PSAP

UniProt ID: P07602
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

PSAP encodes prosaposin, a 524-residue lysosomal glycoprotein that is the common precursor of the four saposins (saposin A, B, C and D). In the lysosome, prosaposin is proteolytically processed into these four small (~80-residue), heat-stable, non-enzymatic saposin domains, each of which functions as a sphingolipid-activator / lipid-transfer protein. The saposins extract or solubilise membrane glycosphingolipids and present them to their cognate acid hydrolases: saposin A activates galactosylceramidase (GALC); saposin B activates arylsulfatase A (ARSA, sulfatide degradation), beta-galactosidase and alpha-galactosidase A; saposin C activates acid beta-glucosylceramidase (GBA1) and protects it from proteolysis; and saposin D activates acid ceramidase (ASAH1) and acid sphingomyelinase. Through these cofactor activities PSAP is essential for lysosomal sphingolipid/glycosphingolipid catabolism. Intact, secreted prosaposin additionally acts as a neurotrophic and myelinotrophic factor, signalling through the G-protein-coupled receptors GPR37 and GPR37L1, and serves as a trafficking chaperone that facilitates lysosomal delivery of progranulin. Prosaposin localises to the lysosome and is also secreted as a fully glycosylated ~70 kDa protein; its lysosomal targeting is mediated by sortilin (SORT1). Complete loss of prosaposin causes combined saposin deficiency, a fatal infantile sphingolipid storage disorder, whereas deficiencies of individual saposins phenocopy the corresponding enzyme diseases (saposin A ~ Krabbe disease, saposin B ~ metachromatic leukodystrophy, saposin C ~ atypical Gaucher disease); variants in the saposin D domain are also linked to Parkinson disease (PARK24).

