SMPD1

UniProt ID: P17405
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

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.

Existing Annotations Review

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-1β and tumor necrosis factor-α 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-1β and tumor necrosis factor-α 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-1β
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

Core Functions

Zn2+-dependent lysosomal acid sphingomyelinase that hydrolyzes sphingomyelin to ceramide and phosphocholine (EC 3.1.4.12) in the acidic lumen of the lysosome/endolysosome, catalyzing the committed step of lysosomal sphingomyelin catabolism.

Molecular Function:
sphingomyelin phosphodiesterase activity
Directly Involved In:
sphingomyelin catabolic process
Cellular Locations:
lysosomal lumen
Supporting Evidence:
  • PMID:22573858
    Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH.
  • PMID:16787399
    Acid sphingomyelinase (ASM), a member of the saposin-like protein (SAPLIP) family, is a lysosomal hydrolase that converts sphingomyelin to ceramide.
  • file:human/SMPD1/SMPD1-uniprot.txt
    Binds 2 Zn(2+) ions per subunit

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
file:human/SMPD1/SMPD1-uniprot.txt
UniProtKB P17405 (ASM_HUMAN) record for human SMPD1 / acid sphingomyelinase
PMID:12563314
Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts.
PMID:15877209
Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study.
PMID:16787399
The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin and mannose 6-phosphate receptor.
PMID:1718266
Molecular basis of acid sphingomyelinase deficiency in a patient with Niemann-Pick disease type A.
PMID:17303575
Activation of acid sphingomyelinase by protein kinase Cdelta-mediated phosphorylation.
PMID:1840600
Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs.
PMID:18815062
Characterization of common SMPD1 mutations causing types A and B Niemann-Pick disease and generation of mutation-specific mouse models.
PMID:19279008
Acid beta-glucosidase 1 counteracts p38delta-dependent induction of interleukin-6: possible role for ceramide as an anti-inflammatory lipid.
PMID:19279011
Involvement of acid beta-glucosidase 1 in the salvage pathway of ceramide formation.
PMID:20530211
Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair.
PMID:20807762
Regulated secretion of acid sphingomyelinase: implications for selectivity of ceramide formation.
PMID:20956541
Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function.
PMID:21098024
A novel mechanism of lysosomal acid sphingomyelinase maturation: requirement for carboxyl-terminal proteolytic processing.
PMID:21157428
Caspase-8 and caspase-7 sequentially mediate proteolytic activation of acid sphingomyelinase in TNF-R1 receptosomes.
PMID:22573858
Ebolavirus requires acid sphingomyelinase activity and plasma membrane sphingomyelin for infection.
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
PMID:25339683
Acid sphingomyelinase activity is regulated by membrane lipids and facilitates cholesterol transfer by NPC2.
PMID:26084044
Alleged Detrimental Mutations in the SMPD1 Gene in Patients with Niemann-Pick Disease.
PMID:27498570
Endolysosomes Are the Principal Intracellular Sites of Acid Hydrolase Activity.
PMID:27659707
Structural and functional analysis of the ASM p.Ala359Asp mutant that causes acid sphingomyelinase deficiency.
PMID:33163980
Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells.
PMID:7670466
Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease.
PMID:8702487
Zn2+-stimulated sphingomyelinase is secreted by many cell types and is a product of the acid sphingomyelinase gene.
PMID:8706124
Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis.
PMID:9030779
Functional characterization of the N-glycosylation sites of human acid sphingomyelinase by site-directed mutagenesis.
PMID:9660788
The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene.
Reactome:R-HSA-1605797
SMPD1 hydrolyzes SPHM
Reactome:R-HSA-9769740
Coagulation pathway
Reactome:R-HSA-9769742
SMPD1 converts sphingomyelin to ceramide
Reactome:R-HSA-9840310
Glycosphingolipid catabolism

Suggested Questions for Experts

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)?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(SMPD1-notes.md)

SMPD1 (P17405) review notes

Human sphingomyelin phosphodiesterase 1 / lysosomal acid sphingomyelinase (ASM, aSMase).
UniProtKB P17405 (ASM_HUMAN), HGNC:11120, gene on chr 11p15.4.

Deep research provider note: falcon is out of credits (HTTP 402), so no
-deep-research-falcon.md was generated. This review is grounded in the seeded
UniProt record (SMPD1-uniprot.txt), the GOA TSV, and the 26 cached
publications/PMID_*.md files, all of which were present.

Core biology (verified)

  • Molecular function: sphingomyelin phosphodiesterase (EC 3.1.4.12); hydrolyses
    sphingomyelin + H2O -> ceramide + phosphocholine. UniProt CC FUNCTION:
    "Converts sphingomyelin to ceramide" (PubMed:12563314, 1840600, 18815062,
    25339683, 27659707, 33163980). Catalytic activity RHEA:19253 EC=3.1.4.12.
    Zn2+-dependent (2 Zn2+ per subunit; COFACTOR Name=Zn(2+)). Also has EC 3.1.4.3
    phospholipase C activity toward phosphatidylcholine (PubMed:25339683).
    GOA carries the primary MF as GO:0004767 (sphingomyelin phosphodiesterase
    activity) with many EXP/IDA/TAS lines, and GO:0061750 (acid sphingomyelin
    phosphodiesterase activity, a child) with IBA/IDA/IEA lines.
  • Biological process: sphingomyelin/ceramide metabolism — sphingomyelin
    catabolic process (GO:0006685), producing ceramide. Note: GOA labels ceramide
    production as "ceramide biosynthetic process" (GO:0046513) as well as
    "sphingomyelin catabolic process" (GO:0006685) — same reaction, two aspects.
  • Localization: lysosome / lysosomal lumen (GO:0005764 / GO:0043202),
    endolysosome (GO:0036019); also a secreted (Zn2+-activated) form in the
    extracellular region (GO:0005576), arising from alternative trafficking of the
    same precursor (PubMed:8702487, 9660788, 20807762, 21098024). Lysosomal
    targeting via M6P receptor and sortilin (PubMed:16787399).
  • Disease: Niemann-Pick disease types A (NPDA, MIM:257200) and B (NPDB,
    MIM:607616) — acid sphingomyelinase deficiency, a lysosomal storage disorder
    from failure to hydrolyze sphingomyelin to ceramide (UniProt DISEASE;
    PubMed:1718266, 7670466, 15877209, 18815062, 27659707).

Two enzymatic forms (one gene)

Lysosomal L-SMase (Zn2+-independent because Zn2+ acquired during trafficking) and
secretory S-SMase (Zn2+-dependent) arise from differential trafficking of a common
precursor, NOT alternative splicing (PubMed:8702487, 9660788, 20807762, 21098024).
Secreted form induced by IL1B/TNF/IFNG and by bacterial/viral infection; secretion
depends on Ser508 phosphorylation (PubMed:17303575, 20807762).

Secondary/pleiotropic roles (real but non-core)

  • Stress-induced apoptosis via ceramide (ionizing radiation, UV, TNF/CD95)
    (PubMed:8706124, 17303575, 20956541).
  • Plasma-membrane repair: Ca2+-triggered lysosomal exocytosis releases ASM, which
    converts outer-leaflet SM to ceramide, promoting endocytosis of lesions
    (PubMed:20530211).
  • Host defense / pathogen entry: ceramide-rich membrane platforms for P. aeruginosa
    (PubMed:12563314); ASM activity required for Ebola (PubMed:22573858) and
    SARS-CoV-2 (PubMed:33163980) entry.
  • Cholesterol export from endolysosomes / NPC2-mediated transfer (PubMed:25339683).

