SMPD1 encodes lysosomal acid sphingomyelinase (ASM/aSMase), a Zn2+-dependent sphingomyelin phosphodiesterase (EC 3.1.4.12) that hydrolyzes sphingomyelin and water to ceramide and phosphocholine. It is the principal enzyme of lysosomal sphingomyelin catabolism, acting in the acidic lumen of the lysosome/endolysosome. A single protein precursor gives rise, by differential trafficking rather than alternative splicing, to two enzymatic forms: a lysosomal form (L-SMase) targeted to lysosomes via mannose-6-phosphate receptor and sortilin, and a Zn2+-activated secreted form (S-SMase) released to the extracellular space, whose secretion is induced by inflammatory cytokines and by bacterial and viral infection. The ceramide generated by ASM serves as a bioactive lipid second messenger, and ASM contributes to stress-induced apoptosis, ceramide-rich membrane platform formation, plasma membrane repair, cholesterol export from endolysosomes, and host-pathogen interactions. Loss-of-function mutations cause acid sphingomyelinase deficiency, the lysosomal storage disorder Niemann-Pick disease types A and B.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Secreted (S-SMase) form of ASM acts in the extracellular space. Consistent with experimental localization of a Zn2+-activated secreted form of the ASM gene product and with the phylogenetically conserved secreted role of this family. Reason: A secreted, Zn2+-stimulated form of ASM is well documented experimentally (e.g. PMID:8702487, PMID:9660788); the IBA is consistent with the human evidence and with the family. Non-core relative to the lysosomal catalytic role but valid. Supporting Evidence: PMID:8702487 We now show that Zn-SMase activity is secreted by human and murine macrophages, human skin fibroblasts, microglial cells, and several other cells in culture |
| GO:0005764 lysosome | IBA GO_REF:0000033 | ACCEPT | Summary: ASM is a lysosomal hydrolase that acts within the lysosome, the core site of its sphingomyelin-degrading activity. Strongly supported by human experimental evidence and phylogenetically conserved. Reason: The lysosomal site of action is the core cellular component for ASM and is independently supported by multiple human IDA localizations and by UniProt SUBCELLULAR LOCATION (Lysosome). Supporting Evidence: PMID:16787399 Acid sphingomyelinase (ASM), a member of the saposin-like protein (SAPLIP) family, is a lysosomal hydrolase that converts sphingomyelin to ceramide. |
| GO:0046513 ceramide biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: ASM hydrolyzes sphingomyelin to ceramide, so it contributes to cellular ceramide production. In GO this reaction is captured both as ceramide biosynthesis (GO:0046513) and as sphingomyelin catabolism (GO:0006685); they describe the two aspects of the same hydrolysis. Reason: The conversion of sphingomyelin to ceramide is the defining physiological reaction of ASM and is extensively documented; ceramide generation is genuinely a biosynthetic outcome of this catabolic step. Retained, though the sphingomyelin catabolic process term is the more precise primary BP. Supporting Evidence: PMID:16787399 Acid sphingomyelinase (ASM), a member of the saposin-like protein (SAPLIP) family, is a lysosomal hydrolase that converts sphingomyelin to ceramide. |
| GO:0006685 sphingomyelin catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: ASM catalyzes the committed step of lysosomal sphingomyelin degradation, hydrolyzing sphingomyelin to ceramide and phosphocholine. This is the core biological process for the gene. Reason: Core catabolic process, supported by human experimental data and by the phylogenetic tree; represents the correct level of specificity for the BP. Supporting Evidence: PMID:22573858 Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH. |
| GO:0061750 acid sphingomyelin phosphodiesterase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Acid sphingomyelin phosphodiesterase activity (a child of GO:0004767 specifying the acidic pH optimum) is the defining molecular function of ASM. Strongly supported by human experiment and conserved across the family. Reason: Correct, appropriately specific MF term capturing the acid pH optimum of lysosomal ASM. Core molecular function. Supporting Evidence: PMID:22573858 Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH. |
| GO:0001778 plasma membrane repair | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ASM contributes to Ca2+-triggered plasma membrane repair by converting outer-leaflet sphingomyelin to ceramide after lysosomal exocytosis. This is a real but non-core, context-dependent role. Reason: Supported experimentally in human/rodent cells (PMID:20530211), but this is a downstream physiological consequence of extracellular ASM activity, not the core lysosomal catabolic function. Supporting Evidence: PMID:20530211 the lysosomal enzyme acid sphingomyelinase (ASM) is released extracellularly when cells are wounded in the presence of Ca(2+) |
| GO:0004767 sphingomyelin phosphodiesterase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Sphingomyelin phosphodiesterase activity (EC 3.1.4.12, RHEA:19253) is the core molecular function of ASM, hydrolyzing sphingomyelin to ceramide and phosphocholine. This IEA is corroborated by extensive human experimental evidence. Reason: Correct core MF; the automated EC/RHEA/InterPro mapping agrees with experimental annotations (multiple EXP/IDA lines) and with UniProt EC=3.1.4.12. Supporting Evidence: file:human/SMPD1/SMPD1-uniprot.txt Reaction=a sphingomyelin + H2O = phosphocholine + an N-acylsphing-4- |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Reflects the secreted S-SMase form of ASM in the extracellular region. Consistent with UniProt SUBCELLULAR LOCATION (Secreted) and human experimental localization. Reason: Non-core but valid; the secreted form is well documented. Duplicate of experimentally supported extracellular-region annotations. Supporting Evidence: PMID:8702487 Zn2+-stimulated sphingomyelinase is secreted by many cell types and is a product |
| GO:0005764 lysosome | IEA GO_REF:0000044 | ACCEPT | Summary: Lysosome is the core localization of ASM, from the UniProtKB subcellular location vocabulary mapping. Extensively supported by human IDA evidence. Reason: Correct core CC; agrees with UniProt SUBCELLULAR LOCATION and multiple experimental localizations. Supporting Evidence: file:human/SMPD1/SMPD1-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0005811 lipid droplet | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Lipid droplet localization is derived from the UniProt subcellular location vocabulary (based on PubMed:25339683). A minor, non-core localization. Reason: Reported in UniProt as a Lipid droplet location, but peripheral to the core lysosomal function; retained as a non-core observation. Supporting Evidence: file:human/SMPD1/SMPD1-uniprot.txt Lipid droplet |
| GO:0006685 sphingomyelin catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Core biological process of ASM (lysosomal sphingomyelin degradation), here inferred electronically and independently confirmed by human experiment. Reason: Correct core BP; automated ARBA/InterPro mapping agrees with the experimental annotations. Supporting Evidence: PMID:22573858 Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic hydrolase activity is a high-level parent of the specific sphingomyelin phosphodiesterase activity already annotated. Uninformative on its own. Reason: True but far too general given that the precise MF (GO:0004767 sphingomyelin phosphodiesterase activity) is annotated with strong evidence. An InterPro2GO broad mapping; over-annotation relative to the specific term. Supporting Evidence: file:human/SMPD1/SMPD1-uniprot.txt Reaction=a sphingomyelin + H2O = phosphocholine + an N-acylsphing-4- |