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005576 extracellular region
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Prosaposin is secreted as a ~70 kDa glycoprotein and is well documented in extracellular fluids and the extracellular space; the extracellular pool includes the neurotrophic prosaposin ligand for GPR37/GPR37L1. This phylogenetic (IBA) localization is consistent with the UniProt Secreted annotation and with multiple proteomic detections.
Reason: Well supported by UniProt subcellular location (Secreted) and by HDA proteomics annotations; a genuine, though non-core, localization for the secreted prosaposin form (the core compartment is the lysosome).
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005764 lysosome
IBA
GO_REF:0000033 		ACCEPT
Summary: The lysosome is the principal site of action of prosaposin and the saposins, where the precursor is proteolytically processed and the saposin cofactors activate acid hydrolases for sphingolipid degradation. This is a core cellular component for the gene.
Reason: Strongly supported by UniProt (Lysosome subcellular location) and by experimental IDA annotations; represents the core site of saposin activator function.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: Lysosome
GO:0006629 lipid metabolic process
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Prosaposin/saposins participate in lysosomal lipid (sphingolipid) metabolism as non-enzymatic activator cofactors. This broad process term is correct but less informative than the specific glycosphingolipid catabolic role captured in core_functions.
Reason: Correct but general; the specific and core process is glycosphingolipid/sphingolipid catabolism (see core_functions and the sphingolipid metabolic process IEA). Retained as a broader parent.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
act as activator proteins for lysosomal sphingolipid-degrading enzymes, facilitating the hydrolysis of sphingolipids
GO:0030882 lipid antigen binding
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Saposins (notably saposin C/D and the related GM2 activator family) bind and load lipid antigens onto CD1 molecules for antigen presentation, and structural work explicitly notes a role in lipid antigen presentation. This is a genuine but peripheral activity relative to the core sphingolipid-catabolic cofactor function.
Reason: Lipid antigen binding/presentation is an established but non-core saposin function; keep as an accurate phylogenetic annotation, not a core function.
Supporting Evidence:
PMID:18462685
Human saposins are essential proteins required for degradation of sphingolipids and lipid antigen presentation.
GO:0060736 prostate gland growth
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Secreted prosaposin has trophic/growth-promoting effects reported in prostate biology, propagated here by phylogenetic inference. This is a tissue-specific developmental role of the secreted prosaposin form, well outside the core lysosomal cofactor function.
Reason: Plausible tissue-specific trophic role of secreted prosaposin (IBA), but peripheral to the gene's core function; retained as non-core.
GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Secreted prosaposin is a ligand for the Gi-coupled receptors GPR37 and GPR37L1, consistent with an adenylate cyclase-inhibiting (Gi) GPCR signaling pathway. This reflects the neurotrophic prosaposin signalling role, not the intralysosomal cofactor function.
Reason: Consistent with the GPR37/GPR37L1 neurotrophic-signalling role of secreted prosaposin; genuine but non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
these effects are mediated by its G protein-coupled receptors, GPR37 and GPR37L1
GO:0019216 regulation of lipid metabolic process
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: As an activator of lysosomal lipid-degrading hydrolases, prosaposin/saposins modulate the rate of sphingolipid catabolism, which can be framed as regulation of lipid metabolism. This is a general regulatory framing of the core cofactor activity.
Reason: Regulatory framing of the activator role; correct but subsumed by the more specific activator MF and catabolic BP in core_functions.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
act as activator proteins for lysosomal sphingolipid-degrading enzymes
GO:0005576 extracellular region
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Extracellular region localization derived from the UniProt Secreted subcellular-location mapping. Consistent with prosaposin being secreted as a glycoprotein; a genuine non-core location.
Reason: Correct SubCell-derived location for the secreted prosaposin form; non-core relative to the lysosome.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005764 lysosome
IEA
GO_REF:0000120 		ACCEPT
Summary: Lysosome localization from combined IEA methods (InterPro saposin domains + SubCell). This is the core site of prosaposin/saposin action and is strongly corroborated experimentally.
Reason: Correct core localization, redundant with and confirmed by experimental IDA lysosome annotations.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: Lysosome
GO:0006629 lipid metabolic process
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: InterPro-based mapping to lipid metabolic process. Correct at a broad level given the saposin role in lysosomal lipid catabolism, but superseded by more specific terms.
Reason: Broadly correct parent term; the specific catabolic process is captured in core_functions.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
facilitating the hydrolysis of sphingolipids by extracting lipid substrates from membranes
GO:0006665 sphingolipid metabolic process
IEA
GO_REF:0000002 		MODIFY
Summary: InterPro saposin-domain mapping to sphingolipid metabolic process. This is the correct and central biological process for PSAP - the saposins are cofactors for lysosomal sphingolipid degradation. A more specific catabolic term (glycosphingolipid catabolic process) is provided in core_functions.
Reason: Accurate but general; PSAP specifically drives sphingolipid/glycosphingolipid CATABOLISM. Modify toward the specific catabolic process while retaining the sphingolipid metabolism essence.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
act as activator proteins for lysosomal sphingolipid-degrading enzymes
GO:0008289 lipid binding
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA-derived lipid binding. Saposins are bona fide lipid-binding/lipid-transfer proteins that extract glycosphingolipids and phospholipids from membranes; this molecular function is well supported experimentally (ganglioside and phospholipid binding IDAs).
Reason: Correct molecular function, corroborated by experimental ganglioside- and phospholipid-binding annotations; broader parent of the specific activator MF in core_functions.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
extracting lipid substrates from membranes and presenting them to their respective enzymes
GO:0030290 sphingolipid activator protein activity
IDA
file:human/PSAP/PSAP-uniprot.txt 		NEW
Summary: Proposed core molecular function. The four saposins derived from prosaposin are the canonical non-enzymatic sphingolipid-activator proteins that stimulate lysosomal sphingolipid-degrading hydrolases (glucosylceramidase, galactosylceramidase, cerebroside-sulfatase, alpha- and beta-galactosidase, sphingomyelin phosphodiesterase). This term (GO:0030290) is the specific, informative MF for PSAP but is not currently present in the GOA TSV; it is added here as a NEW annotation to reflect the core function.
Reason: The most informative molecular-function term for prosaposin/saposins is not in the current GOA (which spreads the MF across lipid/ganglioside/phospholipid binding). GO:0030290 directly captures the non-catalytic sphingolipid-activator cofactor activity that defines this gene; added as a NEW core annotation. Supported by decades of biochemistry (UniProt FUNCTION) and the term's own definition.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
act as activator proteins for lysosomal sphingolipid-degrading enzymes, facilitating the hydrolysis of sphingolipids
GO:0010467 gene expression
IEA
GO_REF:0000117 		MARK AS OVER ANNOTATED
Summary: ARBA electronic mapping to the very broad process gene expression. There is no evidence that prosaposin functions as a transcription/translation factor; the experimental link (PMID:27356620) is to post-translational regulation of progranulin protein levels, not gene expression per se. This IEA mapping is uninformative/over-broad.
Reason: Vague, over-broad ARBA mapping not reflecting a real gene-expression role; the underlying biology is post-translational regulation of progranulin abundance (see the IDA/IMP entries).
GO:0042802 identical protein binding
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA-derived identical protein binding, consistent with prosaposin/saposin self-association (prosaposin oligomerization required for sorting; saposin homodimers). Supported experimentally by the protein homodimerization activity IDA (PMID:18462685).
Reason: Consistent with documented prosaposin oligomerization and saposin homodimer formation.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
[Saposin-B]: Homodimer
GO:0005515 protein binding
IPI
PMID:16713569
A protein-protein interaction network for human inherited at... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding IPI from an ataxia/Purkinje-cell protein-interaction network (interactor ZBED1/O96006). The generic term protein binding conveys no specific molecular function and the interaction is not clearly linked to prosaposin biology.
Reason: Uninformative high-throughput protein binding annotation; per curation guidance the bare protein binding term should not be treated as a core function. Retained but flagged as over-annotated rather than removed (experimental IPI).
GO:0005515 protein binding
IPI
PMID:24872419
Mesotrypsin and caspase-14 participate in prosaposin process... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding IPI capturing the prosaposin-CASP14 (caspase-14, P31944) interaction during epidermal prosaposin processing. The interaction is real and biologically meaningful (processing), but is more informatively captured by the protease binding annotation from the same paper.
Reason: Redundant with, and less informative than, the GO:0002020 protease binding annotation from the same study; the generic protein binding term is uninformative.
Supporting Evidence:
PMID:24872419
mesotrypsin generated saposins A-D from prosaposin
GO:0005515 protein binding
IPI
PMID:26370502
Prosaposin facilitates sortilin-independent lysosomal traffi... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding IPI for the prosaposin-progranulin (GRN, P28799) interaction. This interaction underlies the physiologically important PSAP-mediated lysosomal trafficking of progranulin, better captured by the lysosomal transport annotations from the same study.
Reason: The generic protein binding term is uninformative; the underlying PSAP-GRN interaction and its consequence are captured by GO:0007041 lysosomal transport (PMID:26370502).
Supporting Evidence:
PMID:26370502
prosaposin (PSAP) interacts with PGRN and facilitates its lysosomal
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		MARK AS OVER ANNOTATED
Summary: Bare protein binding IPI from a large-scale binary interactome map (HuRI), reporting interactions with ZBED1 (O96006), PEX5 (P50542-3) and APPBP2 (Q92624). Generic and high-throughput.
Reason: High-throughput binary-interactome protein binding, uninformative as a molecular function; flagged rather than removed.
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding IPI from a neurodegenerative-disease interactome map (interactors include APP/P05067, LYN/P07948, CSNK1D/P48730-2). Generic high-throughput evidence.
Reason: High-throughput interactome protein binding; uninformative bare term, flagged not removed.
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding IPI from a proteome-scale interaction network (BioPlex; interactor GRN/P28799). Recapitulates the PSAP-progranulin interaction in a high-throughput setting.
Reason: Generic high-throughput protein binding; the PSAP-GRN interaction it reflects is better represented by the lysosomal-transport annotations. Flagged, not removed.
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-9840334 		ACCEPT
Summary: Lysosomal lumen localization from the Reactome reaction in which prosaposin is cleaved. This is the core compartment where prosaposin is processed and the saposins act on glycosphingolipids.
Reason: Correct core localization consistent with UniProt Lysosome and experimental lysosome IDAs.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
The lysosomal precursor is proteolytically processed to 4 small peptides
GO:0005576 extracellular region
HDA
PMID:27559042
Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin... 		KEEP AS NON CORE
Summary: High-throughput (HDA) proteomic detection of prosaposin in the extracellular region. Consistent with the secreted prosaposin form; non-core localization.