Annotation issues flagged

  • PMID:19279008 and PMID:19279011 are about acid beta-glucosidase 1 (GBA1), not
    SMPD1.     The BHF-UCL IMP annotations transferred to SMPD1 for GO:0043409
    (negative regulation of MAPK cascade), GO:0023021 (termination of signal
    transduction), and GO:0046513 (ceramide biosynthetic process) rest on papers
    whose experimental manipulations (siRNA/overexpression) target GBA1. 19279011
    mentions that acid sphingomyelinase "has been implicated, in part, in providing
    substrate" for the salvage pathway, but the IMP evidence is on GBA1. Per policy
    (do not REMOVE experimental annotations whose full text I cannot fully verify),
    these are marked MARK_AS_OVER_ANNOTATED / UNDECIDED rather than REMOVE, with the
    GBA1-vs-SMPD1 concern documented.
  • GO:0034480 (phosphatidylcholine phospholipase C activity) IDA PMID:25339683 is a
    genuine in-vitro side activity (EC 3.1.4.3) but not the core/physiological
    function; kept as non-core. The FlyBase-assigned IDA line (row 31) for the same
    term against PMID:25339683 is a human enzyme paper; kept as non-core.
  • Bare protein binding GO:0005515 IPIs (CASP7 PMID:21157428; NPC1 partner
    Q99523 PMID:16787399) are uninformative MF — MARK_AS_OVER_ANNOTATED per policy.
  • IEA phosphatidylcholine phospholipase C (row 14) and hydrolase activity
    (row 13) are broad; PLC C activity accepted as non-core, generic hydrolase
    marked over-annotated (uninformative parent).