| GO:0034480 phosphatidylcholine phospholipase C activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: ASM also hydrolyzes phosphatidylcholine (EC 3.1.4.3), a genuine secondary activity demonstrated in vitro but not its core physiological function. Reason: Real side activity (UniProt EC=3.1.4.3; PMID:25339683), but secondary to sphingomyelin hydrolysis; kept as non-core rather than core MF. Supporting Evidence: PMID:25339683 Besides SM, ASM also cleaves liposomal phosphatidylcholine. |
| GO:0005515 protein binding | IPI PMID:21157428 Caspase-8 and caspase-7 sequentially mediate proteolytic act... | MARK AS OVER ANNOTATED | Summary: Records a physical interaction between pro-ASM and caspase-7 (which proteolytically activates it in TNF receptosomes). "Protein binding" is uninformative as a molecular function. Reason: The underlying interaction (CASP7-mediated cleavage/activation of ASM) is real (PMID:21157428) but the bare GO:0005515 term conveys no specific function. Per curation policy, bare protein binding IPIs are marked over-annotated rather than accepted as a function. Supporting Evidence: PMID:21157428 we found that caspase-7 mediates A-SMase activation by direct interaction resulting in proteolytic cleavage of the 72-kDa pro-A-SMase zymogen |
| GO:0008270 zinc ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: ASM binds Zn2+ (two ions per subunit) as an essential catalytic cofactor. Well supported experimentally and by the UniProt COFACTOR annotation. Reason: Zn2+ is the catalytic cofactor of ASM; the zinc-binding MF is correct and supported by human IDA (PMID:9660788, PMID:8702487) and UniProt. Supporting Evidence: file:human/SMPD1/SMPD1-uniprot.txt Binds 2 Zn(2+) ions per subunit |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from a rat ortholog (Ensembl Compara). Not a core function and not directly supported by human data in the cited set. Reason: Plausible given ASM's role in stress/pharmacological responses (many cationic amphiphilic drugs inhibit ASM), but only an ortholog-transfer IEA; keep as non-core rather than core. |
| GO:0010212 response to ionizing radiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ASM mediates ceramide generation and apoptosis in response to ionizing radiation; here inferred from a mouse ortholog and independently supported by the human/mouse IMP (PMID:8706124). Reason: Real stress-response role (see PMID:8706124) but a downstream signaling function, not the core catabolic role; kept as non-core. Supporting Evidence: PMID:8706124 lymphoblasts from Niemann-Pick patients, which have an inherited deficiency of acid sphingomyelinase activity, fail to respond to ionizing radiation with ceramide generation and apoptosis |
| GO:0042220 response to cocaine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transfer IEA from rat. No human experimental support in the cited literature; peripheral at best. Reason: Weak, ortholog-only electronic annotation with no supporting human data here; not clearly wrong (ASM responds to diverse stressors/drugs) but far from core. Kept as non-core rather than removed. |
| GO:0042599 lamellar body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Lamellar-body localization inferred from a rat ortholog (Ensembl Compara). Lamellar bodies are lysosome-related organelles, so this is plausible but not a core localization. Reason: Ortholog-transfer IEA; lamellar bodies are lysosome-related surfactant/lipid organelles where a lysosomal hydrolase could plausibly reside, but not supported by human data here. Non-core. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: ASM-generated ceramide promotes stress-induced apoptosis. A real but non-core signaling role, also captured by human/mouse IMP (PMID:8706124). Reason: Supported by the apoptosis-defect phenotype of ASM-deficient cells/mice (PMID:8706124); a downstream signaling consequence of ceramide production, not the core function. Supporting Evidence: PMID:8706124 These genetic models provide definitive evidence for the involvement of acid sphingomyelinase in one form of stress-induced apoptosis. |
| GO:0046513 ceramide biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of ceramide production, the outcome of ASM's sphingomyelin hydrolysis. Duplicate aspect of the sphingomyelin catabolic process. Reason: Correct; ceramide is the product of ASM-catalyzed sphingomyelin hydrolysis, supported by many experimental lines. Supporting Evidence: PMID:22573858 Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH. |
| GO:0061750 acid sphingomyelin phosphodiesterase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of the acid-pH-specific sphingomyelin phosphodiesterase activity, the defining MF of ASM. Corroborated by human experimental data. Reason: Correct, appropriately specific core MF; consistent with the IBA/IDA lines. Supporting Evidence: PMID:22573858 Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH. |
| GO:0007596 blood coagulation | TAS Reactome:R-HSA-9769740 | MARK AS OVER ANNOTATED | Summary: Reactome pathway annotation placing SMPD1 in a coagulation-pathway context. Not an established core or well-supported specific role for ASM. Reason: This appears to derive from Reactome pathway grouping rather than direct evidence that ASM functions in blood coagulation; over-annotation relative to the enzyme's characterized sphingolipid role. |
| GO:0046479 glycosphingolipid catabolic process | TAS Reactome:R-HSA-9840310 | MARK AS OVER ANNOTATED | Summary: Reactome places SMPD1 within a broad glycosphingolipid-catabolism pathway. Sphingomyelin is a phosphosphingolipid, not a glycosphingolipid, so this is broader/less precise than the enzyme's actual reaction. Reason: ASM degrades sphingomyelin (a phosphosphingolipid) to ceramide; grouping it under glycosphingolipid catabolism is a pathway-level generalization. The precise BP (sphingomyelin catabolic process) is already annotated. |
| GO:0004767 sphingomyelin phosphodiesterase activity | TAS Reactome:R-HSA-1605797 | ACCEPT | Summary: Reactome reaction "SMPD1 hydrolyzes SPHM" asserts the core sphingomyelin phosphodiesterase activity. Correct and consistent with all other evidence. Reason: Core MF, authoritatively curated by Reactome and matching experimental data. Supporting Evidence: PMID:22573858 Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH. |
| GO:0004767 sphingomyelin phosphodiesterase activity | TAS Reactome:R-HSA-9769742 | ACCEPT | Summary: Reactome reaction "SMPD1 converts sphingomyelin to ceramide" asserts the core MF. Duplicate of the other Reactome/experimental MF annotations. Reason: Core MF; correctly curated by Reactome. Supporting Evidence: PMID:22573858 Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH. |