Reason: Valid proteomics-based extracellular detection of the secreted form; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005576 extracellular region
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Extracellular region by curator sequence-similarity transfer from the mouse ortholog (Q61207), which is documented as secreted. Consistent with the secreted prosaposin form.
Reason: Correct ISS transfer of the Secreted location from a well-characterized ortholog; non-core relative to the lysosome.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
[Prosaposin]: Secreted {ECO:0000250|UniProtKB:Q61207}
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-1606312 		ACCEPT
Summary: Lysosomal lumen localization from a Reactome glycosphingolipid-catabolism reaction (GLB1 hydrolyzes SapB/C:LacCer), where saposin B/C present lipid to the hydrolase. Core compartment.
Reason: Correct core lysosomal-lumen localization consistent with UniProt and experimental IDAs.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
The lysosomal precursor is proteolytically processed to 4 small peptides
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-1605624 		ACCEPT
Summary: Lysosomal lumen localization from the Reactome reaction in which beta-galactosidase hydrolyses saposin-mobilized GM1 to GM2. Core compartment for the activator function.
Reason: Correct core lysosomal-lumen localization, redundant with other lysosome annotations.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
The lysosomal precursor is proteolytically processed to 4 small peptides
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-1605632 		ACCEPT
Summary: Lysosomal lumen localization from a Reactome reaction (bHEXA/bHEXB hydrolyze PSAP(195-273):Gb4Cer:PE), reflecting saposin-B-mediated lipid presentation. Core compartment.
Reason: Correct core lysosomal-lumen localization.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
The lysosomal precursor is proteolytically processed to 4 small peptides
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-1605724 		ACCEPT
Summary: Lysosomal lumen localization from a Reactome reaction (NEU1,4 hydrolyze PSAP(195-273):GM3:PE) reflecting saposin-B lipid presentation. Core compartment.
Reason: Correct core lysosomal-lumen localization.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
The lysosomal precursor is proteolytically processed to 4 small peptides
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-1605736 		ACCEPT
Summary: Lysosomal lumen localization from a Reactome reaction (GLA hydrolyzes PSAP(195-273):Gb3Cer:PE) reflecting saposin-B lipid presentation. Core compartment.
Reason: Correct core lysosomal-lumen localization.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
The lysosomal precursor is proteolytically processed to 4 small peptides
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-1606807 		ACCEPT
Summary: Lysosomal lumen localization from a Reactome reaction (ARSA removes sulfate from PSAP(195-273):Sulfatide), the canonical saposin-B / arylsulfatase A activation step. Core compartment.
Reason: Correct core lysosomal-lumen localization for the saposin-B sulfatide-desulfation reaction.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
The lysosomal precursor is proteolytically processed to 4 small peptides
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-351341 		ACCEPT
Summary: Lysosomal lumen localization from the Reactome Exocytosis of Proactivator polypeptide reaction. Prosaposin transits the lysosomal lumen en route through the secretory/endolysosomal system.
Reason: Correct core lysosomal-lumen localization consistent with prosaposin trafficking.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
The lysosomal precursor is proteolytically processed to 4 small peptides
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-9840470 		ACCEPT
Summary: Lysosomal lumen localization from a Reactome reaction (PSAP(195-273) dimer:PE binds and mobilizes ligands), representing saposin-B lipid mobilization in the lumen. Core compartment.
Reason: Correct core lysosomal-lumen localization.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
The lysosomal precursor is proteolytically processed to 4 small peptides
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-9840488 		ACCEPT
Summary: Lysosomal lumen localization from a Reactome reaction (PSAP(195-273) forms a dimer), the saposin-B homodimerization step. Core compartment.
Reason: Correct core lysosomal-lumen localization; consistent with saposin-B homodimer formation.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
The lysosomal precursor is proteolytically processed to 4 small peptides
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-9841189 		ACCEPT
Summary: Lysosomal lumen localization from a Reactome reaction (GLA hydrolyzes PSAP(195-273):Gal2Cer:PE) reflecting saposin-B lipid presentation. Core compartment.
Reason: Correct core lysosomal-lumen localization.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
The lysosomal precursor is proteolytically processed to 4 small peptides
GO:0043202 lysosomal lumen
TAS
Reactome:R-HSA-9842115 		ACCEPT
Summary: Lysosomal lumen localization from a Reactome reaction (PSAP(195-273) dimer binds PE), the saposin-B / phosphatidylethanolamine association step in the lumen. Core compartment.
Reason: Correct core lysosomal-lumen localization; consistent with saposin-B co-purifying with PE.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
Saposin-B co-purifies with 1 molecule of phosphatidylethanolamine
GO:0097110 scaffold protein binding
IPI
PMID:23555801
BANK1 and BLK act through phospholipase C gamma 2 in B-cell ... 		MARK AS OVER ANNOTATED
Summary: Scaffold protein binding IPI (interactor Q8NDB2) assigned from a paper on BANK1/BLK/PLCg2 B-cell signalling. The cached publication does not mention prosaposin/PSAP or saposins anywhere in its text, so the supporting evidence for a PSAP scaffold-binding function cannot be verified, and the bare scaffold protein binding term is uninformative regardless.
Reason: The cited reference (a BANK1/BLK B-cell signalling study) does not discuss PSAP; the annotation is a generic binding term that adds no specific molecular function for prosaposin. Flagged rather than removed. See reference_review for the likely citation mismatch.
GO:0010467 gene expression
IDA
PMID:27356620
Prosaposin is a regulator of progranulin levels and oligomer... 		KEEP AS NON CORE
Summary: Experimental finding that PSAP modulates progranulin (PGRN) protein abundance - both PSAP reduction and overexpression raise extracellular PGRN. The annotation is captured here under the very broad gene expression term with a negative-effect qualifier, but the actual mechanism is post-translational regulation of PGRN levels/oligomerization, not transcriptional gene expression.
Reason: Real experimental effect on progranulin protein levels, but the gene expression term is a coarse/imperfect fit (the mechanism is post-translational) and the role is peripheral to PSAP core lysosomal cofactor function. Keep as non-core; do not treat as core.
Supporting Evidence:
PMID:27356620
both PSAP reduction and overexpression lead to significantly elevated extracellular PGRN levels
GO:0010467 gene expression
IMP
PMID:27356620
Prosaposin is a regulator of progranulin levels and oligomer... 		KEEP AS NON CORE
Summary: IMP counterpart of the same PSAP-to-progranulin-level effect (PSAP knockdown/overexpression alters extracellular PGRN and its oligomerization state). Same caveat regarding the coarse gene expression term applies.
Reason: Duplicate evidence (IMP) for the post-translational regulation of progranulin abundance; non-core, and the gene expression term is a loose fit for the actual mechanism.
Supporting Evidence:
PMID:27356620
PSAP knockdown increases PGRN monomers, whereas PSAP overexpression increases PGRN oligomers
GO:0005764 lysosome
IDA
PMID:28541286
Impaired prosaposin lysosomal trafficking in frontotemporal ... 		ACCEPT
Summary: Direct experimental (IDA) demonstration of prosaposin in the lysosome, in the context of PGRN-dependent PSAP lysosomal trafficking in neurons. Confirms the core lysosomal localization.
Reason: Experimental confirmation of core lysosomal localization.
Supporting Evidence:
PMID:28541286
PGRN facilitates neuronal uptake and lysosomal delivery of prosaposin (PSAP)
GO:0007041 lysosomal transport
IMP
PMID:28541286
Impaired prosaposin lysosomal trafficking in frontotemporal ... 		KEEP AS NON CORE
Summary: Reciprocal to the PSAP-progranulin trafficking axis - progranulin promotes lysosomal delivery of prosaposin, and impaired PSAP lysosomal trafficking is implicated in FTLD/NCL. PSAP participates in a lysosomal-transport process as both cargo and chaperone. Moonlighting role of secreted prosaposin.
Reason: Genuine experimental role in lysosomal transport (PSAP-PGRN co-trafficking), but a moonlighting chaperone/cargo function distinct from the core sphingolipid-activator activity.
Supporting Evidence:
PMID:28541286
a role of PGRN in PSAP lysosomal trafficking
GO:0007041 lysosomal transport
IMP
PMID:28835281
Lysosomal processing of progranulin. 		KEEP AS NON CORE
Summary: Study of lysosomal processing of progranulin in which the PSAP-PGRN lysosomal-delivery relationship is examined; PSAP is annotated to lysosomal transport (progranulin co-trafficking). Non-core moonlighting role.
Reason: Supports the lysosomal-transport (progranulin co-trafficking) role; non-core relative to the saposin activator function.
Supporting Evidence:
PMID:28835281
PGRN endocytosed from the extracellular space is also processed in a similar manner
GO:0005764 lysosome
IDA
PMID:26370502
Prosaposin facilitates sortilin-independent lysosomal traffi... 		ACCEPT
Summary: Direct experimental localization of prosaposin to the lysosome in the study establishing the PSAP-progranulin lysosomal-trafficking pathway. Confirms the core lysosomal localization.
Reason: Experimental confirmation of core lysosomal localization.
Supporting Evidence:
PMID:26370502
prosaposin (PSAP) interacts with PGRN and facilitates its lysosomal
GO:0005770 late endosome
IDA
PMID:26370502
Prosaposin facilitates sortilin-independent lysosomal traffi... 		KEEP AS NON CORE
Summary: Direct experimental detection of prosaposin in late endosomes, consistent with its transit through the endolysosomal system during trafficking of itself and progranulin. Non-core compartment on the route to the lysosome.
Reason: Valid endolysosomal-pathway localization (transit compartment); non-core relative to the lysosome.
Supporting Evidence:
PMID:26370502
late endosomes
GO:0007041 lysosomal transport
IDA
PMID:26370502
Prosaposin facilitates sortilin-independent lysosomal traffi... 		KEEP AS NON CORE
Summary: Direct experimental demonstration that prosaposin facilitates lysosomal targeting/delivery of progranulin via CI-M6PR and LRP1 in biosynthetic and endocytic pathways. Establishes PSAP as a trafficking chaperone for progranulin - a moonlighting function.
Reason: Well-supported experimental lysosomal-transport role for progranulin cargo, but a moonlighting chaperone function distinct from the core sphingolipid-activator activity.
Supporting Evidence:
PMID:26370502
facilitates its lysosomal targeting in both biosynthetic and endocytic pathways via the cation-independent mannose 6-phosphate receptor and low density lipoprotein receptor-related protein 1
GO:0002020 protease binding
IPI
PMID:24872419
Mesotrypsin and caspase-14 participate in prosaposin process... 		ACCEPT
Summary: Prosaposin was identified as an interactor of the proteases caspase-14 and epidermal mesotrypsin, which process prosaposin into saposins A-D; mesotrypsin directly generates the saposins from prosaposin. This protease binding reflects the physiological maturation of prosaposin.
Reason: Experimentally supported protease-binding interaction underlying prosaposin processing; informative (unlike bare protein binding) though peripheral to the mature-saposin cofactor activity.
Supporting Evidence:
PMID:24872419
mesotrypsin generated saposins A-D from prosaposin
GO:0005576 extracellular region
HDA
PMID:27068509
Extracellular matrix remodelling in response to venous hyper... 		KEEP AS NON CORE
Summary: High-throughput proteomic detection of prosaposin in extracellular matrix/space (varicose vein proteomics). Consistent with the secreted prosaposin form; non-core location.
Reason: Valid proteomics-based extracellular detection; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005576 extracellular region
HDA
PMID:20551380
Proteomics characterization of extracellular space component... 		KEEP AS NON CORE
Summary: High-throughput proteomic detection of prosaposin in the extracellular space of human aorta. Consistent with the secreted prosaposin form; non-core location.
Reason: Valid proteomics-based extracellular detection; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005576 extracellular region
ISS
PMID:22261194
Proteomics analysis of cardiac extracellular matrix remodeli... 		KEEP AS NON CORE
Summary: Extracellular region assigned by sequence-similarity from a porcine cardiac ECM proteomics dataset (ortholog F1SU97). Consistent with secreted prosaposin; non-core.