📄 View Raw YAML

 
id: P17405
gene_symbol: SMPD1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: 1 (ASM-1)
  id: P17405-1
- name: 2 (ASM-2)
  id: P17405-2
  sequence_note: VSP_000331, VSP_000332
- name: 3 (ASM-3)
  id: P17405-3
  sequence_note: VSP_000333
- name: '4'
  id: P17405-4
  sequence_note: VSP_046964
existing_annotations:
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:8702487
        supporting_text: "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"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
      - reference_id: PMID:16787399
        supporting_text: "Acid sphingomyelinase (ASM), a member of the saposin-like protein (SAPLIP) family, is a lysosomal hydrolase that converts sphingomyelin to ceramide."
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:16787399
        supporting_text: "Acid sphingomyelinase (ASM), a member of the saposin-like protein (SAPLIP) family, is a lysosomal hydrolase that converts sphingomyelin to ceramide."
- term:
    id: GO:0006685
    label: sphingomyelin catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Core catabolic process, supported by human experimental data and by the
      phylogenetic tree; represents the correct level of specificity for the BP.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH."
- term:
    id: GO:0061750
    label: acid sphingomyelin phosphodiesterase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Correct, appropriately specific MF term capturing the acid pH optimum of
      lysosomal ASM. Core molecular function.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH."
- term:
    id: GO:0001778
    label: plasma membrane repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:20530211
        supporting_text: "the lysosomal enzyme acid sphingomyelinase (ASM) is released extracellularly when cells are wounded in the presence of Ca(2+)"
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: file:human/SMPD1/SMPD1-uniprot.txt
        supporting_text: "Reaction=a sphingomyelin + H2O = phosphocholine + an N-acylsphing-4-"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Reflects the secreted S-SMase form of ASM in the extracellular region.
      Consistent with UniProt SUBCELLULAR LOCATION (Secreted) and human experimental
      localization.
    action: KEEP_AS_NON_CORE
    reason: Non-core but valid; the secreted form is well documented. Duplicate of
      experimentally supported extracellular-region annotations.
    supported_by:
      - reference_id: PMID:8702487
        supporting_text: "Zn2+-stimulated sphingomyelinase is secreted by many cell types and is a product"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Lysosome is the core localization of ASM, from the UniProtKB subcellular
      location vocabulary mapping. Extensively supported by human IDA evidence.
    action: ACCEPT
    reason: Correct core CC; agrees with UniProt SUBCELLULAR LOCATION and multiple
      experimental localizations.
    supported_by:
      - reference_id: file:human/SMPD1/SMPD1-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Lipid droplet localization is derived from the UniProt subcellular location
      vocabulary (based on PubMed:25339683). A minor, non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Reported in UniProt as a Lipid droplet location, but peripheral to the
      core lysosomal function; retained as a non-core observation.
    supported_by:
      - reference_id: file:human/SMPD1/SMPD1-uniprot.txt
        supporting_text: "Lipid droplet"
- term:
    id: GO:0006685
    label: sphingomyelin catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Core biological process of ASM (lysosomal sphingomyelin degradation),
      here inferred electronically and independently confirmed by human experiment.
    action: ACCEPT
    reason: Correct core BP; automated ARBA/InterPro mapping agrees with the
      experimental annotations.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH."
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Generic hydrolase activity is a high-level parent of the specific
      sphingomyelin phosphodiesterase activity already annotated. Uninformative on its
      own.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
      - reference_id: file:human/SMPD1/SMPD1-uniprot.txt
        supporting_text: "Reaction=a sphingomyelin + H2O = phosphocholine + an N-acylsphing-4-"
- term:
    id: GO:0034480
    label: phosphatidylcholine phospholipase C activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: ASM also hydrolyzes phosphatidylcholine (EC 3.1.4.3), a genuine secondary
      activity demonstrated in vitro but not its core physiological function.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:25339683
        supporting_text: "Besides SM, ASM also cleaves liposomal phosphatidylcholine."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21157428
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
      - reference_id: PMID:21157428
        supporting_text: "we found that caspase-7 mediates A-SMase activation by direct interaction resulting in proteolytic cleavage of the 72-kDa pro-A-SMase zymogen"
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: ASM binds Zn2+ (two ions per subunit) as an essential catalytic cofactor.
      Well supported experimentally and by the UniProt COFACTOR annotation.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: file:human/SMPD1/SMPD1-uniprot.txt
        supporting_text: "Binds 2 Zn(2+) ions per subunit"
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Electronic transfer from a rat ortholog (Ensembl Compara). Not a core
      function and not directly supported by human data in the cited set.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0010212
    label: response to ionizing radiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: Real stress-response role (see PMID:8706124) but a downstream signaling
      function, not the core catabolic role; kept as non-core.
    supported_by:
      - reference_id: PMID:8706124
        supporting_text: "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"
- term:
    id: GO:0042220
    label: response to cocaine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-transfer IEA from rat. No human experimental support in the cited
      literature; peripheral at best.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0042599
    label: lamellar body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0043065
    label: positive regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: ASM-generated ceramide promotes stress-induced apoptosis. A real but
      non-core signaling role, also captured by human/mouse IMP (PMID:8706124).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:8706124
        supporting_text: "These genetic models provide definitive evidence for the involvement of acid sphingomyelinase in one form of stress-induced apoptosis."
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic annotation of ceramide production, the outcome of ASM's
      sphingomyelin hydrolysis. Duplicate aspect of the sphingomyelin catabolic process.
    action: ACCEPT
    reason: Correct; ceramide is the product of ASM-catalyzed sphingomyelin hydrolysis,
      supported by many experimental lines.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH."
- term:
    id: GO:0061750
    label: acid sphingomyelin phosphodiesterase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation of the acid-pH-specific sphingomyelin phosphodiesterase
      activity, the defining MF of ASM. Corroborated by human experimental data.
    action: ACCEPT
    reason: Correct, appropriately specific core MF; consistent with the IBA/IDA lines.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH."
- term:
    id: GO:0007596
    label: blood coagulation
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9769740
  qualifier: involved_in
  review:
    summary: Reactome pathway annotation placing SMPD1 in a coagulation-pathway context.
      Not an established core or well-supported specific role for ASM.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0046479
    label: glycosphingolipid catabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840310
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605797
  qualifier: enables
  review:
    summary: Reactome reaction "SMPD1 hydrolyzes SPHM" asserts the core sphingomyelin
      phosphodiesterase activity. Correct and consistent with all other evidence.
    action: ACCEPT
    reason: Core MF, authoritatively curated by Reactome and matching experimental data.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH."
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9769742
  qualifier: enables
  review:
    summary: Reactome reaction "SMPD1 converts sphingomyelin to ceramide" asserts the
      core MF. Duplicate of the other Reactome/experimental MF annotations.
    action: ACCEPT
    reason: Core MF; correctly curated by Reactome.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to phosphocholine and ceramide and has optimum activity at acidic pH."
- term:
    id: GO:0036021
    label: endolysosome lumen
  evidence_type: IC
  original_reference_id: PMID:27498570
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:27498570
        supporting_text: "We found that endolysosomes are the principal organelles in which acid hydrolase substrates are cleaved."
- term:
    id: GO:0006685
    label: sphingomyelin catabolic process
  evidence_type: IDA
  original_reference_id: PMID:20807762
  qualifier: involved_in
  review:
    summary: Direct experimental demonstration that ASM (L-SMase/S-SMase) degrades
      cellular sphingomyelin to ceramide in a regulated manner. Supports the core BP.
    action: ACCEPT
    reason: Core catabolic process, directly supported (regulated ASM-dependent ceramide
      formation from sphingomyelin in MCF7 cells).
    supported_by:
      - reference_id: PMID:20807762
        supporting_text: "The acid sphingomyelinase (aSMase) gene gives rise to two distinct enzymes, lysosomal sphingomyelinase (L-SMase) and secretory sphingomyelinase (S-SMase)"
- term:
    id: GO:0061750
    label: acid sphingomyelin phosphodiesterase activity
  evidence_type: IDA
  original_reference_id: PMID:17303575
  qualifier: enables
  review:
    summary: Direct assay of ASM (acid sphingomyelinase) activity, activated by PKCdelta
      phosphorylation at Ser508. Supports the core acid sphingomyelinase MF.
    action: ACCEPT
    reason: Core MF, directly measured; the paper shows PMA/PKCdelta selectively
      activates ASMase, accounting for the majority of induced ceramide.
    supported_by:
      - reference_id: PMID:17303575
        supporting_text: "Here we show that PMA selectively activates ASMase and that ASMase accounts for the majority of PMA-induced ceramide."
- term:
    id: GO:0034480
    label: phosphatidylcholine phospholipase C activity
  evidence_type: IDA
  original_reference_id: PMID:25339683
  qualifier: enables
  review:
    summary: ASM directly cleaves phosphatidylcholine in vitro (EC 3.1.4.3), a genuine
      secondary activity distinct from its principal sphingomyelin hydrolysis.
    action: KEEP_AS_NON_CORE
    reason: Real, directly demonstrated side activity (PMID:25339683) captured also in
      UniProt (EC=3.1.4.3), but secondary to the physiological sphingomyelinase role.
    supported_by:
      - reference_id: PMID:25339683
        supporting_text: "Besides SM, ASM also cleaves liposomal phosphatidylcholine."
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: EXP
  original_reference_id: PMID:12563314
  qualifier: enables
  review:
    summary: Experimental support for ASM sphingomyelin phosphodiesterase activity in
      the context of P. aeruginosa infection triggering ASM activation and ceramide
      release. Core MF.
    action: ACCEPT
    reason: Core MF; the study shows infection triggers activation of the acid
      sphingomyelinase and release of ceramide.
    supported_by:
      - reference_id: PMID:12563314
        supporting_text: "P. aeruginosa infection triggers activation of the acid sphingomyelinase and the release of ceramide in sphingolipid-rich rafts."
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: EXP
  original_reference_id: PMID:15877209
  qualifier: enables
  review:
    summary: ASM sphingomyelin phosphodiesterase activity assayed across a series of
      Niemann-Pick A/B patients (sphingomyelin loading/degradation). Core MF.
    action: ACCEPT
    reason: Core MF; the patient study directly assays ASM-dependent sphingomyelin
      degradation and its loss in ASM deficiency.
    supported_by:
      - reference_id: PMID:15877209
        supporting_text: "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."
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: EXP
  original_reference_id: PMID:1840600
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Core MF; expression of the type 1 transcript in COS-1 cells produced
      catalytically active human ASM.
    supported_by:
      - reference_id: PMID:1840600
        supporting_text: "Only the full-length type 1 transcript encoded catalytically active human ASM, demonstrating its functional integrity."
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: EXP
  original_reference_id: PMID:18815062
  qualifier: enables
  review:
    summary: ASM sphingomyelin phosphodiesterase activity assayed in NPD patient
      fibroblasts homoallelic for common SMPD1 mutations (deficient activity). Core MF.
    action: ACCEPT
    reason: Core MF; in vitro and in situ ASM assays directly measure the enzyme's
      sphingomyelin phosphodiesterase activity (EC 3.1.4.12).
    supported_by:
      - reference_id: PMID:18815062
        supporting_text: "inherited deficiency of acid sphingomyelinase activity (ASM, sphingomyelin phosphodiesterase, EC 3.1.4.12)"
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: EXP
  original_reference_id: PMID:21157428
  qualifier: enables
  review:
    summary: ASM (A-SMase) sphingomyelin phosphodiesterase activity, activated by
      caspase-7 cleavage of the pro-A-SMase zymogen in TNF receptosomes. Core MF.
    action: ACCEPT
    reason: Core MF; the paper measures activation of A-SMase enzymatic activity and its
      dependence on caspase-7-mediated proteolytic cleavage.
    supported_by:
      - reference_id: PMID:21157428
        supporting_text: "we found that caspase-7 mediates A-SMase activation by direct interaction resulting in proteolytic cleavage of the 72-kDa pro-A-SMase zymogen"
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: EXP
  original_reference_id: PMID:26084044
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Core MF; the study assays ASM catalytic activity to distinguish detrimental
      mutations from benign variants.
    supported_by:
      - reference_id: PMID:26084044
        supporting_text: "found them to be common variants of SMPD1 that give rise to normal in vivo and in vitro ASM activity"
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: EXP
  original_reference_id: PMID:8702487
  qualifier: enables
  review:
    summary: Secreted Zn2+-stimulated sphingomyelinase activity shown to be a product of
      the acid sphingomyelinase gene. Core MF (secreted form).
    action: ACCEPT
    reason: Core MF; Zn-SMase (secreted ASM) activity is documented and shown to arise
      from the same gene as lysosomal SMase.
    supported_by:
      - reference_id: PMID:8702487
        supporting_text: "this enzyme and the intracellular lysosomal SMase, which is \nZn-independent, arise from the same gene"
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: EXP
  original_reference_id: PMID:8706124
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Core MF; the genetic rescue (retroviral ASM cDNA restores ceramide
      generation) directly links the enzyme to sphingomyelin-to-ceramide conversion.
    supported_by:
      - reference_id: PMID:8706124
        supporting_text: "These abnormalities are reversible up on restoration of acid \nsphingomyelinase activity by retroviral transfer of human acid \nsphingomyelinase cDNA."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: EXP
  original_reference_id: PMID:12563314
  qualifier: located_in
  review:
    summary: Secreted ASM acts extracellularly (on the outer plasma-membrane leaflet)
      during P. aeruginosa infection. Non-core localization of the secreted form.
    action: KEEP_AS_NON_CORE
    reason: The secreted extracellular form is real and functionally important in host
      defense, but is non-core relative to the lysosomal catalytic role.
    supported_by:
      - reference_id: PMID:12563314
        supporting_text: "P. aeruginosa infection triggers activation of the acid sphingomyelinase and the release of ceramide in sphingolipid-rich rafts."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: EXP
  original_reference_id: PMID:9030779
  qualifier: located_in
  review:
    summary: Study of ASM N-glycosylation, secretion, and processing; consistent with a
      secreted extracellular form. Non-core localization.
    action: KEEP_AS_NON_CORE
    reason: The secreted form is supported, but extracellular localization is non-core
      relative to the lysosomal site of action.
    supported_by:
      - reference_id: PMID:9030779
        supporting_text: "Most soluble lysosomal enzymes require a mannose-6-phosphate recognition marker \npresent on asparagine-linked oligosaccharides for proper targeting to lysosomes."
- term:
    id: GO:0043409
    label: negative regulation of MAPK cascade
  evidence_type: IMP
  original_reference_id: PMID:19279008
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
      - reference_id: PMID:19279008
        supporting_text: "knockdown of GBA1 by small \ninterfering RNAs or pharmacological inhibition of GBA1 promoted further \nactivation of p38 after PMA treatment, implicating the GBA1-ceramide pathway in \nthe termination of p38 activation"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605797
  qualifier: located_in
  review:
    summary: ASM acts in the lysosomal lumen, the acidic compartment where it hydrolyzes
      sphingomyelin. A precise refinement of the lysosomal localization. Core CC.
    action: ACCEPT
    reason: Correct core localization; the soluble lysosomal hydrolase resides in the
      lysosomal lumen. Curated by Reactome and consistent with UniProt.
    supported_by:
      - reference_id: file:human/SMPD1/SMPD1-uniprot.txt
        supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0046598
    label: positive regulation of viral entry into host cell
  evidence_type: IDA
  original_reference_id: PMID:33163980
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:33163980
        supporting_text: "pharmacological inhibition of \nacid sphingomyelinase with amitriptyline, imipramine, fluoxetine, sertraline, \nescitalopram, or maprotiline or genetic downregulation of the enzyme prevents \ninfection"
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: IDA
  original_reference_id: PMID:33163980
  qualifier: enables
  review:
    summary: ASM sphingomyelin phosphodiesterase activity directly demonstrated