| GO:0036021 endolysosome lumen | IC PMID:27498570 Endolysosomes Are the Principal Intracellular Sites of Acid ... | ACCEPT | Summary: Inferred (IC) that ASM acid-hydrolase activity operates in the endolysosome lumen, consistent with the finding that endolysosomes are the principal sites of acid hydrolase activity. Reason: Reasonable curator inference; endolysosome lumen is a refinement of the lysosomal site of action and is supported by PMID:27498570 and by ASM's acid pH optimum. Supporting Evidence: PMID:27498570 We found that endolysosomes are the principal organelles in which acid hydrolase substrates are cleaved. |
| GO:0006685 sphingomyelin catabolic process | IDA PMID:20807762 Regulated secretion of acid sphingomyelinase: implications f... | ACCEPT | Summary: Direct experimental demonstration that ASM (L-SMase/S-SMase) degrades cellular sphingomyelin to ceramide in a regulated manner. Supports the core BP. Reason: Core catabolic process, directly supported (regulated ASM-dependent ceramide formation from sphingomyelin in MCF7 cells). Supporting Evidence: PMID:20807762 The acid sphingomyelinase (aSMase) gene gives rise to two distinct enzymes, lysosomal sphingomyelinase (L-SMase) and secretory sphingomyelinase (S-SMase) |
| GO:0061750 acid sphingomyelin phosphodiesterase activity | IDA PMID:17303575 Activation of acid sphingomyelinase by protein kinase Cdelta... | ACCEPT | Summary: Direct assay of ASM (acid sphingomyelinase) activity, activated by PKCdelta phosphorylation at Ser508. Supports the core acid sphingomyelinase MF. Reason: Core MF, directly measured; the paper shows PMA/PKCdelta selectively activates ASMase, accounting for the majority of induced ceramide. Supporting Evidence: PMID:17303575 Here we show that PMA selectively activates ASMase and that ASMase accounts for the majority of PMA-induced ceramide. |
| GO:0034480 phosphatidylcholine phospholipase C activity | IDA PMID:25339683 Acid sphingomyelinase activity is regulated by membrane lipi... | KEEP AS NON CORE | Summary: ASM directly cleaves phosphatidylcholine in vitro (EC 3.1.4.3), a genuine secondary activity distinct from its principal sphingomyelin hydrolysis. Reason: Real, directly demonstrated side activity (PMID:25339683) captured also in UniProt (EC=3.1.4.3), but secondary to the physiological sphingomyelinase role. Supporting Evidence: PMID:25339683 Besides SM, ASM also cleaves liposomal phosphatidylcholine. |
| GO:0004767 sphingomyelin phosphodiesterase activity | EXP PMID:12563314 Host defense against Pseudomonas aeruginosa requires ceramid... | ACCEPT | Summary: Experimental support for ASM sphingomyelin phosphodiesterase activity in the context of P. aeruginosa infection triggering ASM activation and ceramide release. Core MF. Reason: Core MF; the study shows infection triggers activation of the acid sphingomyelinase and release of ceramide. Supporting Evidence: PMID:12563314 P. aeruginosa infection triggers activation of the acid sphingomyelinase and the release of ceramide in sphingolipid-rich rafts. |
| GO:0004767 sphingomyelin phosphodiesterase activity | EXP PMID:15877209 Acid sphingomyelinase deficiency. Phenotype variability with... | ACCEPT | Summary: ASM sphingomyelin phosphodiesterase activity assayed across a series of Niemann-Pick A/B patients (sphingomyelin loading/degradation). Core MF. Reason: Core MF; the patient study directly assays ASM-dependent sphingomyelin degradation and its loss in ASM deficiency. Supporting Evidence: PMID:15877209 The sphingomyelin loading test in living fibroblasts resulted in total degradation from less than 2% in classical type A to 70-80% in classical type B. |
| GO:0004767 sphingomyelin phosphodiesterase activity | EXP PMID:1840600 Human acid sphingomyelinase. Isolation, nucleotide sequence ... | ACCEPT | Summary: Cloning/expression study showing that the full-length type 1 ASM cDNA encodes catalytically active human acid sphingomyelinase (EC 3.1.4.12). Core MF. Reason: Core MF; expression of the type 1 transcript in COS-1 cells produced catalytically active human ASM. Supporting Evidence: PMID:1840600 Only the full-length type 1 transcript encoded catalytically active human ASM, demonstrating its functional integrity. |
| GO:0004767 sphingomyelin phosphodiesterase activity | EXP PMID:18815062 Characterization of common SMPD1 mutations causing types A a... | ACCEPT | Summary: ASM sphingomyelin phosphodiesterase activity assayed in NPD patient fibroblasts homoallelic for common SMPD1 mutations (deficient activity). Core MF. Reason: Core MF; in vitro and in situ ASM assays directly measure the enzyme's sphingomyelin phosphodiesterase activity (EC 3.1.4.12). Supporting Evidence: PMID:18815062 inherited deficiency of acid sphingomyelinase activity (ASM, sphingomyelin phosphodiesterase, EC 3.1.4.12) |
| GO:0004767 sphingomyelin phosphodiesterase activity | EXP PMID:21157428 Caspase-8 and caspase-7 sequentially mediate proteolytic act... | ACCEPT | Summary: ASM (A-SMase) sphingomyelin phosphodiesterase activity, activated by caspase-7 cleavage of the pro-A-SMase zymogen in TNF receptosomes. Core MF. Reason: Core MF; the paper measures activation of A-SMase enzymatic activity and its dependence on caspase-7-mediated proteolytic cleavage. Supporting Evidence: PMID:21157428 we found that caspase-7 mediates A-SMase activation by direct interaction resulting in proteolytic cleavage of the 72-kDa pro-A-SMase zymogen |
| GO:0004767 sphingomyelin phosphodiesterase activity | EXP PMID:26084044 Alleged Detrimental Mutations in the SMPD1 Gene in Patients ... | ACCEPT | Summary: ASM activity measured in vivo and in vitro when evaluating alleged SMPD1 missense variants; establishes catalytic activity of the wild-type enzyme. Core MF. Reason: Core MF; the study assays ASM catalytic activity to distinguish detrimental mutations from benign variants. Supporting Evidence: PMID:26084044 found them to be common variants of SMPD1 that give rise to normal in vivo and in vitro ASM activity |
| GO:0004767 sphingomyelin phosphodiesterase activity | EXP PMID:8702487 Zn2+-stimulated sphingomyelinase is secreted by many cell ty... | ACCEPT | Summary: Secreted Zn2+-stimulated sphingomyelinase activity shown to be a product of the acid sphingomyelinase gene. Core MF (secreted form). Reason: Core MF; Zn-SMase (secreted ASM) activity is documented and shown to arise from the same gene as lysosomal SMase. Supporting Evidence: PMID:8702487 this enzyme and the intracellular lysosomal SMase, which is Zn-independent, arise from the same gene |
| GO:0004767 sphingomyelin phosphodiesterase activity | EXP PMID:8706124 Acid sphingomyelinase-deficient human lymphoblasts and mice ... | ACCEPT | Summary: ASM activity assayed via ceramide generation in response to ionizing radiation; ASM-deficient cells fail to generate ceramide, restored by ASM cDNA. Core MF. Reason: Core MF; the genetic rescue (retroviral ASM cDNA restores ceramide generation) directly links the enzyme to sphingomyelin-to-ceramide conversion. Supporting Evidence: PMID:8706124 These abnormalities are reversible up on restoration of acid sphingomyelinase activity by retroviral transfer of human acid sphingomyelinase cDNA. |
| GO:0005576 extracellular region | EXP PMID:12563314 Host defense against Pseudomonas aeruginosa requires ceramid... | KEEP AS NON CORE | Summary: Secreted ASM acts extracellularly (on the outer plasma-membrane leaflet) during P. aeruginosa infection. Non-core localization of the secreted form. Reason: The secreted extracellular form is real and functionally important in host defense, but is non-core relative to the lysosomal catalytic role. Supporting Evidence: PMID:12563314 P. aeruginosa infection triggers activation of the acid sphingomyelinase and the release of ceramide in sphingolipid-rich rafts. |
