SMPD2

Summary: ER-associated nSMase1 contributes to the core membrane lipid-hydrolysis function.

Reason: The exact target leaf PTN002487871 descends from ER IBD PTN000273522. Full PMID:25168245 fractionation and immunocytochemistry detect phosphorylated nSMase1 at ER/Golgi membranes during the same stress responses linked to activity and ceramide generation. Localization to a functional compartment is part of the core synthesis; it is not automatically non-core because it is a location. ORGANELLES check (2026-11-06) - the PAINT ER IBD on PTN000273522 is seeded by fission-yeast Css1 (PomBase SPBC32F12.01c) and budding-yeast Isc1 (SGD S000000821), and the human protein independently supports the organelle - overexpressed human nSMase1 colocalized with ER and Golgi markers in HEK293 cells (PMID:10681556, abstract) and endogenous phosphorylated nSMase1 co-stained with calnexin in stressed Jurkat cells (PMID:25168245). This is a resident membrane enzyme, not a biosynthetic transit pool. The is_active_in qualifier is reasonable but soft - the activated (phosphorylated) form is seen at the ER, but no assay measures sphingomyelin hydrolysis in a purified ER fraction (the microsomal fraction was checked only with pan-cadherin). The ER membrane is added as a separate NEW IC row; this root row stays.

Summary: Retain the supported cell-surface membrane context.

Reason: The source supports plasma-membrane or cell-periphery association, complementing intracellular membrane observations. Retain this as a contextual location without asserting that it is exclusive or the dominant compartment in every cell. The original qualifier is preserved; part_of is a valid relation for an integral membrane constituent and is not invalidated by a separate located_in assertion.

Summary: Phylogenetic inference of the classical neutral sphingomyelinase activity. This is directly supported by human experimental data (IDA, PMID:10608884 and PMID:14741383) and by the UniProt EC 3.1.4.12 catalytic-activity block, so it is a well-supported core molecular function.

Summary: Sphingomyelin metabolism is consistent with the enzyme's sphingomyelin phosphodiesterase activity and the UniProt-stated sphingolipid-metabolism pathway. A sound higher-level biological process for this gene.

Summary: Sphingolipid catabolism is a core process encompassing sphingomyelin hydrolysis.

Reason: The broad process is biologically correct and directly connected to the established catalytic activity. A more specific sphingomyelin-catabolism annotation does not make this source assertion non-core.

Summary: The underlying neutral-SMase assay is real, but its attribution to SMPD2 needs isoform-level adjudication.

Reason: Live QuickGO traces the rat donor Q9ET64 to PMID:12473648. Its full Methods, Fig. 4 and Discussion distinguish rat perfusion/activity assays from bovine endothelial immunoblots, using antiserum from Bernardo et al. (PMID:10713073) against a purified bovine neutral SMase. Later PMID:16517606 identifies a new nSMase3 from a peptide of a previously purified bovine enzyme. This reagent history raises a concrete isoform-identity question that the abstract-only cache concealed. It does not establish that SMPD2 cannot occupy caveolae or respond to mechanical stimuli. Keep the inference unresolved pending antigen/peptide tracing and later target-specific evidence; do not remove an experimental curator assertion based on the paper title or organism.

Summary: SMPD2 directly generates ceramide by sphingomyelin hydrolysis, including in stressed human cells.

Reason: Sphingomyelin hydrolysis is itself a ceramide-producing reaction, within the GO:0046513 definition. Full PMID:25168245 Fig. 7 directly tests endogenous human SMPD2 RNAi in Jurkat T cells: stress/Fas-induced nSMase activity and ceramide accumulation are reduced after depletion, while upstream JNK/c-jun phosphorylation persists. Baseline ceramide is comparable in controls and depleted cells. Earlier unstimulated overexpression results and the importance of SMPD3 in other settings do not negate this conditional human SMPD2 function. The enzyme performs the lipid cleavage; it is not merely a substrate or a marker of the process.

Summary: Replace the uninformative catalytic-activity label with the established phosphodiester-hydrolase class.

Reason: SMPD2 is an experimentally characterized phosphodiester hydrolase. A broad valid electronic term is under-specific, not an exaggerated claim; GO:0008081 covers its supported sphingomyelin, sphingosylphosphocholine and lysoglycerophosphocholine hydrolysis.

Proposed replacements: phosphoric diester hydrolase activity

Summary: Electronic assignment of the sphingomyelin phosphodiesterase activity via ARBA/RHEA/EC mapping. Correct and redundant with the experimental IDA annotations to the same term.

Summary: Retain the supported cell-surface membrane context.

Reason: The source supports plasma-membrane or cell-periphery association, complementing intracellular membrane observations. Retain this as a contextual location without asserting that it is exclusive or the dominant compartment in every cell. The original qualifier is preserved; part_of is a valid relation for an integral membrane constituent and is not invalidated by a separate located_in assertion.