      (activation upon SARS-CoV-2 infection with surface ceramide release). Core MF.
    action: ACCEPT
    reason: Core MF; infection activates ASM and triggers ceramide release on the cell
      surface.
    supported_by:
      - reference_id: PMID:33163980
        supporting_text: "Infection activates acid sphingomyelinase and triggers a release of \nceramide on the cell surface."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:33163980
  qualifier: is_active_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Supported (surface ceramide release), but extracellular action is non-core
      relative to the lysosomal role.
    supported_by:
      - reference_id: PMID:33163980
        supporting_text: "Infection activates acid sphingomyelinase and triggers a release of \nceramide on the cell surface."
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:33163980
  qualifier: is_active_in
  review:
    summary: ASM acts in the lysosome, its core site of activity (the enzyme is
      normally lysosomal, recruited to the surface upon infection). Core CC.
    action: ACCEPT
    reason: Core localization; consistent with the enzyme being a lysosomal hydrolase.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Normally, \nASMase is located in lysosomes and endosomes, but membrane damage or the \ninteraction with some bacterial and viral pathogens can trigger its recruitment \nto the plasma membrane."
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:33163980
  qualifier: involved_in
  review:
    summary: ASM produces ceramide (from sphingomyelin) upon infection. Ceramide
      generation is the product side of the core sphingomyelin catabolic reaction.
    action: ACCEPT
    reason: Correct; directly supported by the demonstrated ceramide release upon ASM
      activation.
    supported_by:
      - reference_id: PMID:33163980
        supporting_text: "Infection activates acid sphingomyelinase and triggers a release of \nceramide on the cell surface."
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9769742
  qualifier: located_in
  review:
    summary: ASM can be recruited to the plasma membrane (outer leaflet) upon stress or
      infection, where the secreted/surface form generates ceramide. Non-core.
    action: KEEP_AS_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.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "membrane damage or the \ninteraction with some bacterial and viral pathogens can trigger its recruitment \nto the plasma membrane"
- term:
    id: GO:0001778
    label: plasma membrane repair
  evidence_type: IDA
  original_reference_id: PMID:20530211
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_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.
    supported_by:
      - reference_id: PMID:20530211
        supporting_text: "conversion of \nplasma membrane sphingomyelin to ceramide by this lysosomal enzyme promotes \nlesion internalization"
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: IDA
  original_reference_id: PMID:22573858
  qualifier: enables
  review:
    summary: ASM sphingomyelin phosphodiesterase activity directly assayed (required for
      Ebolavirus infection; ASM converts SM to phosphocholine and ceramide). Core MF.
    action: ACCEPT
    reason: Core MF; the paper states and depends on ASM converting sphingomyelin to
      phosphocholine and ceramide.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to \nphosphocholine and ceramide and has optimum activity at acidic pH."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:20530211
  qualifier: located_in
  review:
    summary: ASM is released extracellularly from wounded cells (Ca2+-dependent lysosomal
      exocytosis). Documents the secreted/extracellular form. Non-core.
    action: KEEP_AS_NON_CORE
    reason: Directly demonstrated extracellular release of ASM upon wounding, but
      non-core relative to the lysosomal site.
    supported_by:
      - reference_id: PMID:20530211
        supporting_text: "the lysosomal enzyme acid sphingomyelinase (ASM) is released extracellularly \nwhen cells are wounded in the presence of Ca(2+)"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:22573858
  qualifier: located_in
  review:
    summary: Surface-localized/secreted ASM detected extracellularly during Ebolavirus
      binding. Non-core localization of the secreted form.
    action: KEEP_AS_NON_CORE
    reason: Supported (surface-localized ASMase associated with virus binding), but
      non-core relative to the lysosomal role.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "the binding of virus-like particles to cells is \nstrongly associated with surface-localized ASMase"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:20530211
  qualifier: located_in
  review:
    summary: ASM is a lysosomal enzyme; the paper repeatedly identifies it as "the
      lysosomal enzyme acid sphingomyelinase." Core CC.
    action: ACCEPT
    reason: Core localization, directly supported.
    supported_by:
      - reference_id: PMID:20530211
        supporting_text: "the lysosomal enzyme acid sphingomyelinase (ASM)"
- term:
    id: GO:0006685
    label: sphingomyelin catabolic process
  evidence_type: IDA
  original_reference_id: PMID:22573858
  qualifier: involved_in
  review:
    summary: ASM converts sphingomyelin to phosphocholine and ceramide; the core
      sphingomyelin catabolic process, directly demonstrated in the infection context.
    action: ACCEPT
    reason: Core BP, directly supported by the stated ASM reaction.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to \nphosphocholine and ceramide and has optimum activity at acidic pH."
- term:
    id: GO:0009615
    label: response to virus
  evidence_type: IDA
  original_reference_id: PMID:22573858
  qualifier: involved_in
  review:
    summary: ASM activity is required for Ebolavirus infection; ASM participates in the
      cellular response to virus. Non-core host-pathogen role.
    action: KEEP_AS_NON_CORE
    reason: Supported (ASM activity and plasma-membrane SM required for EBOV infection),
      but a context-specific role rather than a core function.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Our work suggests that ASMase activity and SM presence are necessary for \nefficient infection of cells by EBOV."
- term:
    id: GO:0010212
    label: response to ionizing radiation
  evidence_type: IMP
  original_reference_id: PMID:8706124
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Strong genetic (IMP) evidence for ASM in the ionizing-radiation response,
      but downstream of the core catabolic function.
    supported_by:
      - reference_id: PMID:8706124
        supporting_text: "lymphoblasts from \nNiemann-Pick patients, which have an inherited deficiency of acid \nsphingomyelinase activity, fail to respond to ionizing radiation with ceramide \ngeneration and apoptosis"
- term:
    id: GO:0042060
    label: wound healing
  evidence_type: IDA
  original_reference_id: PMID:20530211
  qualifier: involved_in
  review:
    summary: ASM promotes plasma membrane repair after cell wounding. "Wound healing" is
      a broad framing of the membrane-repair role. Non-core.
    action: KEEP_AS_NON_CORE
    reason: Related to the demonstrated plasma-membrane-repair role; a broad but
      defensible BP framing. Non-core relative to the catabolic function.
    supported_by:
      - reference_id: PMID:20530211
        supporting_text: "Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and \nplasma membrane repair."
- term:
    id: GO:0043065
    label: positive regulation of apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:8706124
  qualifier: involved_in
  review:
    summary: ASM-generated ceramide promotes stress-induced apoptosis; ASM-deficient
      cells/mice are defective in radiation-induced apoptosis. Non-core signaling role.
    action: KEEP_AS_NON_CORE
    reason: Definitive genetic evidence for ASM in one form of stress-induced apoptosis,
      but a downstream signaling consequence of ceramide production.
    supported_by:
      - reference_id: PMID:8706124
        supporting_text: "These genetic models provide definitive evidence for the involvement of acid \nsphingomyelinase in one form of stress-induced apoptosis."
- term:
    id: GO:0045807
    label: positive regulation of endocytosis
  evidence_type: IDA
  original_reference_id: PMID:20530211
  qualifier: involved_in
  review:
    summary: Extracellular ASM converts plasma-membrane SM to ceramide, promoting a
      rapid endocytosis that internalizes membrane lesions. Non-core.
    action: KEEP_AS_NON_CORE
    reason: Directly demonstrated (ASM-dependent injury-induced endocytosis), but a
      downstream physiological role of extracellular ASM.
    supported_by:
      - reference_id: PMID:20530211
        supporting_text: "Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and \nplasma membrane repair."
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:8706124
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Correct; genetic evidence directly links ASM to ceramide generation.
    supported_by:
      - reference_id: PMID:8706124
        supporting_text: "fail to respond to ionizing radiation with ceramide \ngeneration and apoptosis"
- term:
    id: GO:0046718
    label: symbiont entry into host cell
  evidence_type: IDA
  original_reference_id: PMID:22573858
  qualifier: involved_in
  review:
    summary: ASM activity is required for Ebolavirus entry into host cells (surface
      ceramide facilitates entry). Non-core host-pathogen role.