| GO:0005576 extracellular region | EXP PMID:9030779 Functional characterization of the N-glycosylation sites of ... | KEEP AS NON CORE | Summary: Study of ASM N-glycosylation, secretion, and processing; consistent with a secreted extracellular form. Non-core localization. Reason: The secreted form is supported, but extracellular localization is non-core relative to the lysosomal site of action. Supporting Evidence: PMID:9030779 Most soluble lysosomal enzymes require a mannose-6-phosphate recognition marker present on asparagine-linked oligosaccharides for proper targeting to lysosomes. |
| GO:0043409 negative regulation of MAPK cascade | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | MARK AS OVER ANNOTATED | Summary: The cited paper (PMID:19279008) is primarily about acid beta-glucosidase 1 (GBA1) counteracting p38delta-dependent IL-6 induction via the ceramide salvage pathway; the experimental manipulations target GBA1, not SMPD1. Reason: Per curation policy I do not REMOVE an experimental (IMP) annotation whose full text I cannot fully verify. However, the cached abstract shows the IMP is built on GBA1 knockdown/overexpression, and "negative regulation of MAPK cascade" is at best an indirect, ceramide-mediated effect for ASM. Flagged as over-annotated pending curator confirmation that SMPD1 (not GBA1) was assayed. Supporting Evidence: PMID:19279008 knockdown of GBA1 by small interfering RNAs or pharmacological inhibition of GBA1 promoted further activation of p38 after PMA treatment, implicating the GBA1-ceramide pathway in the termination of p38 activation |
| GO:0043202 lysosomal lumen | TAS Reactome:R-HSA-1605797 | ACCEPT | Summary: ASM acts in the lysosomal lumen, the acidic compartment where it hydrolyzes sphingomyelin. A precise refinement of the lysosomal localization. Core CC. Reason: Correct core localization; the soluble lysosomal hydrolase resides in the lysosomal lumen. Curated by Reactome and consistent with UniProt. Supporting Evidence: file:human/SMPD1/SMPD1-uniprot.txt SUBCELLULAR LOCATION: Lysosome |
| GO:0046598 positive regulation of viral entry into host cell | IDA PMID:33163980 Pharmacological Inhibition of Acid Sphingomyelinase Prevents... | KEEP AS NON CORE | Summary: ASM activity is required for SARS-CoV-2 uptake; pharmacological or genetic inhibition of ASM prevents infection, so ASM positively promotes viral entry. A non-core, host-pathogen role. Reason: Directly supported (ASM inhibition blocks SARS-CoV-2 uptake), but this is a context-specific consequence of surface ceramide generation, not the core function. Supporting Evidence: PMID:33163980 pharmacological inhibition of acid sphingomyelinase with amitriptyline, imipramine, fluoxetine, sertraline, escitalopram, or maprotiline or genetic downregulation of the enzyme prevents infection |
| GO:0004767 sphingomyelin phosphodiesterase activity | IDA PMID:33163980 Pharmacological Inhibition of Acid Sphingomyelinase Prevents... | ACCEPT | Summary: ASM sphingomyelin phosphodiesterase activity directly demonstrated (activation upon SARS-CoV-2 infection with surface ceramide release). Core MF. Reason: Core MF; infection activates ASM and triggers ceramide release on the cell surface. Supporting Evidence: PMID:33163980 Infection activates acid sphingomyelinase and triggers a release of ceramide on the cell surface. |
| GO:0005576 extracellular region | IDA PMID:33163980 Pharmacological Inhibition of Acid Sphingomyelinase Prevents... | KEEP AS NON CORE | Summary: Secreted/surface ASM acts at the cell surface (outer plasma-membrane leaflet / extracellular space) to generate ceramide during viral infection. Non-core localization of the secreted form. Reason: Supported (surface ceramide release), but extracellular action is non-core relative to the lysosomal role. Supporting Evidence: PMID:33163980 Infection activates acid sphingomyelinase and triggers a release of ceramide on the cell surface. |
| GO:0005764 lysosome | IDA PMID:33163980 Pharmacological Inhibition of Acid Sphingomyelinase Prevents... | ACCEPT | Summary: ASM acts in the lysosome, its core site of activity (the enzyme is normally lysosomal, recruited to the surface upon infection). Core CC. Reason: Core localization; consistent with the enzyme being a lysosomal hydrolase. Supporting Evidence: PMID:22573858 Normally, ASMase is located in lysosomes and endosomes, but membrane damage or the interaction with some bacterial and viral pathogens can trigger its recruitment to the plasma membrane. |
| GO:0046513 ceramide biosynthetic process | IDA PMID:33163980 Pharmacological Inhibition of Acid Sphingomyelinase Prevents... | ACCEPT | Summary: ASM produces ceramide (from sphingomyelin) upon infection. Ceramide generation is the product side of the core sphingomyelin catabolic reaction. Reason: Correct; directly supported by the demonstrated ceramide release upon ASM activation. Supporting Evidence: PMID:33163980 Infection activates acid sphingomyelinase and triggers a release of ceramide on the cell surface. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9769742 | KEEP AS NON CORE | Summary: ASM can be recruited to the plasma membrane (outer leaflet) upon stress or infection, where the secreted/surface form generates ceramide. Non-core. Reason: Plasma-membrane localization of the recruited/secreted form is documented (PMID:22573858) but non-core relative to the lysosomal site of action. Supporting Evidence: PMID:22573858 membrane damage or the interaction with some bacterial and viral pathogens can trigger its recruitment to the plasma membrane |
| GO:0001778 plasma membrane repair | IDA PMID:20530211 Exocytosis of acid sphingomyelinase by wounded cells promote... | KEEP AS NON CORE | Summary: ASM released from lysosomes during wounding converts plasma-membrane sphingomyelin to ceramide, promoting endocytosis of lesions and membrane repair. Directly demonstrated but non-core. Reason: Strong direct evidence (ASM-deficient/NPA cells defective in repair, rescued by recombinant ASM), but a downstream physiological role of extracellular ASM, not the core catabolic function. Supporting Evidence: PMID:20530211 conversion of plasma membrane sphingomyelin to ceramide by this lysosomal enzyme promotes lesion internalization |
| GO:0004767 sphingomyelin phosphodiesterase activity | IDA PMID:22573858 Ebolavirus requires acid sphingomyelinase activity and plasm... | ACCEPT | Summary: ASM sphingomyelin phosphodiesterase activity directly assayed (required for Ebolavirus infection; ASM converts SM to phosphocholine and ceramide). Core MF. Reason: Core MF; the paper states and depends on ASM converting sphingomyelin to phosphocholine and ceramide. Supporting Evidence: PMID:22573858 Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH. |
| GO:0005576 extracellular region | IDA PMID:20530211 Exocytosis of acid sphingomyelinase by wounded cells promote... | KEEP AS NON CORE | Summary: ASM is released extracellularly from wounded cells (Ca2+-dependent lysosomal exocytosis). Documents the secreted/extracellular form. Non-core. Reason: Directly demonstrated extracellular release of ASM upon wounding, but non-core relative to the lysosomal site. Supporting Evidence: PMID:20530211 the lysosomal enzyme acid sphingomyelinase (ASM) is released extracellularly when cells are wounded in the presence of Ca(2+) |