Reason: Ortholog-based extracellular localization consistent with the secreted form; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005576 extracellular region
IDA
PMID:1454804
Binding and transport of gangliosides by prosaposin. 		KEEP AS NON CORE
Summary: Prosaposin is described as existing as a secretory protein (and as an integral membrane protein), directly supporting its extracellular localization. Non-core relative to the lysosome.
Reason: Direct evidence for the secreted prosaposin form; non-core localization.
Supporting Evidence:
PMID:1454804
Prosaposin exists as a secretory protein and as an integral membrane protein
GO:1905572 ganglioside GM1 transport to membrane
IDA
PMID:1454804
Binding and transport of gangliosides by prosaposin. 		ACCEPT
Summary: Prosaposin and saposins transferred gangliosides (including GM1) from donor liposomes to acceptor membranes, directly demonstrating ganglioside transport activity. This lipid-transfer function underlies the activator role (presenting glycosphingolipids to hydrolases).
Reason: Direct experimental evidence for ganglioside transport between membranes, a specific manifestation of the saposin lipid-transfer/presentation function.
Supporting Evidence:
PMID:1454804
Prosaposin and saposins transferred gangliosides from donor liposomes to erythrocyte ghost membranes
GO:1905573 ganglioside GM1 binding
IDA
PMID:1454804
Binding and transport of gangliosides by prosaposin. 		ACCEPT
Summary: Prosaposin and saposins formed stable complexes with multiple gangliosides, including the gangliotetraose (a-series) gangliosides such as GM1, demonstrating direct ganglioside binding.
Reason: Direct experimental binding of GM1-type gangliosides, consistent with the lipid-binding activator function.
Supporting Evidence:
PMID:1454804
formed stable complexes with 13 different gangliosides
GO:1905574 ganglioside GM2 binding
IDA
PMID:1454804
Binding and transport of gangliosides by prosaposin. 		ACCEPT
Summary: Ganglioside binding assay showing stable complex formation with a panel of 13 gangliosides, supporting direct binding of GM2-type gangliosides.
Reason: Direct experimental ganglioside binding; consistent with lipid-binding function.
Supporting Evidence:
PMID:1454804
formed stable complexes with 13 different gangliosides
GO:1905575 ganglioside GM3 binding
IDA
PMID:1454804
Binding and transport of gangliosides by prosaposin. 		ACCEPT
Summary: Ganglioside binding assay showing stable complex formation with a panel of 13 gangliosides, supporting direct binding of GM3-type gangliosides.
Reason: Direct experimental ganglioside binding; consistent with lipid-binding function.
Supporting Evidence:
PMID:1454804
formed stable complexes with 13 different gangliosides
GO:1905576 ganglioside GT1b binding
IDA
PMID:1454804
Binding and transport of gangliosides by prosaposin. 		ACCEPT
Summary: Ganglioside binding assay showing stable complex formation with a panel of 13 gangliosides, spanning a- and b-series; supports direct binding of GT1b (a b-series ganglioside), reported to bind with lower affinity.
Reason: Direct experimental ganglioside binding; b-series gangliosides bound with lower affinity.
Supporting Evidence:
PMID:1454804
b series gangliosides, O-acetylated gangliosides, and gangliosides with shorter carbohydrate chains, were bound with lower affinity
GO:1905577 ganglioside GP1c binding
IDA
PMID:1454804
Binding and transport of gangliosides by prosaposin. 		ACCEPT
Summary: Ganglioside binding assay showing stable complex formation with a panel of 13 gangliosides, supporting direct binding of GP1c-type gangliosides.
Reason: Direct experimental ganglioside binding; consistent with lipid-binding function.
Supporting Evidence:
PMID:1454804
formed stable complexes with 13 different gangliosides
GO:0005543 phospholipid binding
IDA
PMID:14674747
Solution structure of human saposin C: pH-dependent interact... 		ACCEPT
Summary: Saposin C binds phospholipid vesicles/membranes in a pH-dependent, reversible manner (NMR study), directly demonstrating phospholipid binding. Membrane binding is essential for saposin C to activate lysosomal lipid degradation.
Reason: Direct experimental evidence for saposin C phospholipid/membrane binding, integral to the activator/lipid-transfer function.
Supporting Evidence:
PMID:14674747
the binding of saposin C to phospholipid vesicles is a pH-controlled reversible process
GO:0042803 protein homodimerization activity
IDA
PMID:18462685
Crystal structures of human saposins C andD: implications fo... 		ACCEPT
Summary: Crystal structures show saposin C forming domain-swapped homodimers and saposin D forming a defined homodimer (confirmed in solution), directly supporting protein homodimerization activity. Saposin B likewise functions as a homodimer.
Reason: Direct structural evidence for saposin homodimerization; consistent with the functional dimeric lipid-binding shells of the saposins.
Supporting Evidence:
PMID:18462685
two crystal structures of human saposin C in an "open" configuration with unusual domain swapped homodimers
GO:0005515 protein binding
IPI
PMID:22431521
The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) ... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding IPI reflecting the prosaposin-sortilin (SORT1) interaction examined in the CLN5/endosomal-sorting study; unlike prosaposin, CLN5 does not require sortilin for lysosomal localization. The generic term is uninformative, though the underlying PSAP-sortilin interaction is real and relevant to lysosomal targeting.
Reason: Uninformative bare protein binding term; the biologically meaningful PSAP-SORT1 interaction (lysosomal targeting) is documented in UniProt SUBUNIT and better captured functionally elsewhere.
Supporting Evidence:
PMID:22431521
CLN5, unlike prosaposin, does not require sortilin to localize to the lysosomal compartment
GO:0005764 lysosome
IDA
PMID:22431521
The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) ... 		ACCEPT
Summary: Prosaposin is used as a sortilin-dependent lysosomal cargo in this study; its lysosomal localization is directly observed. Confirms the core lysosomal localization.
Reason: Experimental confirmation of core lysosomal localization.
Supporting Evidence:
PMID:22431521
CLN5, unlike prosaposin, does not require sortilin to localize to the lysosomal compartment
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-6798739 		KEEP AS NON CORE
Summary: Plasma membrane localization from a Reactome neutrophil-degranulation (azurophil granule exocytosis) reaction. Reflects transient association during secretion of granule contents rather than a stable functional plasma-membrane pool.
Reason: Reactome degranulation pathway localization; peripheral/transient, non-core.
GO:0035577 azurophil granule membrane
TAS
Reactome:R-HSA-6798739 		KEEP AS NON CORE
Summary: Azurophil granule membrane localization from a Reactome neutrophil-degranulation reaction, reflecting prosaposin cargo in neutrophil secretory granules. Non-core.
Reason: Neutrophil granule localization from the degranulation pathway; non-core.
GO:0010506 regulation of autophagy
TAS
PMID:22949512
Reduced cathepsins B and D cause impaired autophagic degrada... 		KEEP AS NON CORE
Summary: In saposin C-deficient fibroblasts, autophagic degradation is impaired (delayed autolysosome degradation, reduced cathepsins B/D). This links PSAP/saposin C to autophagy, but as a downstream consequence of impaired lysosomal function rather than a direct autophagy-regulatory role.
Reason: Autophagy phenotype is a secondary consequence of saposin C deficiency and lysosomal dysfunction; genuine but indirect and non-core.
Supporting Evidence:
PMID:22949512
Reduced cathepsins B and D cause impaired autophagic degradation
GO:0070062 extracellular exosome
HDA
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expres... 		KEEP AS NON CORE
Summary: High-throughput proteomic detection of prosaposin in exosomes (prostatic secretions). Consistent with the secreted prosaposin form; non-core localization.
Reason: Proteomics-based exosome detection of the secreted form; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005576 extracellular region
HDA
PMID:16502470
Human colostrum: identification of minor proteins in the aqu... 		KEEP AS NON CORE
Summary: High-throughput proteomic detection of prosaposin in human colostrum/milk aqueous phase, consistent with the secreted prosaposin form (prosaposin is abundant in milk). Non-core.
Reason: Proteomics-based extracellular detection of the secreted form; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005576 extracellular region
TAS
Reactome:R-HSA-380073 		KEEP AS NON CORE
Summary: Extracellular region from a Reactome Gi-GPCR signalling reaction, reflecting secreted prosaposin acting as an extracellular GPCR ligand (GPR37/GPR37L1). Non-core.
Reason: Extracellular localization tied to the secreted prosaposin GPCR-ligand role; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005576 extracellular region
TAS
Reactome:R-HSA-5336182 		KEEP AS NON CORE
Summary: Extracellular region from the Reactome reaction GPR37 binds prosaptide, i.e. secreted prosaposin/prosaptide engaging its GPCR. Non-core.
Reason: Extracellular localization for the secreted prosaposin GPCR-ligand role; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005576 extracellular region
TAS
Reactome:R-HSA-5336184 		KEEP AS NON CORE
Summary: Extracellular region from the Reactome reaction GPR37L binds prosaposin, reflecting secreted prosaposin engaging GPR37L1. Non-core.
Reason: Extracellular localization for the secreted prosaposin GPCR-ligand role; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005576 extracellular region
TAS
Reactome:R-HSA-749454 		KEEP AS NON CORE
Summary: Extracellular region from a Reactome Gi-GPCR complex-dissociation reaction, part of the secreted-prosaposin GPCR signalling pathway. Non-core.
Reason: Extracellular localization for the secreted prosaposin GPCR-ligand role; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005576 extracellular region
TAS
Reactome:R-HSA-749456 		KEEP AS NON CORE
Summary: Extracellular region from a Reactome ligand-GPCR-Gi binding reaction, part of the secreted prosaposin GPCR signalling pathway. Non-core.
Reason: Extracellular localization for the secreted prosaposin GPCR-ligand role; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0070062 extracellular exosome
HDA
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exos... 		KEEP AS NON CORE
Summary: High-throughput proteomic detection of prosaposin in urinary exosomes. Consistent with the secreted prosaposin form; non-core localization.
Reason: Proteomics-based exosome detection of the secreted form; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005515 protein binding
IPI
PMID:20709014
Regulation of cell proliferation and apoptosis through fibro... 		MARK AS OVER ANNOTATED
Summary: Bare protein binding IPI capturing the prosaposin-fibrocystin/polyductin (FPC, PKHD1 product; P08F94) interaction identified by yeast two-hybrid and confirmed by GST pull-down/co-IP. The interaction is real and proposed to modulate cell proliferation/apoptosis, but the generic term is uninformative.
Reason: Uninformative bare protein binding term; the specific PSAP-fibrocystin interaction is documented but its molecular function for prosaposin is not captured by this generic term. Flagged, not removed (experimental IPI).
Supporting Evidence:
PMID:20709014
we confirmed the interaction between FPC and prosaposin
GO:0005576 extracellular region
TAS
Reactome:R-HSA-351341 		KEEP AS NON CORE
Summary: Extracellular region from the Reactome Exocytosis of Proactivator polypeptide reaction, reflecting secretion of prosaposin. Consistent with the secreted form; non-core.
Reason: Extracellular localization from the prosaposin-exocytosis reaction; non-core.
Supporting Evidence:
file:human/PSAP/PSAP-uniprot.txt
SUBCELLULAR LOCATION: [Prosaposin]: Secreted
GO:0005765 lysosomal membrane
TAS
Reactome:R-HSA-1605591 		ACCEPT
Summary: Lysosomal membrane localization from the Reactome reaction GBA1:SAPC hydrolyzes GlcCer, where saposin C acts at the lysosomal membrane to present glucosylceramide to glucocerebrosidase. Consistent with saposin C membrane association during the core activator reaction.
Reason: Correct - saposin C associates with the lysosomal (intralysosomal) membrane to present substrate to GBA1; consistent with the pH-dependent membrane-binding of saposin C.
Supporting Evidence:
PMID:14674747
Saposin C binds to membranes to activate lipid degradation in lysosomes
GO:0005765 lysosomal membrane
TAS
Reactome:R-HSA-9840334 		ACCEPT
Summary: Lysosomal membrane localization from the Reactome reaction PSAP is cleaved, reflecting the membrane-associated processing/action of prosaposin and saposins in the lysosome. Consistent with the lysosomal site of function.
Reason: Correct lysosomal-membrane localization consistent with the intralysosomal membrane-associated saposin function.
Supporting Evidence:
PMID:14674747
Saposin C binds to membranes to activate lipid degradation in lysosomes