    action: KEEP_AS_NON_CORE
    reason: Supported (ASM and SM necessary for efficient EBOV infection), but a
      context-specific role, not a core function.
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: "Our work suggests that ASMase activity and SM presence are necessary for \nefficient infection of cells by EBOV."
- term:
    id: GO:0071277
    label: cellular response to calcium ion
  evidence_type: IDA
  original_reference_id: PMID:20530211
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:20530211
        supporting_text: "acid sphingomyelinase (ASM) is released extracellularly \nwhen cells are wounded in the presence of Ca(2+)"
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: IDA
  original_reference_id: PMID:21098024
  qualifier: enables
  review:
    summary: ASM (aSMase) catalyzes hydrolysis of sphingomyelin to ceramide; the paper
      characterizes maturation of the catalytically active L-SMase. Core MF.
    action: ACCEPT
    reason: Core MF; the study directly measures aSMase activity of the mature enzyme.
    supported_by:
      - reference_id: PMID:21098024
        supporting_text: "Acid sphingomyelinase (aSMase) catalyzes the hydrolysis of sphingomyelin (SM) to \nform the bioactive lipid ceramide (Cer)."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:17303575
  qualifier: located_in
  review:
    summary: Secreted ASM in the extracellular space; secretion depends on Ser508
      phosphorylation. Non-core localization of the secreted form.
    action: KEEP_AS_NON_CORE
    reason: Supported (secreted form and its regulation), but non-core relative to the
      lysosomal site of action.
    supported_by:
      - reference_id: PMID:17303575
        supporting_text: "Phosphorylation of Ser(508) proved to be an indispensable step for ASMase \nactivation and membrane translocation in response to PMA."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:20807762
  qualifier: located_in
  review:
    summary: Secreted S-SMase in the extracellular medium, induced by IL-1 and TNF.
      Non-core localization of the secreted form.
    action: KEEP_AS_NON_CORE
    reason: Directly demonstrated cytokine-regulated secretion of S-SMase, but non-core
      relative to the lysosomal role.
    supported_by:
      - reference_id: PMID:20807762
        supporting_text: "Interleukin-1β and tumor necrosis \nfactor-α induced a time- and dose-dependent increase in S-SMase secretion and \nactivity"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:21098024
  qualifier: located_in
  review:
    summary: The Zn2+-dependent secreted S-SMase form is released to the extracellular
      space via the Golgi secretory pathway. Non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Supported (S-SMase secretion), but non-core relative to the lysosomal
      catalytic role.
    supported_by:
      - reference_id: PMID:21098024
        supporting_text: "a zinc (Zn(2+))-independent lysosomal aSMase (L-SMase) and a Zn(2+)-dependent \nsecreted aSMase (S-SMase) that arise from alternative trafficking of a single \nprotein precursor"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:20807762
  qualifier: located_in
  review:
    summary: Lysosomal L-SMase form localizes to lysosomes. Core CC.
    action: ACCEPT
    reason: Core localization; the lysosomal form is one of the two gene products
      characterized here.
    supported_by:
      - reference_id: PMID:20807762
        supporting_text: "two distinct enzymes, lysosomal sphingomyelinase (L-SMase) and secretory sphingomyelinase (S-SMase)"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:21098024
  qualifier: located_in
  review:
    summary: Mature L-SMase colocalizes with the lysosomal marker LAMP1; the enzyme is
      processed within/near endolysosomes. Core CC.
    action: ACCEPT
    reason: Core localization, directly demonstrated by colocalization with LAMP1.
    supported_by:
      - reference_id: PMID:21098024
        supporting_text: "mature L-SMase \ncolocalized with the lysosomal marker LAMP1"
- term:
    id: GO:0034340
    label: response to type I interferon
  evidence_type: IDA
  original_reference_id: PMID:20807762
  qualifier: involved_in
  review:
    summary: S-SMase secretion/activity is induced by inflammatory cytokines. Type I
      interferon response is a non-core, regulated aspect of the secreted form.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:20807762
        supporting_text: "MCF7 breast carcinoma cells stably transfected with V5-aSMase(WT) \nwere treated with inflammatory cytokines"
- term:
    id: GO:0034612
    label: response to tumor necrosis factor
  evidence_type: IDA
  original_reference_id: PMID:20807762
  qualifier: involved_in
  review:
    summary: TNF-alpha induces S-SMase secretion and activity and selective C16-ceramide
      formation. A non-core, cytokine-regulated response of the secreted form.
    action: KEEP_AS_NON_CORE
    reason: Directly supported (TNF-alpha induces S-SMase), but a regulated response
      rather than a core molecular function.
    supported_by:
      - reference_id: PMID:20807762
        supporting_text: "Interleukin-1β and tumor necrosis \nfactor-α induced a time- and dose-dependent increase in S-SMase secretion and \nactivity"
- term:
    id: GO:0034644
    label: cellular response to UV
  evidence_type: IDA
  original_reference_id: PMID:17303575
  qualifier: involved_in
  review:
    summary: UV radiation induces ASM phosphorylation at Ser508 and activation, linking
      ASM to the UV stress response. Non-core signaling role.
    action: KEEP_AS_NON_CORE
    reason: Supported (UV induces ASMase phosphorylation/activation), but a downstream
      stress-response role, not the core catabolic function.
    supported_by:
      - reference_id: PMID:17303575
        supporting_text: "UV radiation also induced phosphorylation of ASMase at serine 508."
- term:
    id: GO:0036019
    label: endolysosome
  evidence_type: IDA
  original_reference_id: PMID:17303575
  qualifier: located_in
  review:
    summary: ASM localizes to the endolysosomal compartment, a refinement of the
      lysosomal site of action. Core CC.
    action: ACCEPT
    reason: Endolysosome is consistent with the acid-pH lysosomal site of ASM activity
      and supported by the localization/translocation data.
    supported_by:
      - reference_id: PMID:17303575
        supporting_text: "Phosphorylation of Ser(508) proved to be an indispensable step for ASMase \nactivation and membrane translocation in response to PMA."
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:17303575
  qualifier: involved_in
  review:
    summary: ASM accounts for the majority of PMA/PKCdelta-induced ceramide; directly
      links ASM activity to ceramide production. Product side of the core reaction.
    action: ACCEPT
    reason: Correct; ASM directly generates ceramide, as shown by the S508A dominant-
      negative blocking ceramide formation.
    supported_by:
      - reference_id: PMID:17303575
        supporting_text: "Here we show that PMA selectively activates ASMase and that ASMase \naccounts for the majority of PMA-induced ceramide."
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:20807762
  qualifier: involved_in
  review:
    summary: ASM (L-SMase/S-SMase) generates specific ceramide species from
      sphingomyelin in a regulated manner. Product side of the core catabolic reaction.
    action: ACCEPT
    reason: Correct; directly demonstrated regulated ceramide formation by ASM.
    supported_by:
      - reference_id: PMID:20807762
        supporting_text: "elevated cellular levels of specific long-chain and very long-chain ceramide \nspecies"
- term:
    id: GO:0061750
    label: acid sphingomyelin phosphodiesterase activity
  evidence_type: IDA
  original_reference_id: PMID:20807762
  qualifier: enables
  review:
    summary: Direct measurement of L-SMase and S-SMase (acid sphingomyelinase) activity.
      Core MF.
    action: ACCEPT
    reason: Core MF, directly assayed for both enzymatic forms.
    supported_by:
      - reference_id: PMID:20807762
        supporting_text: "MCF7 expressing \nV5-aSMase(WT) exhibited increased S-SMase and L-SMase activity"
- term:
    id: GO:0070555
    label: response to interleukin-1
  evidence_type: IDA
  original_reference_id: PMID:20807762
  qualifier: involved_in
  review:
    summary: IL-1beta induces S-SMase secretion, activity, and regulated C16-ceramide
      generation. A non-core, cytokine-regulated response.
    action: KEEP_AS_NON_CORE
    reason: Directly supported (IL-1beta induces S-SMase secretion), but a regulated
      response, not a core function.
    supported_by:
      - reference_id: PMID:20807762
        supporting_text: "Secretion of the S508A mutant was also defective in response to IL-1β"
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: IDA
  original_reference_id: PMID:9660788
  qualifier: enables
  review:
    summary: Both secretory and lysosomal sphingomyelinase (products of the ASM gene)
      are directly activated by zinc and possess sphingomyelin phosphodiesterase
      activity. Core MF.
    action: ACCEPT
    reason: Core MF; the paper directly assays and compares S-SMase and L-SMase activity
      and zinc dependence.
    supported_by:
      - reference_id: PMID:9660788
        supporting_text: "both S-SMase and L-SMase, \nwhich contain several highly conserved zinc-binding motifs, are directly \nactivated by zinc"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16787399
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
