Structure of LIMP-2 provides functional insights with implic... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation; partner UniProtKB:Q14108 is LIMP-2/SCARB2, whose crystal structure shows the helical bundle where beta-glucocerebrosidase binds. Reason: Bare 'protein binding' is uninformative. The underlying LIMP-2 interaction is captured more informatively by the scavenger-receptor-binding / SCARB2-trafficking annotations; do not treat this generic term as a function. Supporting Evidence: PMID:24162852 LIMP-2 shows a helical bundle where Ξ²-glucocerebrosidase binds |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | ACCEPT | Summary: HDA annotation: GBA identified by proteomics of purified placental lysosomal membranes, consistent with its peripheral lysosomal-membrane association. Reason: Supports lysosomal-membrane localization via lysosomal membrane proteomics; consistent with the enzyme's peripheral membrane association. Correct localization. Supporting Evidence: PMID:17897319 In membranes purified from placental lysosomes, we identified 58 proteins, known to reside at least partially in the lysosomal membrane |
| GO:0005102 signaling receptor binding | ISS PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | KEEP AS NON CORE | Summary: ISS annotation to signaling receptor binding, based on GBA binding its trafficking receptor LIMP-2/SCARB2. Reason: Captures the physiologically important GBA-LIMP-2 interaction (LIMP-2 is a receptor for lysosomal targeting of GCase), but 'signaling receptor binding' is imprecise and describes a trafficking interaction, not the core catalytic function. Retain as non-core. Supporting Evidence: PMID:18022370 LIMP-2 as the mannose-6-phosphate-independent trafficking receptor for beta-glucocerebrosidase |
| GO:0005765 lysosomal membrane | ISS PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | ACCEPT | Summary: ISS annotation to lysosomal membrane, based on GBA's LIMP-2-mediated lysosomal targeting and its membrane association. Reason: Consistent with the enzyme's peripheral lysosomal-membrane association and LIMP-2-dependent delivery. Correct localization. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Lysosome membrane |
| GO:0043202 lysosomal lumen | ISS PMID:18022370 LIMP-2 is a receptor for lysosomal mannose-6-phosphate-indep... | ACCEPT | Summary: ISS annotation to lysosomal lumen; GBA acts on the lumenal side of the lysosomal membrane after LIMP-2-mediated delivery. Reason: Consistent with UniProt (lumenal side) and the enzyme's action on lumenal glucosylceramide. Core localization. Supporting Evidence: file:human/GBA/GBA-uniprot.txt Lumenal side |
| GO:0046512 sphingosine biosynthetic process | IMP PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | KEEP AS NON CORE | Summary: IMP annotation: GBA1 generates sphingosine (from GlcCer-derived ceramide) for the salvage pathway; silencing GBA1 decreases sphingosine generation. Reason: Real but downstream of the core hydrolase reaction: sphingosine arises after GlcCer -> ceramide -> sphingosine. GBA does not directly synthesize sphingosine (a ceramidase does), so this is a pathway-level, non-core role. Supporting Evidence: PMID:19279011 Silencing GBA1 blocked PMA-induced degradation of glucosylceramide and generation of sphingosine |
| GO:0046513 ceramide biosynthetic process | IMP PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | KEEP AS NON CORE | Summary: IMP annotation: GBA1 activity generates ceramide (from glucosylceramide) in the PKC-activated salvage pathway; forced GBA1 expression increases ceramide. Reason: Ceramide is the direct product of GBA's GlcCer hydrolysis, so this 'ceramide biosynthetic' role is really the catabolic reaction viewed from the product side, contributing to the salvage pathway. Retain as non-core; the core term is glucosylceramide catabolic process. Supporting Evidence: PMID:19279011 forced expression of GBA1 increased ceramide levels |
| GO:0004348 glucosylceramidase activity | IDA PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | ACCEPT | Summary: IDA annotation: GBA1 hydrolyses glucosylceramide to form lysosomal ceramide, providing sphingosine for the ceramide salvage pathway. Reason: Directly supports the core glucosylceramidase activity (GlcCer hydrolysis to ceramide). Correct core molecular function. Supporting Evidence: PMID:19279011 acid beta-glucosidase 1 (GBA1), which hydrolyzes glucosylceramide to form lysosomal ceramide |
| GO:0006680 glucosylceramide catabolic process | IMP PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | ACCEPT | Summary: IMP annotation: silencing GBA1 blocks PMA-induced degradation of glucosylceramide, confirming its role in glucosylceramide catabolism. Reason: Loss-of-function (siRNA) directly links GBA1 to glucosylceramide degradation. Core process. Supporting Evidence: PMID:19279011 Silencing GBA1 blocked PMA-induced degradation of glucosylceramide and generation of sphingosine |
| GO:0023021 termination of signal transduction | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: IMP annotation: the GBA1-ceramide pathway terminates p38 (MAPK) signalling; GBA knockdown prolongs p38 activation in MCF-7 cells. Reason: Real but indirect: GBA affects signal termination through the ceramide it generates, not by directly acting on the signalling machinery. Retain as non-core downstream signalling role. Supporting Evidence: PMID:19279008 implicating the GBA1-ceramide pathway in the termination of p38 activation |
| GO:0032715 negative regulation of interleukin-6 production | IDA PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | KEEP AS NON CORE | Summary: IDA annotation: increasing cellular ceramide (via the GBA1 pathway) attenuates IL-6 production; GBA knockdown causes IL-6 hyperproduction. Reason: Supported experimentally, but the effect on IL-6 is mediated by GBA-generated ceramide acting on p38delta, i.e. a downstream signalling consequence rather than a direct GBA function. Retain as non-core. Supporting Evidence: PMID:19279008 increasing cellular ceramide with cell-permeable ceramide treatment resulted in attenuation of the IL-6 response |
| GO:0071356 cellular response to tumor necrosis factor | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | MARK AS OVER ANNOTATED | Summary: IMP annotation to cellular response to TNF, from the same GBA1-ceramide-p38delta signalling study. Reason: The study centers on PKC/PMA-induced p38delta/IL-6 signalling in MCF-7 cells; a direct GBA role in TNF response is not clearly established and would be an indirect ceramide-mediated effect at best. Over-annotation. Supporting Evidence: PMID:19279008 possible role for ceramide as an anti-inflammatory lipid |
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