Summary: Retain curated interaction evidence without assigning it a specific physiological role.

Reason: Remove the generic protein-binding annotation because it does not describe a specific molecular function. The interaction evidence and source attribution are retained; this curation action does not assert that the reported association is false. The inspected evidence does not justify an informative replacement function for this particular row.

Summary: Retain curated interaction evidence without assigning it a specific physiological role.

Reason: Remove the generic protein-binding annotation because it does not describe a specific molecular function. The interaction evidence and source attribution are retained; this curation action does not assert that the reported association is false. The inspected evidence does not justify an informative replacement function for this particular row.

Summary: Retain curated interaction evidence without assigning it a specific physiological role.

Reason: Remove the generic protein-binding annotation because it does not describe a specific molecular function. The interaction evidence and source attribution are retained; this curation action does not assert that the reported association is false. The inspected evidence does not justify an informative replacement function for this particular row.

Summary: Retain curated interaction evidence without assigning it a specific physiological role.

Reason: Remove the generic protein-binding annotation because it does not describe a specific molecular function. The interaction evidence and source attribution are retained; this curation action does not assert that the reported association is false. The inspected evidence does not justify an informative replacement function for this particular row.

Summary: The underlying neutral-SMase assay is real, but its attribution to SMPD2 needs isoform-level adjudication.

Reason: Live QuickGO traces the rat donor Q9ET64 to PMID:12473648. Its full Methods, Fig. 4 and Discussion distinguish rat perfusion/activity assays from bovine endothelial immunoblots, using antiserum from Bernardo et al. (PMID:10713073) against a purified bovine neutral SMase. Later PMID:16517606 identifies a new nSMase3 from a peptide of a previously purified bovine enzyme. This reagent history raises a concrete isoform-identity question that the abstract-only cache concealed. It does not establish that SMPD2 cannot occupy caveolae or respond to mechanical stimuli. Keep the inference unresolved pending antigen/peptide tracing and later target-specific evidence; do not remove an experimental curator assertion based on the paper title or organism.

Summary: Sphingomyelin catabolism transferred from the mouse ortholog (O70572). Consistent with the human experimental IDA annotations to the same term and with the sphingomyelin phosphodiesterase activity.

Summary: The underlying neutral-SMase assay is real, but its attribution to SMPD2 needs isoform-level adjudication.

Reason: Live QuickGO traces the rat donor Q9ET64 to PMID:12473648. Its full Methods, Fig. 4 and Discussion distinguish rat perfusion/activity assays from bovine endothelial immunoblots, using antiserum from Bernardo et al. (PMID:10713073) against a purified bovine neutral SMase. Later PMID:16517606 identifies a new nSMase3 from a peptide of a previously purified bovine enzyme. This reagent history raises a concrete isoform-identity question that the abstract-only cache concealed. It does not establish that SMPD2 cannot occupy caveolae or respond to mechanical stimuli. Keep the inference unresolved pending antigen/peptide tracing and later target-specific evidence; do not remove an experimental curator assertion based on the paper title or organism.

Summary: SMPD2 participates in conditional intracellular ceramide signaling.

Reason: The electronic transfer traces to rat Q9ET64 and PMID:12473648, whose precise neutral-SMase identity is under separate adjudication after reading the full reagent history. Independently, full human PMID:25168245 Fig. 7 places endogenous SMPD2-dependent ceramide formation downstream of JNK during stress/Fas responses. Its catalytic production of the signaling lipid is actual pathway work. Retain this contextual signaling role without claiming that every stress or the mechanical response is mediated by SMPD2.

Summary: SMPD2 directly generates ceramide by sphingomyelin hydrolysis, including in stressed human cells.

Reason: Sphingomyelin hydrolysis is itself a ceramide-producing reaction, within the GO:0046513 definition. Full PMID:25168245 Fig. 7 directly tests endogenous human SMPD2 RNAi in Jurkat T cells: stress/Fas-induced nSMase activity and ceramide accumulation are reduced after depletion, while upstream JNK/c-jun phosphorylation persists. Baseline ceramide is comparable in controls and depleted cells. Earlier unstimulated overexpression results and the importance of SMPD3 in other settings do not negate this conditional human SMPD2 function. The enzyme performs the lipid cleavage; it is not merely a substrate or a marker of the process.

Summary: Sphingolipid metabolic process from ARBA/UniPathway mapping. Directly matches the UniProt-stated pathway (sphingolipid metabolism) and the enzyme's hydrolysis of sphingomyelin and sphingosylphosphocholine.

Summary: Retain the supported cell-surface membrane context.