      - reference_id: PMID:16787399
        supporting_text: "Co-immunoprecipitation assays \nconfirmed the interaction between sortilin and ASM."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:16787399
  qualifier: located_in
  review:
    summary: Over-expression of truncated sortilin enhances ASM secretion, consistent
      with a secreted extracellular form. Non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Supported (ASM secretion), but non-core relative to the lysosomal site.
    supported_by:
      - reference_id: PMID:16787399
        supporting_text: "over-expression of truncated sortilin accelerated and enhanced \nthe secretion of ASM from COS-7 cells and I-cells"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:9660788
  qualifier: located_in
  review:
    summary: Secretory SMase (S-SMase) arises via the Golgi secretory pathway and is
      released extracellularly. Non-core localization of the secreted form.
    action: KEEP_AS_NON_CORE
    reason: Supported (S-SMase trafficking through the Golgi secretory pathway to
      secretion), but non-core relative to the lysosomal role.
    supported_by:
      - reference_id: PMID:9660788
        supporting_text: "S-SMase arises by trafficking through the Golgi secretory \npathway"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:16787399
  qualifier: located_in
  review:
    summary: ASM is targeted to lysosomes via sortilin and the M6P receptor; the paper
      directly studies its lysosomal trafficking. Core CC.
    action: ACCEPT
    reason: Core localization, directly supported by trafficking and confocal data.
    supported_by:
      - reference_id: PMID:16787399
        supporting_text: "The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin and \nmannose 6-phosphate receptor."
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:9660788
  qualifier: located_in
  review:
    summary: Lysosomal SMase (L-SMase) is trafficked to and resides in lysosomes. Core
      CC.
    action: ACCEPT
    reason: Core localization; the paper characterizes L-SMase trafficking to lysosomes.
    supported_by:
      - reference_id: PMID:9660788
        supporting_text: "L-SMase is exposed to \ncellular Zn2+ during trafficking to lysosomes, in lysosomes"
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IDA
  original_reference_id: PMID:9660788
  qualifier: enables
  review:
    summary: ASM contains conserved zinc-binding motifs and both forms are directly
      activated by zinc; Zn2+ is the catalytic cofactor. Supported core MF.
    action: ACCEPT
    reason: Zinc binding is the catalytic-cofactor MF of ASM, directly demonstrated.
    supported_by:
      - reference_id: PMID:9660788
        supporting_text: "both S-SMase and L-SMase, \nwhich contain several highly conserved zinc-binding motifs, are directly \nactivated by zinc"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:27659707
  qualifier: located_in
  review:
    summary: Structural/functional analysis of an ASM disease mutant; consistent with
      the secreted extracellular form. Non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Supported by the study of the ASM protein (secreted form), but non-core
      relative to the lysosomal site.
    supported_by:
      - reference_id: PMID:27659707
        supporting_text: "Niemann-Pick disease (NPD) type A and B are recessive hereditary disorders \ncaused by deficiency in acid sphingomyelinase (ASM)."
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:27659707
  qualifier: located_in
  review:
    summary: ASM (whose deficiency causes NPD) is a lysosomal enzyme; the mutant analysis
      concerns the lysosomal enzyme. Core CC.
    action: ACCEPT
    reason: Core localization, consistent with ASM being a lysosomal hydrolase.
    supported_by:
      - reference_id: PMID:27659707
        supporting_text: "Niemann-Pick disease (NPD) type A and B are recessive hereditary disorders \ncaused by deficiency in acid sphingomyelinase (ASM)."
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:8702487
  qualifier: located_in
  review:
    summary: Secreted Zn2+-stimulated SMase is released into the extracellular medium by
      many cell types. Non-core localization of the secreted form.
    action: KEEP_AS_NON_CORE
    reason: Directly demonstrated secretion of Zn-SMase, but non-core relative to the
      lysosomal site.
    supported_by:
      - reference_id: PMID:8702487
        supporting_text: "We now show that \nZn-SMase activity is secreted by human and murine macrophages, human skin \nfibroblasts, microglial cells, and several other cells in culture"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:18815062
  qualifier: located_in
  review:
    summary: Fluorescence microscopy showed ASM polypeptides trafficked to lysosomes.
      Core CC.
    action: ACCEPT
    reason: Core localization, directly demonstrated (mutant and wild-type ASM
      trafficked to lysosomes).
    supported_by:
      - reference_id: PMID:18815062
        supporting_text: "the mutant ASM \npolypeptides were expressed at normal levels and trafficked to lysosomes"
- term:
    id: GO:0006685
    label: sphingomyelin catabolic process
  evidence_type: IDA
  original_reference_id: PMID:18815062
  qualifier: involved_in
  review:
    summary: ASM (sphingomyelin phosphodiesterase, EC 3.1.4.12) degrades sphingomyelin;
      the study assays ASM sphingomyelin-hydrolyzing activity in patient cells. Core BP.
    action: ACCEPT
    reason: Core catabolic process; ASM activity (sphingomyelin degradation) is directly
      assayed via BODIPY-sphingomyelin hydrolysis.
    supported_by:
      - reference_id: PMID:18815062
        supporting_text: "inherited deficiency of acid sphingomyelinase activity (ASM, sphingomyelin phosphodiesterase, EC 3.1.4.12)"
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IDA
  original_reference_id: PMID:8702487
  qualifier: enables
  review:
    summary: The secreted form of the ASM gene product is Zn2+-stimulated, reflecting
      zinc binding as its catalytic cofactor. Supported core MF.
    action: ACCEPT
    reason: Zinc binding is the catalytic cofactor MF of ASM; the Zn2+-stimulated
      activity is directly demonstrated.
    supported_by:
      - reference_id: PMID:8702487
        supporting_text: "an acidic Zn2+-stimulated \nsphingomyelinase (Zn-SMase)"
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:18815062
  qualifier: involved_in
  review:
    summary: ASM assay measures conversion of BODIPY-sphingomyelin to BODIPY-ceramide,
      i.e. ceramide production. Product side of the core catabolic reaction.
    action: ACCEPT
    reason: Correct; ceramide is the direct product measured in the ASM activity assay.
    supported_by:
      - reference_id: PMID:18815062
        supporting_text: "the hydrolytic BODIPY-C12-ceramide (B12CER) product was detected and quantified by HPLC"
- term:
    id: GO:0061750
    label: acid sphingomyelin phosphodiesterase activity
  evidence_type: IDA
  original_reference_id: PMID:18815062
  qualifier: enables
  review:
    summary: In vitro and in situ acid sphingomyelinase activity assays on patient
      fibroblasts homoallelic for common SMPD1 mutations. Core MF.
    action: ACCEPT
    reason: Core MF, directly assayed (in vitro and in situ acid sphingomyelinase
      assays).
    supported_by:
      - reference_id: PMID:18815062
        supporting_text: "In vitro and in situ enzyme assays \nrevealed marked deficiencies of ASM activity in NPD cell lines homoallelic for \neach mutation"
- term:
    id: GO:0061750
    label: acid sphingomyelin phosphodiesterase activity
  evidence_type: IDA
  original_reference_id: PMID:8702487
  qualifier: enables
  review:
    summary: Acid, Zn2+-stimulated sphingomyelinase activity of the ASM gene product,
      directly assayed. Core MF.
    action: ACCEPT
    reason: Core MF; the study demonstrates the acidic Zn2+-stimulated sphingomyelinase
      activity is a product of the acid sphingomyelinase gene.
    supported_by:
      - reference_id: PMID:8702487
        supporting_text: "an acidic Zn2+-stimulated \nsphingomyelinase (Zn-SMase)"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:20956541
  qualifier: located_in
  review:
    summary: ASM (A-SMase) resides in intracellular compartments (lysosomes) from which
      it translocates to the plasma membrane upon CD95 stimulation. Core CC.
    action: ACCEPT
    reason: Core localization; the study describes A-SMase translocating from
      intracellular compartments (lysosomes) to the plasma membrane.
    supported_by:
      - reference_id: PMID:20956541
        supporting_text: >-
          A-SMase is activated through translocation from intracellular
          compartments to the plasma membrane in an exocytic pathway requiring
          the t-SNARE protein syntaxin 4
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IDA
  original_reference_id: PMID:20956541
  qualifier: located_in
  review:
    summary: ASM localizes to endosomal/intracellular compartments prior to CD95-induced
      translocation. Consistent with the endolysosomal site of action. Non-core detail.
    action: KEEP_AS_NON_CORE
    reason: Endosomal localization is part of the endolysosomal trafficking of ASM;
      supported but non-core relative to the lysosomal lumen catalytic site.
    supported_by:
      - reference_id: PMID:20956541
        supporting_text: >-
          A-SMase is activated through translocation from intracellular
          compartments to the plasma membrane
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:20956541