| GO:0005576 extracellular region | IDA PMID:22573858 Ebolavirus requires acid sphingomyelinase activity and plasm... | KEEP AS NON CORE | Summary: Surface-localized/secreted ASM detected extracellularly during Ebolavirus binding. Non-core localization of the secreted form. Reason: Supported (surface-localized ASMase associated with virus binding), but non-core relative to the lysosomal role. Supporting Evidence: PMID:22573858 the binding of virus-like particles to cells is strongly associated with surface-localized ASMase |
| GO:0005764 lysosome | IDA PMID:20530211 Exocytosis of acid sphingomyelinase by wounded cells promote... | ACCEPT | Summary: ASM is a lysosomal enzyme; the paper repeatedly identifies it as "the lysosomal enzyme acid sphingomyelinase." Core CC. Reason: Core localization, directly supported. Supporting Evidence: PMID:20530211 the lysosomal enzyme acid sphingomyelinase (ASM) |
| GO:0006685 sphingomyelin catabolic process | IDA PMID:22573858 Ebolavirus requires acid sphingomyelinase activity and plasm... | ACCEPT | Summary: ASM converts sphingomyelin to phosphocholine and ceramide; the core sphingomyelin catabolic process, directly demonstrated in the infection context. Reason: Core BP, directly supported by the stated ASM reaction. Supporting Evidence: PMID:22573858 Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH. |
| GO:0009615 response to virus | IDA PMID:22573858 Ebolavirus requires acid sphingomyelinase activity and plasm... | KEEP AS NON CORE | Summary: ASM activity is required for Ebolavirus infection; ASM participates in the cellular response to virus. Non-core host-pathogen role. Reason: Supported (ASM activity and plasma-membrane SM required for EBOV infection), but a context-specific role rather than a core function. Supporting Evidence: PMID:22573858 Our work suggests that ASMase activity and SM presence are necessary for efficient infection of cells by EBOV. |
| GO:0010212 response to ionizing radiation | IMP PMID:8706124 Acid sphingomyelinase-deficient human lymphoblasts and mice ... | KEEP AS NON CORE | Summary: ASM-deficient lymphoblasts/mice fail to generate ceramide and undergo apoptosis after ionizing radiation, implicating ASM in the radiation response. Non-core signaling role. Reason: Strong genetic (IMP) evidence for ASM in the ionizing-radiation response, but downstream of the core catabolic function. Supporting Evidence: PMID:8706124 lymphoblasts from Niemann-Pick patients, which have an inherited deficiency of acid sphingomyelinase activity, fail to respond to ionizing radiation with ceramide generation and apoptosis |
| GO:0042060 wound healing | IDA PMID:20530211 Exocytosis of acid sphingomyelinase by wounded cells promote... | KEEP AS NON CORE | Summary: ASM promotes plasma membrane repair after cell wounding. "Wound healing" is a broad framing of the membrane-repair role. Non-core. Reason: Related to the demonstrated plasma-membrane-repair role; a broad but defensible BP framing. Non-core relative to the catabolic function. Supporting Evidence: PMID:20530211 Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:8706124 Acid sphingomyelinase-deficient human lymphoblasts and mice ... | KEEP AS NON CORE | Summary: ASM-generated ceramide promotes stress-induced apoptosis; ASM-deficient cells/mice are defective in radiation-induced apoptosis. Non-core signaling role. Reason: Definitive genetic evidence for ASM in one form of stress-induced apoptosis, but a downstream signaling consequence of ceramide production. Supporting Evidence: PMID:8706124 These genetic models provide definitive evidence for the involvement of acid sphingomyelinase in one form of stress-induced apoptosis. |
| GO:0045807 positive regulation of endocytosis | IDA PMID:20530211 Exocytosis of acid sphingomyelinase by wounded cells promote... | KEEP AS NON CORE | Summary: Extracellular ASM converts plasma-membrane SM to ceramide, promoting a rapid endocytosis that internalizes membrane lesions. Non-core. Reason: Directly demonstrated (ASM-dependent injury-induced endocytosis), but a downstream physiological role of extracellular ASM. Supporting Evidence: PMID:20530211 Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. |
| GO:0046513 ceramide biosynthetic process | IMP PMID:8706124 Acid sphingomyelinase-deficient human lymphoblasts and mice ... | ACCEPT | Summary: ASM is required for ceramide generation in response to ionizing radiation (ASM-deficient cells fail to generate ceramide, rescued by ASM cDNA). Ceramide production is the product side of the core reaction. Reason: Correct; genetic evidence directly links ASM to ceramide generation. Supporting Evidence: PMID:8706124 fail to respond to ionizing radiation with ceramide generation and apoptosis |
| GO:0046718 symbiont entry into host cell | IDA PMID:22573858 Ebolavirus requires acid sphingomyelinase activity and plasm... | KEEP AS NON CORE | Summary: ASM activity is required for Ebolavirus entry into host cells (surface ceramide facilitates entry). Non-core host-pathogen role. Reason: Supported (ASM and SM necessary for efficient EBOV infection), but a context-specific role, not a core function. Supporting Evidence: PMID:22573858 Our work suggests that ASMase activity and SM presence are necessary for efficient infection of cells by EBOV. |
| GO:0071277 cellular response to calcium ion | IDA PMID:20530211 Exocytosis of acid sphingomyelinase by wounded cells promote... | KEEP AS NON CORE | Summary: Ca2+ influx triggers lysosomal exocytosis of ASM during wounding; ASM release is Ca2+-dependent. A non-core, upstream-regulated aspect of the membrane-repair role. Reason: Supported (Ca2+-dependent release of ASM), but peripheral to the core function; reflects the trigger for ASM secretion rather than the enzyme's activity. Supporting Evidence: PMID:20530211 acid sphingomyelinase (ASM) is released extracellularly when cells are wounded in the presence of Ca(2+) |
| GO:0004767 sphingomyelin phosphodiesterase activity | IDA PMID:21098024 A novel mechanism of lysosomal acid sphingomyelinase maturat... | ACCEPT | Summary: ASM (aSMase) catalyzes hydrolysis of sphingomyelin to ceramide; the paper characterizes maturation of the catalytically active L-SMase. Core MF. Reason: Core MF; the study directly measures aSMase activity of the mature enzyme. Supporting Evidence: PMID:21098024 Acid sphingomyelinase (aSMase) catalyzes the hydrolysis of sphingomyelin (SM) to form the bioactive lipid ceramide (Cer). |
| GO:0005576 extracellular region | IDA PMID:17303575 Activation of acid sphingomyelinase by protein kinase Cdelta... | KEEP AS NON CORE | Summary: Secreted ASM in the extracellular space; secretion depends on Ser508 phosphorylation. Non-core localization of the secreted form. Reason: Supported (secreted form and its regulation), but non-core relative to the lysosomal site of action. Supporting Evidence: PMID:17303575 Phosphorylation of Ser(508) proved to be an indispensable step for ASMase activation and membrane translocation in response to PMA. |