Core Functions

As the precursor of saposins A-D, prosaposin provides non-enzymatic sphingolipid-activator protein cofactors that stimulate lysosomal sphingolipid-degrading hydrolases (galactosylceramidase, arylsulfatase A, beta-galactosidase, alpha-galactosidase A, acid beta-glucosylceramidase, acid ceramidase and sphingomyelinase), driving glycosphingolipid catabolism in the lysosome.

Molecular Function:
sphingolipid activator protein activity
Directly Involved In:
glycosphingolipid catabolic process
Cellular Locations:
lysosome lysosomal lumen
Supporting Evidence:
  • file:human/PSAP/PSAP-uniprot.txt
    Saposins are specific low-molecular mass non-enzymatic glycoproteins that act as activator proteins for lysosomal sphingolipid-degrading enzymes

The saposins act as lipid-binding/lipid-transfer proteins that extract or solubilise membrane glycosphingolipids (including gangliosides and sulfatide) and phospholipids and present them to their cognate acid hydrolases, enabling sphingolipid catabolism in the lysosome.

Molecular Function:
lipid binding
Directly Involved In:
sphingolipid catabolic process
Cellular Locations:
lysosome lysosomal lumen
Supporting Evidence:
  • file:human/PSAP/PSAP-uniprot.txt
    extracting lipid substrates from membranes and presenting them to their respective enzymes
  • PMID:1454804
    Prosaposin and saposins transferred gangliosides from donor liposomes to erythrocyte ghost membranes

References

file:human/PSAP/PSAP-uniprot.txt
UniProtKB P07602 (SAP_HUMAN) prosaposin entry
GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF: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:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:1454804
Binding and transport of gangliosides by prosaposin.
PMID:14674747
Solution structure of human saposin C: pH-dependent interaction with phospholipid vesicles.
PMID:16502470
Human colostrum: identification of minor proteins in the aqueous phase by proteomics.
PMID:16713569
A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.
PMID:18462685
Crystal structures of human saposins C andD: implications for lipid recognition and membrane interactions.
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
PMID:20551380
Proteomics characterization of extracellular space components in the human aorta.
PMID:20709014
Regulation of cell proliferation and apoptosis through fibrocystin-prosaposin interaction.
PMID:22261194
Proteomics analysis of cardiac extracellular matrix remodeling in a porcine model of ischemia/reperfusion injury.
PMID:22431521
The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) in endosomal sorting.
PMID:22949512
Reduced cathepsins B and D cause impaired autophagic degradation that can be almost completely restored by overexpression of these two proteases in Sap C-deficient fibroblasts.
PMID:23533145
In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
PMID:23555801
BANK1 and BLK act through phospholipase C gamma 2 in B-cell signaling.
PMID:24872419
Mesotrypsin and caspase-14 participate in prosaposin processing: potential relevance to epidermal permeability barrier formation.
PMID:26370502
Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin.
PMID:27068509
Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins.
PMID:27356620
Prosaposin is a regulator of progranulin levels and oligomerization.
PMID:27559042
Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial Fibrillation.
PMID:28541286
Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations.
PMID:28835281
Lysosomal processing of progranulin.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
Reactome:R-HSA-1605591
GBA1:SAPC hydrolyzes GlcCer
Reactome:R-HSA-1605624
Beta-galactosidases hydrolyse mobilized GM1 to mobilized GM2
Reactome:R-HSA-1605632
bHEXA,bHEXB hydrolyze PSAP(195-273):Gb4Cer:PE
Reactome:R-HSA-1605724
NEU1,4 hydrolyze PSAP(195-273):GM3:PE
Reactome:R-HSA-1605736
GLA hydrolyzes PSAP(195-273):Gb3Cer:PE
Reactome:R-HSA-1606312
GLB1 hydrolyzes SapB/C:LacCer
Reactome:R-HSA-1606807
ARSA removes sulfate from PSAP(195-273):Sulfatide
Reactome:R-HSA-351341
Exocytosis of Proactivator polypeptide
Reactome:R-HSA-380073
Liganded Gi-activating GPCR acts as a GEF for Gi
Reactome:R-HSA-5336182
GPR37 binds prosaptide
Reactome:R-HSA-5336184
GPR37L binds prosaposin
Reactome:R-HSA-6798739
Exocytosis of azurophil granule membrane proteins
Reactome:R-HSA-749454
The Ligand:GPCR:Gi complex dissociates
Reactome:R-HSA-749456
Liganded Gi-activating GPCRs bind inactive heterotrimeric G-protein Gi
Reactome:R-HSA-9840334
PSAP is cleaved
Reactome:R-HSA-9840470
PSAP(195-273) dimer:PE binds and mobilizes ligands
Reactome:R-HSA-9840488
PSAP(195-273) forms a dimer
Reactome:R-HSA-9841189
GLA hydrolyzes PSAP(195-273):Gal2Cer:PE
Reactome:R-HSA-9842115
PSAP(195-273) dimer binds PE

📚 Additional Documentation

Notes

(PSAP-notes.md)

PSAP (Prosaposin) review notes

UniProtKB: P07602 (SAP_HUMAN), HGNC:9498, gene PSAP (syn. GLBA, SAP1). 524 aa precursor.

Deep research: falcon provider is OUT OF CREDITS (HTTP 402); no -deep-research-falcon.md
was generated. Review grounded in PSAP-uniprot.txt, the seeded GOA (PSAP-goa.tsv),
and cached publications/PMID_*.md (all 23 GOA-cited PMIDs are cached).

Core biology

Prosaposin is the precursor of four saposins (A, B, C, D) — small (~80 aa), heat-stable,
non-enzymatic lysosomal sphingolipid-activator proteins produced by sequential proteolytic
cleavage of prosaposin in the lysosome. Each saposin binds/extracts a membrane glycosphingolipid
and presents it to the cognate acid hydrolase:
- Saposin A -> galactosylceramidase (GALC, EC 3.2.1.46); patient SapA deficiency phenocopies Krabbe (KRBSAPA).
- Saposin B -> arylsulfatase A (ARSA, sulfatide), beta-galactosidase (GM1), alpha-galactosidase A (Gb3); SapB deficiency = MLD (MLDSAPB).
- Saposin C -> acid beta-glucosidase/glucosylceramidase (GBA1); also protects GCase from proteolysis; SapC deficiency = atypical Gaucher (GDSAPC).
- Saposin D -> acid ceramidase (ASAH1) and acid sphingomyelinase.
[file:human/PSAP/PSAP-uniprot.txt FUNCTION lines 502-538]

Intact secreted prosaposin is also a neurotrophic/myelinotrophic factor acting through
GPCRs GPR37 and GPR37L1 (ERK signaling) [UniProt FUNCTION 511-515; PMID:10383054].

Localization: Lysosome (SUBCELL 560-561) and Secreted as a 70 kDa glycoprotein
(SUBCELL 562-565). Sortilin/SORT1 mediates lysosomal targeting (C-terminus).

Disease: complete PSAP loss = combined saposin deficiency (PSAPD, MIM 611721), fatal storage
disorder in infancy. Individual saposin deficiencies phenocopy the cognate enzyme disease.
PARK24 (autosomal dominant Parkinson) from SapD-domain variants.

Chosen core_functions terms (verified current via OLS)

  • MF GO:0030290 sphingolipid activator protein activity — def: "Any of a group of peptide
    cofactors of enzymes for the lysosomal degradation of sphingolipids. They stimulate various
    enzymes, including glucosylceramidase, galactosylceramidase, cerebroside-sulfatase,
    alpha-galactosidase, beta-galactosidase, and sphingomyelin phosphodiesterase." This is the exact
    non-catalytic activator MF for saposins (do NOT assign a catalytic/EC activity).
  • BP GO:0046479 glycosphingolipid catabolic process (current) / GO:0030149 sphingolipid catabolic process.
  • CC GO:0005764 lysosome / GO:0043202 lysosomal lumen (both in GOA), plus GO:0005576 extracellular region.

Note: GOA MF for PSAP is spread across lipid/ganglioside binding (GO:0008289 lipid binding IEA;
GO:1905573-77 ganglioside binding IDA; GO:0005543 phospholipid binding IDA; GO:0030882 lipid
antigen binding IBA) plus protein-binding IPIs. GO:0030290 is NOT currently in the GOA TSV but is
the most informative activator MF; added as a core_functions MF (author-supplied, validated).

Key verbatim-quote sources (grep-verified in cache)

  • Ganglioside binding/transport: PMID:1454804 (abstract).
  • SapC phospholipid/membrane binding: PMID:14674747.
  • Saposin homodimerization: PMID:18462685.
  • PSAP<->progranulin lysosomal trafficking: PMID:26370502, PMID:28541286, PMID:28835281.
  • PSAP regulates progranulin levels/oligomerization: PMID:27356620.
  • SapC deficiency & autophagy: PMID:22949512.
  • Prosaposin processing by mesotrypsin/caspase-14 (protease binding): PMID:24872419.

Annotation-specific judgments

  • Lysosome / lysosomal lumen / extracellular region CC: all ACCEPT (well supported, multiple lines).
  • IBA lipid metabolic process (GO:0006629) ACCEPT; IEA sphingolipid metabolic process (GO:0006665)
    MODIFY -> glycosphingolipid catabolic process is more informative but keep essence; I ACCEPT the
    KW-based process terms as broadly correct and add specific core_functions.
  • GO:0030882 lipid antigen binding (IBA): saposins do present lipid antigens (CD1); KEEP_AS_NON_CORE.
  • GO:0060736 prostate gland growth (IBA), GO:0007193 adenylate cyclase-inhibiting GPCR pathway (IBA),
    GO:0019216 regulation of lipid metabolic process (IBA): non-core secreted-prosaposin/GPR37 roles ->
    KEEP_AS_NON_CORE.
  • GO:0010467 gene expression (IEA ARBA; IDA/IMP PMID:27356620): the ARBA IEA is a vague/spurious
    mapping -> MARK_AS_OVER_ANNOTATED. The IDA/IMP (PMID:27356620) are experimental (PSAP regulates
    PGRN levels); keep but non-core, "gene expression" is a coarse term for a post-translational
    effect -> KEEP_AS_NON_CORE with note.
  • Bare protein binding IPIs (GO:0005515): MARK_AS_OVER_ANNOTATED (uninformative), never REMOVE.
  • GO:0097110 scaffold protein binding (PMID:23555801): cached paper is about BANK1/BLK/PLCg2 and does
    NOT mention PSAP; cannot verify -> MARK_AS_OVER_ANNOTATED + reference_review flag (likely wrong paper).
  • GO:0002020 protease binding (PMID:24872419): experimental IPI, prosaposin interacts with
    caspase-14/mesotrypsin during processing -> ACCEPT (non-core).
  • Lysosomal transport (GO:0007041) IMP/IDA (PMID:26370502, 28541286, 28835281): experimental; PSAP
    mediates progranulin lysosomal delivery -> ACCEPT (non-core, moonlighting chaperone role).
  • Ganglioside binding GO:1905573-77 + GM1 transport GO:1905572 (IDA PMID:1454804): ACCEPT.
  • GO:0042803 protein homodimerization (IDA PMID:18462685): saposin dimers -> ACCEPT.
  • GO:0010506 regulation of autophagy (TAS PMID:22949512): downstream consequence of SapC deficiency ->
    KEEP_AS_NON_CORE.
  • Exosome / plasma membrane / azurophil granule membrane CC (HDA/TAS): secreted-protein
    proteomics detections -> KEEP_AS_NON_CORE.
  • ISS extracellular region (Q61207 mouse ortholog; F1SU97): ACCEPT.