Reason: The source supports plasma-membrane or cell-periphery association, complementing intracellular membrane observations. Retain this as a contextual location without asserting that it is exclusive or the dominant compartment in every cell. The original qualifier is preserved; part_of is a valid relation for an integral membrane constituent and is not invalidated by a separate located_in assertion.

Summary: Direct assay of the recombinant protein confirms sphingomyelin phosphodiesterase activity in vitro (Mg2+-dependent hydrolysis of sphingomyelin to ceramide and phosphocholine). This is the classical cloned activity and a core molecular function, although the same study shows the cellular activity is predominantly lyso-PAF-PLC.

Summary: Direct in vitro demonstration that human nSMase1 hydrolyzes sphingomyelin (and sphingosylphosphocholine) under detergent-free conditions. Supports the core sphingomyelin phosphodiesterase molecular function.

Summary: Retain the supported cell-surface membrane context.

Reason: The source supports plasma-membrane or cell-periphery association, complementing intracellular membrane observations. Retain this as a contextual location without asserting that it is exclusive or the dominant compartment in every cell. The original qualifier is preserved; part_of is a valid relation for an integral membrane constituent and is not invalidated by a separate located_in assertion.

Summary: Direct evidence linking the enzyme's in vitro sphingomyelin hydrolysis to sphingomyelin catabolism. The most specific and appropriate biological process for the sphingomyelin phosphodiesterase activity.

Summary: Direct evidence of sphingomyelin hydrolysis supporting sphingomyelin catabolism. Appropriate specific biological process for the enzyme.

Summary: The phosphodiester-hydrolase class correctly spans the demonstrated substrate chemistry.

Reason: These experiments support several phosphodiester-cleaving activities. GO:0004629 specifically describes cleavage between phosphate and glycerol, and therefore fits lyso-PAF/lyso-PC but does not encompass sphingosylphosphocholine, which has a sphingoid backbone. Replacing the entire broad source annotation by that glycerophospholipase term would lose supported chemistry. Keep the broad class and describe the substrate-specific activities in the core synthesis.

Summary: The phosphodiester-hydrolase class correctly spans the demonstrated substrate chemistry.

Reason: These experiments support several phosphodiester-cleaving activities. GO:0004629 specifically describes cleavage between phosphate and glycerol, and therefore fits lyso-PAF/lyso-PC but does not encompass sphingosylphosphocholine, which has a sphingoid backbone. Replacing the entire broad source annotation by that glycerophospholipase term would lose supported chemistry. Keep the broad class and describe the substrate-specific activities in the core synthesis.

Summary: Retain the supported cell-surface membrane context.

Reason: The source supports plasma-membrane or cell-periphery association, complementing intracellular membrane observations. Retain this as a contextual location without asserting that it is exclusive or the dominant compartment in every cell. The original qualifier is preserved; part_of is a valid relation for an integral membrane constituent and is not invalidated by a separate located_in assertion.

Summary: Retain the supported cell-surface membrane context.

Reason: The source supports plasma-membrane or cell-periphery association, complementing intracellular membrane observations. Retain this as a contextual location without asserting that it is exclusive or the dominant compartment in every cell. The original qualifier is preserved; part_of is a valid relation for an integral membrane constituent and is not invalidated by a separate located_in assertion.

Summary: Proposed sub-compartment. nSMase1 is a multi-pass membrane enzyme with two predicted C-terminal transmembrane helices, and both overexpressed and endogenous human protein colocalize with ER markers, which places it in the ER membrane. The existing annotations stop at the organelle.

Reason: Added under the ORGANELLES policy (rule 4, 2026-11-06), beside the root GO:0005783 IBA row, which is kept. Two independent lines agree. (1) Topology - UniProt predicts two helical transmembrane segments (330-350, 354-374) and curates a multi-pass membrane protein, and removing one or both of these segments abolishes activity (PMID:10681556), so the enzyme works as a membrane-embedded protein. (2) ER location of the human protein in two laboratories - overexpressed nSMase1 in HEK293 cells colocalized with ER and Golgi marker proteins and fractionated to microsomes (PMID:10681556, abstract only), and endogenous phosphorylated nSMase1 co-stained with the ER marker calnexin in Jurkat T cells under stress and Fas stimulation (PMID:25168245). A third, supportive line is the PAINT ER IBD seeded by the yeast orthologues Css1 and Isc1. Caveats - the TM segments are predicted, membrane orientation of the active site has not been tested by protease protection, the HEK293 result is from overexpression, and the Jurkat microsomal fraction was checked only with pan-cadherin, hence IC rather than IDA. The Golgi and plasma-membrane pools are recorded by other rows and are not asserted here. core_functions is left at the ER root because sphingomyelin hydrolysis has not been measured in an ER-membrane preparation itself.