| GO:0005576 extracellular region | IDA PMID:20807762 Regulated secretion of acid sphingomyelinase: implications f... | KEEP AS NON CORE | Summary: Secreted S-SMase in the extracellular medium, induced by IL-1 and TNF. Non-core localization of the secreted form. Reason: Directly demonstrated cytokine-regulated secretion of S-SMase, but non-core relative to the lysosomal role. Supporting Evidence: PMID:20807762 Interleukin-1Ξ² and tumor necrosis factor-Ξ± induced a time- and dose-dependent increase in S-SMase secretion and activity |
| GO:0005576 extracellular region | IDA PMID:21098024 A novel mechanism of lysosomal acid sphingomyelinase maturat... | KEEP AS NON CORE | Summary: The Zn2+-dependent secreted S-SMase form is released to the extracellular space via the Golgi secretory pathway. Non-core localization. Reason: Supported (S-SMase secretion), but non-core relative to the lysosomal catalytic role. Supporting Evidence: PMID:21098024 a zinc (Zn(2+))-independent lysosomal aSMase (L-SMase) and a Zn(2+)-dependent secreted aSMase (S-SMase) that arise from alternative trafficking of a single protein precursor |
| GO:0005764 lysosome | IDA PMID:20807762 Regulated secretion of acid sphingomyelinase: implications f... | ACCEPT | Summary: Lysosomal L-SMase form localizes to lysosomes. Core CC. Reason: Core localization; the lysosomal form is one of the two gene products characterized here. Supporting Evidence: PMID:20807762 two distinct enzymes, lysosomal sphingomyelinase (L-SMase) and secretory sphingomyelinase (S-SMase) |
| GO:0005764 lysosome | IDA PMID:21098024 A novel mechanism of lysosomal acid sphingomyelinase maturat... | ACCEPT | Summary: Mature L-SMase colocalizes with the lysosomal marker LAMP1; the enzyme is processed within/near endolysosomes. Core CC. Reason: Core localization, directly demonstrated by colocalization with LAMP1. Supporting Evidence: PMID:21098024 mature L-SMase colocalized with the lysosomal marker LAMP1 |
| GO:0034340 response to type I interferon | IDA PMID:20807762 Regulated secretion of acid sphingomyelinase: implications f... | KEEP AS NON CORE | Summary: S-SMase secretion/activity is induced by inflammatory cytokines. Type I interferon response is a non-core, regulated aspect of the secreted form. Reason: The paper's core demonstration is IL-1/TNF induction of S-SMase; interferon responsiveness is part of the broader inflammatory-cytokine regulation (UniProt notes IFNG). Non-core and only indirectly supported here. Supporting Evidence: PMID:20807762 MCF7 breast carcinoma cells stably transfected with V5-aSMase(WT) were treated with inflammatory cytokines |
| GO:0034612 response to tumor necrosis factor | IDA PMID:20807762 Regulated secretion of acid sphingomyelinase: implications f... | KEEP AS NON CORE | Summary: TNF-alpha induces S-SMase secretion and activity and selective C16-ceramide formation. A non-core, cytokine-regulated response of the secreted form. Reason: Directly supported (TNF-alpha induces S-SMase), but a regulated response rather than a core molecular function. Supporting Evidence: PMID:20807762 Interleukin-1Ξ² and tumor necrosis factor-Ξ± induced a time- and dose-dependent increase in S-SMase secretion and activity |
| GO:0034644 cellular response to UV | IDA PMID:17303575 Activation of acid sphingomyelinase by protein kinase Cdelta... | KEEP AS NON CORE | Summary: UV radiation induces ASM phosphorylation at Ser508 and activation, linking ASM to the UV stress response. Non-core signaling role. Reason: Supported (UV induces ASMase phosphorylation/activation), but a downstream stress-response role, not the core catabolic function. Supporting Evidence: PMID:17303575 UV radiation also induced phosphorylation of ASMase at serine 508. |
| GO:0036019 endolysosome | IDA PMID:17303575 Activation of acid sphingomyelinase by protein kinase Cdelta... | ACCEPT | Summary: ASM localizes to the endolysosomal compartment, a refinement of the lysosomal site of action. Core CC. Reason: Endolysosome is consistent with the acid-pH lysosomal site of ASM activity and supported by the localization/translocation data. Supporting Evidence: PMID:17303575 Phosphorylation of Ser(508) proved to be an indispensable step for ASMase activation and membrane translocation in response to PMA. |
| GO:0046513 ceramide biosynthetic process | IDA PMID:17303575 Activation of acid sphingomyelinase by protein kinase Cdelta... | ACCEPT | Summary: ASM accounts for the majority of PMA/PKCdelta-induced ceramide; directly links ASM activity to ceramide production. Product side of the core reaction. Reason: Correct; ASM directly generates ceramide, as shown by the S508A dominant- negative blocking ceramide formation. Supporting Evidence: PMID:17303575 Here we show that PMA selectively activates ASMase and that ASMase accounts for the majority of PMA-induced ceramide. |
| GO:0046513 ceramide biosynthetic process | IDA PMID:20807762 Regulated secretion of acid sphingomyelinase: implications f... | ACCEPT | Summary: ASM (L-SMase/S-SMase) generates specific ceramide species from sphingomyelin in a regulated manner. Product side of the core catabolic reaction. Reason: Correct; directly demonstrated regulated ceramide formation by ASM. Supporting Evidence: PMID:20807762 elevated cellular levels of specific long-chain and very long-chain ceramide species |
| GO:0061750 acid sphingomyelin phosphodiesterase activity | IDA PMID:20807762 Regulated secretion of acid sphingomyelinase: implications f... | ACCEPT | Summary: Direct measurement of L-SMase and S-SMase (acid sphingomyelinase) activity. Core MF. Reason: Core MF, directly assayed for both enzymatic forms. Supporting Evidence: PMID:20807762 MCF7 expressing V5-aSMase(WT) exhibited increased S-SMase and L-SMase activity |
| GO:0070555 response to interleukin-1 | IDA PMID:20807762 Regulated secretion of acid sphingomyelinase: implications f... | KEEP AS NON CORE | Summary: IL-1beta induces S-SMase secretion, activity, and regulated C16-ceramide generation. A non-core, cytokine-regulated response. Reason: Directly supported (IL-1beta induces S-SMase secretion), but a regulated response, not a core function. Supporting Evidence: PMID:20807762 Secretion of the S508A mutant was also defective in response to IL-1Ξ² |
| GO:0004767 sphingomyelin phosphodiesterase activity | IDA PMID:9660788 The cellular trafficking and zinc dependence of secretory an... | ACCEPT | Summary: Both secretory and lysosomal sphingomyelinase (products of the ASM gene) are directly activated by zinc and possess sphingomyelin phosphodiesterase activity. Core MF. Reason: Core MF; the paper directly assays and compares S-SMase and L-SMase activity and zinc dependence. Supporting Evidence: PMID:9660788 both S-SMase and L-SMase, which contain several highly conserved zinc-binding motifs, are directly activated by zinc |
| GO:0005515 protein binding | IPI PMID:16787399 The lysosomal trafficking of acid sphingomyelinase is mediat... | MARK AS OVER ANNOTATED | Summary: Records the physical interaction between ASM and sortilin (with:from UniProtKB:Q99523, SORT1), which mediates ASM's lysosomal targeting. "Protein binding" is uninformative as a molecular function term. Reason: The underlying ASM-sortilin interaction is real and functionally meaningful (lysosomal trafficking; PMID:16787399), but the bare GO:0005515 term conveys no specific function. Per policy, bare protein binding IPIs are over-annotated. Supporting Evidence: PMID:16787399 Co-immunoprecipitation assays confirmed the interaction between sortilin and ASM. |