📄 View Raw YAML

 
id: P07602
gene_symbol: PSAP
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PSAP encodes prosaposin, a 524-residue lysosomal glycoprotein that is the common precursor
  of the four saposins (saposin A, B, C and D). In the lysosome, prosaposin is proteolytically
  processed into these four small (~80-residue), heat-stable, non-enzymatic saposin domains,
  each of which functions as a sphingolipid-activator / lipid-transfer protein. The saposins
  extract or solubilise membrane glycosphingolipids and present them to their cognate acid
  hydrolases: saposin A activates galactosylceramidase (GALC); saposin B activates arylsulfatase A
  (ARSA, sulfatide degradation), beta-galactosidase and alpha-galactosidase A; saposin C activates
  acid beta-glucosylceramidase (GBA1) and protects it from proteolysis; and saposin D activates acid
  ceramidase (ASAH1) and acid sphingomyelinase. Through these cofactor activities PSAP is essential
  for lysosomal sphingolipid/glycosphingolipid catabolism. Intact, secreted prosaposin additionally
  acts as a neurotrophic and myelinotrophic factor, signalling through the G-protein-coupled receptors
  GPR37 and GPR37L1, and serves as a trafficking chaperone that facilitates lysosomal delivery of
  progranulin. Prosaposin localises to the lysosome and is also secreted as a fully glycosylated
  ~70 kDa protein; its lysosomal targeting is mediated by sortilin (SORT1). Complete loss of
  prosaposin causes combined saposin deficiency, a fatal infantile sphingolipid storage disorder,
  whereas deficiencies of individual saposins phenocopy the corresponding enzyme diseases
  (saposin A ~ Krabbe disease, saposin B ~ metachromatic leukodystrophy, saposin C ~ atypical
  Gaucher disease); variants in the saposin D domain are also linked to Parkinson disease (PARK24).
alternative_products:
- name: Sap-mu-0
  id: P07602-1
- name: Sap-mu-6
  id: P07602-2
  sequence_note: VSP_006014
- name: Sap-mu-9
  id: P07602-3
  sequence_note: VSP_006015
existing_annotations:
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Prosaposin is secreted as a ~70 kDa glycoprotein and is well documented in
      extracellular fluids and the extracellular space; the extracellular pool includes the
      neurotrophic prosaposin ligand for GPR37/GPR37L1. This phylogenetic (IBA) localization is
      consistent with the UniProt Secreted annotation and with multiple proteomic detections.
    action: KEEP_AS_NON_CORE
    reason: Well supported by UniProt subcellular location (Secreted) and by HDA proteomics
      annotations; a genuine, though non-core, localization for the secreted prosaposin form (the
      core compartment is the lysosome).
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: The lysosome is the principal site of action of prosaposin and the saposins, where
      the precursor is proteolytically processed and the saposin cofactors activate acid hydrolases
      for sphingolipid degradation. This is a core cellular component for the gene.
    action: ACCEPT
    reason: Strongly supported by UniProt (Lysosome subcellular location) and by experimental IDA
      annotations; represents the core site of saposin activator function.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Prosaposin/saposins participate in lysosomal lipid (sphingolipid) metabolism as
      non-enzymatic activator cofactors. This broad process term is correct but less informative
      than the specific glycosphingolipid catabolic role captured in core_functions.
    action: KEEP_AS_NON_CORE
    reason: Correct but general; the specific and core process is glycosphingolipid/sphingolipid
      catabolism (see core_functions and the sphingolipid metabolic process IEA). Retained as a
      broader parent.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: act as activator proteins for lysosomal
        sphingolipid-degrading enzymes, facilitating the hydrolysis of
        sphingolipids
- term:
    id: GO:0030882
    label: lipid antigen binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Saposins (notably saposin C/D and the related GM2 activator family) bind and load
      lipid antigens onto CD1 molecules for antigen presentation, and structural work explicitly
      notes a role in lipid antigen presentation. This is a genuine but peripheral activity relative
      to the core sphingolipid-catabolic cofactor function.
    action: KEEP_AS_NON_CORE
    reason: Lipid antigen binding/presentation is an established but non-core saposin function;
      keep as an accurate phylogenetic annotation, not a core function.
    supported_by:
    - reference_id: PMID:18462685
      supporting_text: Human saposins are essential proteins required for degradation of sphingolipids
        and lipid antigen presentation.
- term:
    id: GO:0060736
    label: prostate gland growth
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Secreted prosaposin has trophic/growth-promoting effects reported in prostate biology,
      propagated here by phylogenetic inference. This is a tissue-specific developmental role of the
      secreted prosaposin form, well outside the core lysosomal cofactor function.
    action: KEEP_AS_NON_CORE
    reason: Plausible tissue-specific trophic role of secreted prosaposin (IBA), but peripheral to
      the gene's core function; retained as non-core.
- term:
    id: GO:0007193
    label: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Secreted prosaposin is a ligand for the Gi-coupled receptors GPR37 and GPR37L1,
      consistent with an adenylate cyclase-inhibiting (Gi) GPCR signaling pathway. This reflects the
      neurotrophic prosaposin signalling role, not the intralysosomal cofactor function.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the GPR37/GPR37L1 neurotrophic-signalling role of secreted prosaposin;
      genuine but non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: these effects are mediated by its G protein-coupled receptors,
        GPR37 and GPR37L1
- term:
    id: GO:0019216
    label: regulation of lipid metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: As an activator of lysosomal lipid-degrading hydrolases, prosaposin/saposins modulate
      the rate of sphingolipid catabolism, which can be framed as regulation of lipid metabolism.
      This is a general regulatory framing of the core cofactor activity.
    action: KEEP_AS_NON_CORE
    reason: Regulatory framing of the activator role; correct but subsumed by the more specific
      activator MF and catabolic BP in core_functions.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: act as activator proteins for lysosomal
        sphingolipid-degrading enzymes
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Extracellular region localization derived from the UniProt Secreted subcellular-location
      mapping. Consistent with prosaposin being secreted as a glycoprotein; a genuine non-core location.
    action: KEEP_AS_NON_CORE
    reason: Correct SubCell-derived location for the secreted prosaposin form; non-core relative to the
      lysosome.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Lysosome localization from combined IEA methods (InterPro saposin domains + SubCell).
      This is the core site of prosaposin/saposin action and is strongly corroborated experimentally.
    action: ACCEPT
    reason: Correct core localization, redundant with and confirmed by experimental IDA lysosome
      annotations.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Lysosome"
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based mapping to lipid metabolic process. Correct at a broad level given the
      saposin role in lysosomal lipid catabolism, but superseded by more specific terms.
    action: KEEP_AS_NON_CORE
    reason: Broadly correct parent term; the specific catabolic process is captured in core_functions.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: facilitating the hydrolysis of
        sphingolipids by extracting lipid substrates from membranes
- term:
    id: GO:0006665
    label: sphingolipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro saposin-domain mapping to sphingolipid metabolic process. This is the correct
      and central biological process for PSAP - the saposins are cofactors for lysosomal sphingolipid
      degradation. A more specific catabolic term (glycosphingolipid catabolic process) is provided in
      core_functions.
    action: MODIFY
    reason: Accurate but general; PSAP specifically drives sphingolipid/glycosphingolipid CATABOLISM.
      Modify toward the specific catabolic process while retaining the sphingolipid metabolism essence.
    proposed_replacement_terms:
    - id: GO:0046479
      label: glycosphingolipid catabolic process
    - id: GO:0030149
      label: sphingolipid catabolic process
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: act as activator proteins for lysosomal
        sphingolipid-degrading enzymes
- term:
    id: GO:0008289
    label: lipid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: ARBA-derived lipid binding. Saposins are bona fide lipid-binding/lipid-transfer proteins
      that extract glycosphingolipids and phospholipids from membranes; this molecular function is well
      supported experimentally (ganglioside and phospholipid binding IDAs).
    action: ACCEPT
    reason: Correct molecular function, corroborated by experimental ganglioside- and phospholipid-binding
      annotations; broader parent of the specific activator MF in core_functions.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: extracting lipid substrates from membranes and
        presenting them to their respective enzymes
- term:
    id: GO:0030290
    label: sphingolipid activator protein activity
  evidence_type: IDA
  original_reference_id: file:human/PSAP/PSAP-uniprot.txt
  qualifier: enables
  review:
    summary: Proposed core molecular function. The four saposins derived from prosaposin are the
      canonical non-enzymatic sphingolipid-activator proteins that stimulate lysosomal
      sphingolipid-degrading hydrolases (glucosylceramidase, galactosylceramidase, cerebroside-sulfatase,
      alpha- and beta-galactosidase, sphingomyelin phosphodiesterase). This term (GO:0030290) is the
      specific, informative MF for PSAP but is not currently present in the GOA TSV; it is added here as a
      NEW annotation to reflect the core function.
    action: NEW
    reason: The most informative molecular-function term for prosaposin/saposins is not in the current
      GOA (which spreads the MF across lipid/ganglioside/phospholipid binding). GO:0030290 directly
      captures the non-catalytic sphingolipid-activator cofactor activity that defines this gene; added as
      a NEW core annotation. Supported by decades of biochemistry (UniProt FUNCTION) and the term's own
      definition.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: act as activator proteins for lysosomal
        sphingolipid-degrading enzymes, facilitating the hydrolysis of
        sphingolipids
- term:
    id: GO:0010467
    label: gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA electronic mapping to the very broad process gene expression. There is no evidence
      that prosaposin functions as a transcription/translation factor; the experimental link
      (PMID:27356620) is to post-translational regulation of progranulin protein levels, not gene
      expression per se. This IEA mapping is uninformative/over-broad.
    action: MARK_AS_OVER_ANNOTATED
    reason: Vague, over-broad ARBA mapping not reflecting a real gene-expression role; the underlying
      biology is post-translational regulation of progranulin abundance (see the IDA/IMP entries).
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: ARBA-derived identical protein binding, consistent with prosaposin/saposin self-association