  qualifier: located_in
  review:
    summary: Upon CD95 stimulation, A-SMase translocates to the plasma membrane
      (syntaxin-4-dependent), where it acts on outer-leaflet sphingomyelin. Non-core.
    action: KEEP_AS_NON_CORE
    reason: Directly demonstrated stimulus-induced plasma-membrane translocation, but a
      regulated, non-core localization.
    supported_by:
      - reference_id: PMID:20956541
        supporting_text: >-
          A-SMase is activated through translocation from intracellular
          compartments to the plasma membrane in an exocytic pathway requiring
          the t-SNARE protein syntaxin 4
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: HDA proteomic detection in exosomes; consistent with the secreted form but
      not indicative of a core exosomal function. Non-core.
    supported_by:
      - reference_id: PMID:23533145
        supporting_text: >-
          In-depth proteomic analyses of exosomes isolated from expressed
          prostatic secretions in urine.
- term:
    id: GO:0023021
    label: termination of signal transduction
  evidence_type: IMP
  original_reference_id: PMID:19279008
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
      - reference_id: PMID:19279008
        supporting_text: >-
          implicating the GBA1-ceramide pathway in the termination of p38
          activation
- term:
    id: GO:0046513
    label: ceramide biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:19279011
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
      - reference_id: PMID:19279011
        supporting_text: >-
          acid sphingomyelinase has been implicated, in part, in providing
          substrate for this pathway
- term:
    id: GO:0004767
    label: sphingomyelin phosphodiesterase activity
  evidence_type: TAS
  original_reference_id: PMID:1718266
  qualifier: enables
  review:
    summary: A Niemann-Pick type A mutation abolishes ASM enzymatic activity in
      expression studies, corroborating the core sphingomyelin phosphodiesterase MF.
    action: ACCEPT
    reason: Core MF; expression of the mutant cDNA shows complete loss of ASM enzymatic
      activity, confirming the enzyme's catalytic function.
    supported_by:
      - reference_id: PMID:1718266
        supporting_text: >-
          Expression studies with this abnormal cDNA in COS-1 cells revealed a
          complete loss of enzymatic activity of the mutated protein.
- term:
    id: GO:0006684
    label: sphingomyelin metabolic process
  evidence_type: TAS
  original_reference_id: PMID:7670466
  qualifier: involved_in
  review:
    summary: ASM deficiency causes accumulation of sphingomyelin in tissues, confirming
      ASM's role in sphingomyelin metabolism. Broad parent of the sphingomyelin
      catabolic process.
    action: KEEP_AS_NON_CORE
    reason: Correct but general; the more precise sphingomyelin catabolic process
      (GO:0006685) is the primary BP. Retained as a valid, broader annotation.
    supported_by:
      - reference_id: PMID:7670466
        supporting_text: >-
          the blood cholesterol levels and sphingomyelin in the liver and brain
          were elevated
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: TAS
  original_reference_id: PMID:7670466
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
      - reference_id: PMID:7670466
        supporting_text: >-
          investigations into the role of ASM in signal transduction and
          apoptosis
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: TAS
  original_reference_id: PMID:7670466
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
      - reference_id: PMID:7670466
        supporting_text: >-
          atrophy of the cerebellum and marked deficiency of Purkinje cells was
          evident
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/SMPD1/SMPD1-uniprot.txt
  title: UniProtKB P17405 (ASM_HUMAN) record for human SMPD1 / acid sphingomyelinase
  findings: []
- id: PMID:12563314
  title: Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane
    rafts.
  findings: []
- id: PMID:15877209
  title: Acid sphingomyelinase deficiency. Phenotype variability with prevalence of
    intermediate phenotype in a series of twenty-five Czech and Slovak patients. A
    multi-approach study.
  findings: []
- id: PMID:16787399
  title: The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin
    and mannose 6-phosphate receptor.
  findings: []
- id: PMID:1718266
  title: Molecular basis of acid sphingomyelinase deficiency in a patient with Niemann-Pick
    disease type A.
  findings: []
- id: PMID:17303575
  title: Activation of acid sphingomyelinase by protein kinase Cdelta-mediated phosphorylation.
  findings: []
- id: PMID:1840600
  title: Human acid sphingomyelinase. Isolation, nucleotide sequence and expression
    of the full-length and alternatively spliced cDNAs.
  findings: []
- id: PMID:18815062
  title: Characterization of common SMPD1 mutations causing types A and B Niemann-Pick
    disease and generation of mutation-specific mouse models.
  findings: []
- id: PMID:19279008
  title: 'Acid beta-glucosidase 1 counteracts p38delta-dependent induction of interleukin-6:
    possible role for ceramide as an anti-inflammatory lipid.'
  findings: []
- id: PMID:19279011
  title: Involvement of acid beta-glucosidase 1 in the salvage pathway of ceramide
    formation.
  findings: []
- id: PMID:20530211
  title: Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis
    and plasma membrane repair.
  findings: []
- id: PMID:20807762
  title: 'Regulated secretion of acid sphingomyelinase: implications for selectivity
    of ceramide formation.'
  findings: []
- id: PMID:20956541
  title: Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function.
  findings: []
- id: PMID:21098024
  title: 'A novel mechanism of lysosomal acid sphingomyelinase maturation: requirement
    for carboxyl-terminal proteolytic processing.'
  findings: []
- id: PMID:21157428
  title: Caspase-8 and caspase-7 sequentially mediate proteolytic activation of acid
    sphingomyelinase in TNF-R1 receptosomes.
  findings: []
- id: PMID:22573858
  title: Ebolavirus requires acid sphingomyelinase activity and plasma membrane sphingomyelin
    for infection.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
- id: PMID:25339683
  title: Acid sphingomyelinase activity is regulated by membrane lipids and facilitates
    cholesterol transfer by NPC2.
  findings: []
- id: PMID:26084044
  title: Alleged Detrimental Mutations in the SMPD1 Gene in Patients with Niemann-Pick
    Disease.
  findings: []
- id: PMID:27498570
  title: Endolysosomes Are the Principal Intracellular Sites of Acid Hydrolase Activity.
  findings: []
- id: PMID:27659707
  title: Structural and functional analysis of the ASM p.Ala359Asp mutant that causes
    acid sphingomyelinase deficiency.
  findings: []
- id: PMID:33163980
  title: Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2
    by Epithelial Cells.
  findings: []
- id: PMID:7670466
  title: 'Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick
    disease.'
  findings: []
- id: PMID:8702487
  title: Zn2+-stimulated sphingomyelinase is secreted by many cell types and is a
    product of the acid sphingomyelinase gene.
  findings: []
- id: PMID:8706124
  title: Acid sphingomyelinase-deficient human lymphoblasts and mice are defective
    in radiation-induced apoptosis.
  findings: []
- id: PMID:9030779
  title: Functional characterization of the N-glycosylation sites of human acid sphingomyelinase
    by site-directed mutagenesis.
  findings: []
- id: PMID:9660788
  title: The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase,
    two products of the acid sphingomyelinase gene.
  findings: []
- id: Reactome:R-HSA-1605797
  title: SMPD1 hydrolyzes SPHM
  findings: []
- id: Reactome:R-HSA-9769740
  title: Coagulation pathway
  findings: []
- id: Reactome:R-HSA-9769742
  title: SMPD1 converts sphingomyelin to ceramide
  findings: []
- id: Reactome:R-HSA-9840310
  title: Glycosphingolipid catabolism
  findings: []
core_functions:
  - description: >-
      Zn2+-dependent lysosomal acid sphingomyelinase that hydrolyzes sphingomyelin
      to ceramide and phosphocholine (EC 3.1.4.12) in the acidic lumen of the
      lysosome/endolysosome, catalyzing the committed step of lysosomal
      sphingomyelin catabolism.
    molecular_function:
      id: GO:0004767
      label: sphingomyelin phosphodiesterase activity
    directly_involved_in:
      - id: GO:0006685
        label: sphingomyelin catabolic process
    locations:
      - id: GO:0043202
        label: lysosomal lumen
    supported_by:
      - reference_id: PMID:22573858
        supporting_text: >-
          Acid sphingomyelinase (ASMase) converts the lipid sphingomyelin (SM) to
          phosphocholine and ceramide and has optimum activity at acidic pH.
      - reference_id: PMID:16787399
        supporting_text: >-
          Acid sphingomyelinase (ASM), a member of the saposin-like protein
          (SAPLIP) family, is a lysosomal hydrolase that converts sphingomyelin to
          ceramide.
      - reference_id: file:human/SMPD1/SMPD1-uniprot.txt
        supporting_text: "Binds 2 Zn(2+) ions per subunit"
suggested_questions:
  - question: >-
      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?
  - question: >-
      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)?
suggested_experiments:
  - description: >-
      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.
  - description: >-
      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.