| GO:0005576 extracellular region | IDA PMID:16787399 The lysosomal trafficking of acid sphingomyelinase is mediat... | KEEP AS NON CORE | Summary: Over-expression of truncated sortilin enhances ASM secretion, consistent with a secreted extracellular form. Non-core localization. Reason: Supported (ASM secretion), but non-core relative to the lysosomal site. Supporting Evidence: PMID:16787399 over-expression of truncated sortilin accelerated and enhanced the secretion of ASM from COS-7 cells and I-cells |
| GO:0005576 extracellular region | IDA PMID:9660788 The cellular trafficking and zinc dependence of secretory an... | KEEP AS NON CORE | Summary: Secretory SMase (S-SMase) arises via the Golgi secretory pathway and is released extracellularly. Non-core localization of the secreted form. Reason: Supported (S-SMase trafficking through the Golgi secretory pathway to secretion), but non-core relative to the lysosomal role. Supporting Evidence: PMID:9660788 S-SMase arises by trafficking through the Golgi secretory pathway |
| GO:0005764 lysosome | IDA PMID:16787399 The lysosomal trafficking of acid sphingomyelinase is mediat... | ACCEPT | Summary: ASM is targeted to lysosomes via sortilin and the M6P receptor; the paper directly studies its lysosomal trafficking. Core CC. Reason: Core localization, directly supported by trafficking and confocal data. Supporting Evidence: PMID:16787399 The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin and mannose 6-phosphate receptor. |
| GO:0005764 lysosome | IDA PMID:9660788 The cellular trafficking and zinc dependence of secretory an... | ACCEPT | Summary: Lysosomal SMase (L-SMase) is trafficked to and resides in lysosomes. Core CC. Reason: Core localization; the paper characterizes L-SMase trafficking to lysosomes. Supporting Evidence: PMID:9660788 L-SMase is exposed to cellular Zn2+ during trafficking to lysosomes, in lysosomes |
| GO:0008270 zinc ion binding | IDA PMID:9660788 The cellular trafficking and zinc dependence of secretory an... | ACCEPT | Summary: ASM contains conserved zinc-binding motifs and both forms are directly activated by zinc; Zn2+ is the catalytic cofactor. Supported core MF. Reason: Zinc binding is the catalytic-cofactor MF of ASM, directly demonstrated. Supporting Evidence: PMID:9660788 both S-SMase and L-SMase, which contain several highly conserved zinc-binding motifs, are directly activated by zinc |
| GO:0005576 extracellular region | IDA PMID:27659707 Structural and functional analysis of the ASM p.Ala359Asp mu... | KEEP AS NON CORE | Summary: Structural/functional analysis of an ASM disease mutant; consistent with the secreted extracellular form. Non-core localization. Reason: Supported by the study of the ASM protein (secreted form), but non-core relative to the lysosomal site. Supporting Evidence: PMID:27659707 Niemann-Pick disease (NPD) type A and B are recessive hereditary disorders caused by deficiency in acid sphingomyelinase (ASM). |
| GO:0005764 lysosome | IDA PMID:27659707 Structural and functional analysis of the ASM p.Ala359Asp mu... | ACCEPT | Summary: ASM (whose deficiency causes NPD) is a lysosomal enzyme; the mutant analysis concerns the lysosomal enzyme. Core CC. Reason: Core localization, consistent with ASM being a lysosomal hydrolase. Supporting Evidence: PMID:27659707 Niemann-Pick disease (NPD) type A and B are recessive hereditary disorders caused by deficiency in acid sphingomyelinase (ASM). |
| GO:0005576 extracellular region | IDA PMID:8702487 Zn2+-stimulated sphingomyelinase is secreted by many cell ty... | KEEP AS NON CORE | Summary: Secreted Zn2+-stimulated SMase is released into the extracellular medium by many cell types. Non-core localization of the secreted form. Reason: Directly demonstrated secretion of Zn-SMase, but non-core relative to the lysosomal site. Supporting Evidence: PMID:8702487 We now show that Zn-SMase activity is secreted by human and murine macrophages, human skin fibroblasts, microglial cells, and several other cells in culture |
| GO:0005764 lysosome | IDA PMID:18815062 Characterization of common SMPD1 mutations causing types A a... | ACCEPT | Summary: Fluorescence microscopy showed ASM polypeptides trafficked to lysosomes. Core CC. Reason: Core localization, directly demonstrated (mutant and wild-type ASM trafficked to lysosomes). Supporting Evidence: PMID:18815062 the mutant ASM polypeptides were expressed at normal levels and trafficked to lysosomes |
| GO:0006685 sphingomyelin catabolic process | IDA PMID:18815062 Characterization of common SMPD1 mutations causing types A a... | ACCEPT | Summary: ASM (sphingomyelin phosphodiesterase, EC 3.1.4.12) degrades sphingomyelin; the study assays ASM sphingomyelin-hydrolyzing activity in patient cells. Core BP. Reason: Core catabolic process; ASM activity (sphingomyelin degradation) is directly assayed via BODIPY-sphingomyelin hydrolysis. Supporting Evidence: PMID:18815062 inherited deficiency of acid sphingomyelinase activity (ASM, sphingomyelin phosphodiesterase, EC 3.1.4.12) |
| GO:0008270 zinc ion binding | IDA PMID:8702487 Zn2+-stimulated sphingomyelinase is secreted by many cell ty... | ACCEPT | Summary: The secreted form of the ASM gene product is Zn2+-stimulated, reflecting zinc binding as its catalytic cofactor. Supported core MF. Reason: Zinc binding is the catalytic cofactor MF of ASM; the Zn2+-stimulated activity is directly demonstrated. Supporting Evidence: PMID:8702487 an acidic Zn2+-stimulated sphingomyelinase (Zn-SMase) |
| GO:0046513 ceramide biosynthetic process | IDA PMID:18815062 Characterization of common SMPD1 mutations causing types A a... | ACCEPT | Summary: ASM assay measures conversion of BODIPY-sphingomyelin to BODIPY-ceramide, i.e. ceramide production. Product side of the core catabolic reaction. Reason: Correct; ceramide is the direct product measured in the ASM activity assay. Supporting Evidence: PMID:18815062 the hydrolytic BODIPY-C12-ceramide (B12CER) product was detected and quantified by HPLC |
| GO:0061750 acid sphingomyelin phosphodiesterase activity | IDA PMID:18815062 Characterization of common SMPD1 mutations causing types A a... | ACCEPT | Summary: In vitro and in situ acid sphingomyelinase activity assays on patient fibroblasts homoallelic for common SMPD1 mutations. Core MF. Reason: Core MF, directly assayed (in vitro and in situ acid sphingomyelinase assays). Supporting Evidence: PMID:18815062 In vitro and in situ enzyme assays revealed marked deficiencies of ASM activity in NPD cell lines homoallelic for each mutation |
| GO:0061750 acid sphingomyelin phosphodiesterase activity | IDA PMID:8702487 Zn2+-stimulated sphingomyelinase is secreted by many cell ty... | ACCEPT | Summary: Acid, Zn2+-stimulated sphingomyelinase activity of the ASM gene product, directly assayed. Core MF. Reason: Core MF; the study demonstrates the acidic Zn2+-stimulated sphingomyelinase activity is a product of the acid sphingomyelinase gene. Supporting Evidence: PMID:8702487 an acidic Zn2+-stimulated sphingomyelinase (Zn-SMase) |