      (prosaposin oligomerization required for sorting; saposin homodimers). Supported experimentally by
      the protein homodimerization activity IDA (PMID:18462685).
    action: ACCEPT
    reason: Consistent with documented prosaposin oligomerization and saposin homodimer formation.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "[Saposin-B]: Homodimer"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16713569
  qualifier: enables
  review:
    summary: Bare protein binding IPI from an ataxia/Purkinje-cell protein-interaction network
      (interactor ZBED1/O96006). The generic term protein binding conveys no specific molecular
      function and the interaction is not clearly linked to prosaposin biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative high-throughput protein binding annotation; per curation guidance the bare
      protein binding term should not be treated as a core function. Retained but flagged as over-annotated
      rather than removed (experimental IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24872419
  qualifier: enables
  review:
    summary: Bare protein binding IPI capturing the prosaposin-CASP14 (caspase-14, P31944) interaction
      during epidermal prosaposin processing. The interaction is real and biologically meaningful
      (processing), but is more informatively captured by the protease binding annotation from the same
      paper.
    action: MARK_AS_OVER_ANNOTATED
    reason: Redundant with, and less informative than, the GO:0002020 protease binding annotation from
      the same study; the generic protein binding term is uninformative.
    supported_by:
    - reference_id: PMID:24872419
      supporting_text: mesotrypsin generated saposins A-D from prosaposin
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26370502
  qualifier: enables
  review:
    summary: Bare protein binding IPI for the prosaposin-progranulin (GRN, P28799) interaction. This
      interaction underlies the physiologically important PSAP-mediated lysosomal trafficking of
      progranulin, better captured by the lysosomal transport annotations from the same study.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term is uninformative; the underlying PSAP-GRN interaction and
      its consequence are captured by GO:0007041 lysosomal transport (PMID:26370502).
    supported_by:
    - reference_id: PMID:26370502
      supporting_text: prosaposin (PSAP) interacts with PGRN and facilitates its lysosomal
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Bare protein binding IPI from a large-scale binary interactome map (HuRI), reporting
      interactions with ZBED1 (O96006), PEX5 (P50542-3) and APPBP2 (Q92624). Generic and high-throughput.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput binary-interactome protein binding, uninformative as a molecular function;
      flagged rather than removed.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Bare protein binding IPI from a neurodegenerative-disease interactome map (interactors
      include APP/P05067, LYN/P07948, CSNK1D/P48730-2). Generic high-throughput evidence.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome protein binding; uninformative bare term, flagged not removed.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Bare protein binding IPI from a proteome-scale interaction network (BioPlex; interactor
      GRN/P28799). Recapitulates the PSAP-progranulin interaction in a high-throughput setting.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic high-throughput protein binding; the PSAP-GRN interaction it reflects is better
      represented by the lysosomal-transport annotations. Flagged, not removed.
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840334
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from the Reactome reaction in which prosaposin is cleaved.
      This is the core compartment where prosaposin is processed and the saposins act on glycosphingolipids.
    action: ACCEPT
    reason: Correct core localization consistent with UniProt Lysosome and experimental lysosome IDAs.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: The lysosomal precursor is proteolytically processed to 4 small
        peptides
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:27559042
  qualifier: located_in
  review:
    summary: High-throughput (HDA) proteomic detection of prosaposin in the extracellular region.
      Consistent with the secreted prosaposin form; non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Valid proteomics-based extracellular detection of the secreted form; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Extracellular region by curator sequence-similarity transfer from the mouse ortholog
      (Q61207), which is documented as secreted. Consistent with the secreted prosaposin form.
    action: KEEP_AS_NON_CORE
    reason: Correct ISS transfer of the Secreted location from a well-characterized ortholog; non-core
      relative to the lysosome.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "[Prosaposin]: Secreted\n       {ECO:0000250|UniProtKB:Q61207}"
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1606312
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from a Reactome glycosphingolipid-catabolism reaction
      (GLB1 hydrolyzes SapB/C:LacCer), where saposin B/C present lipid to the hydrolase. Core compartment.
    action: ACCEPT
    reason: Correct core lysosomal-lumen localization consistent with UniProt and experimental IDAs.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: The lysosomal precursor is proteolytically processed to 4 small
        peptides
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605624
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from the Reactome reaction in which beta-galactosidase
      hydrolyses saposin-mobilized GM1 to GM2. Core compartment for the activator function.
    action: ACCEPT
    reason: Correct core lysosomal-lumen localization, redundant with other lysosome annotations.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: The lysosomal precursor is proteolytically processed to 4 small
        peptides
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605632
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from a Reactome reaction (bHEXA/bHEXB hydrolyze
      PSAP(195-273):Gb4Cer:PE), reflecting saposin-B-mediated lipid presentation. Core compartment.
    action: ACCEPT
    reason: Correct core lysosomal-lumen localization.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: The lysosomal precursor is proteolytically processed to 4 small
        peptides
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605724
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from a Reactome reaction (NEU1,4 hydrolyze
      PSAP(195-273):GM3:PE) reflecting saposin-B lipid presentation. Core compartment.
    action: ACCEPT
    reason: Correct core lysosomal-lumen localization.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: The lysosomal precursor is proteolytically processed to 4 small
        peptides
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605736
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from a Reactome reaction (GLA hydrolyzes
      PSAP(195-273):Gb3Cer:PE) reflecting saposin-B lipid presentation. Core compartment.
    action: ACCEPT
    reason: Correct core lysosomal-lumen localization.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: The lysosomal precursor is proteolytically processed to 4 small
        peptides
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1606807
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from a Reactome reaction (ARSA removes sulfate from
      PSAP(195-273):Sulfatide), the canonical saposin-B / arylsulfatase A activation step. Core compartment.
    action: ACCEPT
    reason: Correct core lysosomal-lumen localization for the saposin-B sulfatide-desulfation reaction.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: The lysosomal precursor is proteolytically processed to 4 small
        peptides
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-351341
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from the Reactome Exocytosis of Proactivator polypeptide
      reaction. Prosaposin transits the lysosomal lumen en route through the secretory/endolysosomal system.
    action: ACCEPT
    reason: Correct core lysosomal-lumen localization consistent with prosaposin trafficking.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: The lysosomal precursor is proteolytically processed to 4 small
        peptides
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840470
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from a Reactome reaction (PSAP(195-273) dimer:PE binds and
      mobilizes ligands), representing saposin-B lipid mobilization in the lumen. Core compartment.
    action: ACCEPT
    reason: Correct core lysosomal-lumen localization.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: The lysosomal precursor is proteolytically processed to 4 small
        peptides
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840488
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from a Reactome reaction (PSAP(195-273) forms a dimer),
      the saposin-B homodimerization step. Core compartment.
    action: ACCEPT
    reason: Correct core lysosomal-lumen localization; consistent with saposin-B homodimer formation.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: The lysosomal precursor is proteolytically processed to 4 small
        peptides
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9841189
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from a Reactome reaction (GLA hydrolyzes
      PSAP(195-273):Gal2Cer:PE) reflecting saposin-B lipid presentation. Core compartment.
    action: ACCEPT
    reason: Correct core lysosomal-lumen localization.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: The lysosomal precursor is proteolytically processed to 4 small
        peptides
- term:
    id: GO:0043202
    label: lysosomal lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9842115
  qualifier: located_in
  review:
    summary: Lysosomal lumen localization from a Reactome reaction (PSAP(195-273) dimer binds PE),
      the saposin-B / phosphatidylethanolamine association step in the lumen. Core compartment.
    action: ACCEPT
    reason: Correct core lysosomal-lumen localization; consistent with saposin-B co-purifying with PE.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: Saposin-B co-purifies with 1 molecule of
        phosphatidylethanolamine
- term:
    id: GO:0097110
    label: scaffold protein binding
  evidence_type: IPI
  original_reference_id: PMID:23555801
  qualifier: enables
  review:
    summary: Scaffold protein binding IPI (interactor Q8NDB2) assigned from a paper on BANK1/BLK/PLCg2
      B-cell signalling. The cached publication does not mention prosaposin/PSAP or saposins anywhere in
      its text, so the supporting evidence for a PSAP scaffold-binding function cannot be verified, and the
      bare scaffold protein binding term is uninformative regardless.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited reference (a BANK1/BLK B-cell signalling study) does not discuss PSAP; the
      annotation is a generic binding term that adds no specific molecular function for prosaposin.
      Flagged rather than removed. See reference_review for the likely citation mismatch.
- term:
    id: GO:0010467
    label: gene expression
  evidence_type: IDA
  original_reference_id: PMID:27356620
  qualifier: acts_upstream_of_or_within_negative_effect
  review:
    summary: Experimental finding that PSAP modulates progranulin (PGRN) protein abundance - both PSAP
      reduction and overexpression raise extracellular PGRN. The annotation is captured here under the very