| GO:0005764 lysosome | IDA PMID:20956541 Syntaxin 4 is required for acid sphingomyelinase activity an... | ACCEPT | Summary: ASM (A-SMase) resides in intracellular compartments (lysosomes) from which it translocates to the plasma membrane upon CD95 stimulation. Core CC. Reason: Core localization; the study describes A-SMase translocating from intracellular compartments (lysosomes) to the plasma membrane. Supporting Evidence: PMID:20956541 A-SMase is activated through translocation from intracellular compartments to the plasma membrane in an exocytic pathway requiring the t-SNARE protein syntaxin 4 |
| GO:0005768 endosome | IDA PMID:20956541 Syntaxin 4 is required for acid sphingomyelinase activity an... | KEEP AS NON CORE | Summary: ASM localizes to endosomal/intracellular compartments prior to CD95-induced translocation. Consistent with the endolysosomal site of action. Non-core detail. Reason: Endosomal localization is part of the endolysosomal trafficking of ASM; supported but non-core relative to the lysosomal lumen catalytic site. Supporting Evidence: PMID:20956541 A-SMase is activated through translocation from intracellular compartments to the plasma membrane |
| GO:0005886 plasma membrane | IDA PMID:20956541 Syntaxin 4 is required for acid sphingomyelinase activity an... | KEEP AS NON CORE | Summary: Upon CD95 stimulation, A-SMase translocates to the plasma membrane (syntaxin-4-dependent), where it acts on outer-leaflet sphingomyelin. Non-core. Reason: Directly demonstrated stimulus-induced plasma-membrane translocation, but a regulated, non-core localization. Supporting Evidence: PMID:20956541 A-SMase is activated through translocation from intracellular compartments to the plasma membrane in an exocytic pathway requiring the t-SNARE protein syntaxin 4 |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: ASM was detected in a high-throughput proteomic analysis of urinary prostatic-secretion exosomes. Consistent with the secreted form, but a proteomic survey finding. Reason: HDA proteomic detection in exosomes; consistent with the secreted form but not indicative of a core exosomal function. Non-core. Supporting Evidence: PMID:23533145 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. |
| GO:0023021 termination of signal transduction | IMP PMID:19279008 Acid beta-glucosidase 1 counteracts p38delta-dependent induc... | MARK AS OVER ANNOTATED | Summary: The cited paper (PMID:19279008) attributes termination of p38delta/MAPK signaling to the acid beta-glucosidase 1 (GBA1)-ceramide pathway; its IMP manipulations target GBA1, not SMPD1. Reason: Consistent with policy I do not REMOVE an experimental annotation I cannot fully verify, but the cached abstract shows the termination-of-signaling phenotype is demonstrated by GBA1 knockdown, not SMPD1. Flagged as over-annotated / likely mis-attributed pending curator confirmation. Supporting Evidence: PMID:19279008 implicating the GBA1-ceramide pathway in the termination of p38 activation |
| GO:0046513 ceramide biosynthetic process | IMP PMID:19279011 Involvement of acid beta-glucosidase 1 in the salvage pathwa... | MARK AS OVER ANNOTATED | Summary: The cited paper (PMID:19279011) demonstrates involvement of acid beta-glucosidase 1 (GBA1) in the salvage pathway of ceramide formation; the IMP (GBA1 silencing/overexpression) targets GBA1. ASM is mentioned only as previously implicated in providing substrate. Reason: ASM does generate ceramide (well supported elsewhere in this review), but the experimental evidence in THIS paper concerns GBA1, not SMPD1. Rather than REMOVE an experimental annotation I cannot fully verify, I flag it as an over-annotation likely mis-attributed from a GBA1-focused study. Supporting Evidence: PMID:19279011 acid sphingomyelinase has been implicated, in part, in providing substrate for this pathway |
| GO:0004767 sphingomyelin phosphodiesterase activity | TAS PMID:1718266 Molecular basis of acid sphingomyelinase deficiency in a pat... | ACCEPT | Summary: A Niemann-Pick type A mutation abolishes ASM enzymatic activity in expression studies, corroborating the core sphingomyelin phosphodiesterase MF. Reason: Core MF; expression of the mutant cDNA shows complete loss of ASM enzymatic activity, confirming the enzyme's catalytic function. Supporting Evidence: PMID:1718266 Expression studies with this abnormal cDNA in COS-1 cells revealed a complete loss of enzymatic activity of the mutated protein. |
| GO:0006684 sphingomyelin metabolic process | TAS PMID:7670466 Acid sphingomyelinase deficient mice: a model of types A and... | KEEP AS NON CORE | Summary: ASM deficiency causes accumulation of sphingomyelin in tissues, confirming ASM's role in sphingomyelin metabolism. Broad parent of the sphingomyelin catabolic process. Reason: Correct but general; the more precise sphingomyelin catabolic process (GO:0006685) is the primary BP. Retained as a valid, broader annotation. Supporting Evidence: PMID:7670466 the blood cholesterol levels and sphingomyelin in the liver and brain were elevated |
| GO:0007165 signal transduction | TAS PMID:7670466 Acid sphingomyelinase deficient mice: a model of types A and... | MARK AS OVER ANNOTATED | Summary: ASM/ceramide has an established role in stress signaling; the ASM-deficient mouse model is proposed as a tool for investigating ASM in signal transduction. This is a very general BP. Reason: The generic signal transduction term is at a very high level; ASM's signaling roles are better captured by the specific apoptosis/stress-response annotations. Over-annotated at this level of generality. Supporting Evidence: PMID:7670466 investigations into the role of ASM in signal transduction and apoptosis |
| GO:0007399 nervous system development | TAS PMID:7670466 Acid sphingomyelinase deficient mice: a model of types A and... | MARK AS OVER ANNOTATED | Summary: ASM deficiency causes a neurodegenerative phenotype (cerebellar atrophy, Purkinje-cell loss) in the mouse model and in Niemann-Pick type A. This reflects neurodegeneration/storage pathology rather than a direct developmental function. Reason: The neurological phenotype is a consequence of lysosomal sphingomyelin storage, not evidence that ASM directly drives nervous system development. Over-annotation of a disease/pathology phenotype as a developmental process. Supporting Evidence: PMID:7670466 atrophy of the cerebellum and marked deficiency of Purkinje cells was evident |
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Download this section (compressed HTML)Q: Beyond its constitutive lysosomal sphingomyelin catabolism, to what extent are ASM's diverse signaling roles (apoptosis, plasma-membrane repair, host-pathogen interactions) mediated specifically by the secreted S-SMase form versus the lysosomal L-SMase form?
Q: Are the GBA1-based IMP annotations for termination of signal transduction (GO:0023021) and negative regulation of MAPK cascade (GO:0043409) genuinely supported by SMPD1 loss-of-function evidence, or were they transferred from GBA1-focused studies (PMID:19279008, PMID:19279011)?
Experiment: Quantitative lipidomics of sphingomyelin and ceramide species in isogenic SMPD1-null versus reconstituted human cells to define the substrate spectrum and physiological product profile of ASM under basal and stress conditions.
Experiment: Compartment-resolved activity assays (lysosomal L-SMase vs secreted Zn2+-dependent S-SMase) combined with Ser508-phosphomutant and C-terminal-processing mutants to dissect which form drives each of the reported non-core signaling and membrane-repair functions.
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