      broad gene expression term with a negative-effect qualifier, but the actual mechanism is
      post-translational regulation of PGRN levels/oligomerization, not transcriptional gene expression.
    action: KEEP_AS_NON_CORE
    reason: Real experimental effect on progranulin protein levels, but the gene expression term is a
      coarse/imperfect fit (the mechanism is post-translational) and the role is peripheral to PSAP core
      lysosomal cofactor function. Keep as non-core; do not treat as core.
    supported_by:
    - reference_id: PMID:27356620
      supporting_text: both PSAP reduction and
        overexpression lead to significantly elevated extracellular PGRN levels
- term:
    id: GO:0010467
    label: gene expression
  evidence_type: IMP
  original_reference_id: PMID:27356620
  qualifier: acts_upstream_of_or_within_negative_effect
  review:
    summary: IMP counterpart of the same PSAP-to-progranulin-level effect (PSAP knockdown/overexpression
      alters extracellular PGRN and its oligomerization state). Same caveat regarding the coarse gene
      expression term applies.
    action: KEEP_AS_NON_CORE
    reason: Duplicate evidence (IMP) for the post-translational regulation of progranulin abundance;
      non-core, and the gene expression term is a loose fit for the actual mechanism.
    supported_by:
    - reference_id: PMID:27356620
      supporting_text: PSAP knockdown increases PGRN monomers, whereas PSAP
        overexpression increases PGRN oligomers
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:28541286
  qualifier: located_in
  review:
    summary: Direct experimental (IDA) demonstration of prosaposin in the lysosome, in the context of
      PGRN-dependent PSAP lysosomal trafficking in neurons. Confirms the core lysosomal localization.
    action: ACCEPT
    reason: Experimental confirmation of core lysosomal localization.
    supported_by:
    - reference_id: PMID:28541286
      supporting_text: PGRN facilitates neuronal uptake and lysosomal delivery of prosaposin (PSAP)
- term:
    id: GO:0007041
    label: lysosomal transport
  evidence_type: IMP
  original_reference_id: PMID:28541286
  qualifier: involved_in
  review:
    summary: Reciprocal to the PSAP-progranulin trafficking axis - progranulin promotes lysosomal
      delivery of prosaposin, and impaired PSAP lysosomal trafficking is implicated in FTLD/NCL. PSAP
      participates in a lysosomal-transport process as both cargo and chaperone. Moonlighting role of
      secreted prosaposin.
    action: KEEP_AS_NON_CORE
    reason: Genuine experimental role in lysosomal transport (PSAP-PGRN co-trafficking), but a
      moonlighting chaperone/cargo function distinct from the core sphingolipid-activator activity.
    supported_by:
    - reference_id: PMID:28541286
      supporting_text: a role of PGRN in
        PSAP lysosomal trafficking
- term:
    id: GO:0007041
    label: lysosomal transport
  evidence_type: IMP
  original_reference_id: PMID:28835281
  qualifier: involved_in
  review:
    summary: Study of lysosomal processing of progranulin in which the PSAP-PGRN lysosomal-delivery
      relationship is examined; PSAP is annotated to lysosomal transport (progranulin co-trafficking).
      Non-core moonlighting role.
    action: KEEP_AS_NON_CORE
    reason: Supports the lysosomal-transport (progranulin co-trafficking) role; non-core relative to the
      saposin activator function.
    supported_by:
    - reference_id: PMID:28835281
      supporting_text: PGRN endocytosed from the extracellular space
        is also processed in a similar manner
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:26370502
  qualifier: located_in
  review:
    summary: Direct experimental localization of prosaposin to the lysosome in the study establishing
      the PSAP-progranulin lysosomal-trafficking pathway. Confirms the core lysosomal localization.
    action: ACCEPT
    reason: Experimental confirmation of core lysosomal localization.
    supported_by:
    - reference_id: PMID:26370502
      supporting_text: prosaposin (PSAP) interacts with PGRN and facilitates its lysosomal
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IDA
  original_reference_id: PMID:26370502
  qualifier: located_in
  review:
    summary: Direct experimental detection of prosaposin in late endosomes, consistent with its transit
      through the endolysosomal system during trafficking of itself and progranulin. Non-core compartment
      on the route to the lysosome.
    action: KEEP_AS_NON_CORE
    reason: Valid endolysosomal-pathway localization (transit compartment); non-core relative to the
      lysosome.
    supported_by:
    - reference_id: PMID:26370502
      supporting_text: late endosomes
- term:
    id: GO:0007041
    label: lysosomal transport
  evidence_type: IDA
  original_reference_id: PMID:26370502
  qualifier: involved_in
  review:
    summary: Direct experimental demonstration that prosaposin facilitates lysosomal targeting/delivery
      of progranulin via CI-M6PR and LRP1 in biosynthetic and endocytic pathways. Establishes PSAP as a
      trafficking chaperone for progranulin - a moonlighting function.
    action: KEEP_AS_NON_CORE
    reason: Well-supported experimental lysosomal-transport role for progranulin cargo, but a moonlighting
      chaperone function distinct from the core sphingolipid-activator activity.
    supported_by:
    - reference_id: PMID:26370502
      supporting_text: facilitates its lysosomal
        targeting in both biosynthetic and endocytic pathways via the cation-independent
        mannose 6-phosphate receptor and low density lipoprotein receptor-related
        protein 1
- term:
    id: GO:0002020
    label: protease binding
  evidence_type: IPI
  original_reference_id: PMID:24872419
  qualifier: enables
  review:
    summary: Prosaposin was identified as an interactor of the proteases caspase-14 and epidermal
      mesotrypsin, which process prosaposin into saposins A-D; mesotrypsin directly generates the saposins
      from prosaposin. This protease binding reflects the physiological maturation of prosaposin.
    action: ACCEPT
    reason: Experimentally supported protease-binding interaction underlying prosaposin processing;
      informative (unlike bare protein binding) though peripheral to the mature-saposin cofactor activity.
    supported_by:
    - reference_id: PMID:24872419
      supporting_text: mesotrypsin generated saposins A-D from prosaposin
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:27068509
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of prosaposin in extracellular matrix/space (varicose
      vein proteomics). Consistent with the secreted prosaposin form; non-core location.
    action: KEEP_AS_NON_CORE
    reason: Valid proteomics-based extracellular detection; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:20551380
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of prosaposin in the extracellular space of human aorta.
      Consistent with the secreted prosaposin form; non-core location.
    action: KEEP_AS_NON_CORE
    reason: Valid proteomics-based extracellular detection; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: ISS
  original_reference_id: PMID:22261194
  qualifier: located_in
  review:
    summary: Extracellular region assigned by sequence-similarity from a porcine cardiac ECM proteomics
      dataset (ortholog F1SU97). Consistent with secreted prosaposin; non-core.
    action: KEEP_AS_NON_CORE
    reason: Ortholog-based extracellular localization consistent with the secreted form; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:1454804
  qualifier: located_in
  review:
    summary: Prosaposin is described as existing as a secretory protein (and as an integral membrane
      protein), directly supporting its extracellular localization. Non-core relative to the lysosome.
    action: KEEP_AS_NON_CORE
    reason: Direct evidence for the secreted prosaposin form; non-core localization.
    supported_by:
    - reference_id: PMID:1454804
      supporting_text: Prosaposin exists as a
        secretory protein and as an integral membrane protein
- term:
    id: GO:1905572
    label: ganglioside GM1 transport to membrane
  evidence_type: IDA
  original_reference_id: PMID:1454804
  qualifier: involved_in
  review:
    summary: Prosaposin and saposins transferred gangliosides (including GM1) from donor liposomes to
      acceptor membranes, directly demonstrating ganglioside transport activity. This lipid-transfer
      function underlies the activator role (presenting glycosphingolipids to hydrolases).
    action: ACCEPT
    reason: Direct experimental evidence for ganglioside transport between membranes, a specific
      manifestation of the saposin lipid-transfer/presentation function.
    supported_by:
    - reference_id: PMID:1454804
      supporting_text: Prosaposin and saposins transferred gangliosides from donor
        liposomes to erythrocyte ghost membranes
- term:
    id: GO:1905573
    label: ganglioside GM1 binding
  evidence_type: IDA
  original_reference_id: PMID:1454804
  qualifier: enables
  review:
    summary: Prosaposin and saposins formed stable complexes with multiple gangliosides, including the
      gangliotetraose (a-series) gangliosides such as GM1, demonstrating direct ganglioside binding.
    action: ACCEPT
    reason: Direct experimental binding of GM1-type gangliosides, consistent with the lipid-binding
      activator function.
    supported_by:
    - reference_id: PMID:1454804
      supporting_text: formed stable complexes with 13 different gangliosides
- term:
    id: GO:1905574
    label: ganglioside GM2 binding
  evidence_type: IDA
  original_reference_id: PMID:1454804
  qualifier: enables
  review:
    summary: Ganglioside binding assay showing stable complex formation with a panel of 13 gangliosides,
      supporting direct binding of GM2-type gangliosides.
    action: ACCEPT
    reason: Direct experimental ganglioside binding; consistent with lipid-binding function.
    supported_by:
    - reference_id: PMID:1454804
      supporting_text: formed stable complexes with 13 different gangliosides
- term:
    id: GO:1905575
    label: ganglioside GM3 binding
  evidence_type: IDA
  original_reference_id: PMID:1454804
  qualifier: enables
  review:
    summary: Ganglioside binding assay showing stable complex formation with a panel of 13 gangliosides,
      supporting direct binding of GM3-type gangliosides.
    action: ACCEPT
    reason: Direct experimental ganglioside binding; consistent with lipid-binding function.
    supported_by:
    - reference_id: PMID:1454804
      supporting_text: formed stable complexes with 13 different gangliosides
- term:
    id: GO:1905576
    label: ganglioside GT1b binding
  evidence_type: IDA
  original_reference_id: PMID:1454804
  qualifier: enables
  review:
    summary: Ganglioside binding assay showing stable complex formation with a panel of 13 gangliosides,
      spanning a- and b-series; supports direct binding of GT1b (a b-series ganglioside), reported to bind
      with lower affinity.
    action: ACCEPT
    reason: Direct experimental ganglioside binding; b-series gangliosides bound with lower affinity.
    supported_by:
    - reference_id: PMID:1454804
      supporting_text: b series gangliosides, O-acetylated
        gangliosides, and gangliosides with shorter carbohydrate chains, were bound with
        lower affinity
- term:
    id: GO:1905577
    label: ganglioside GP1c binding
  evidence_type: IDA
  original_reference_id: PMID:1454804
  qualifier: enables
  review:
    summary: Ganglioside binding assay showing stable complex formation with a panel of 13 gangliosides,
      supporting direct binding of GP1c-type gangliosides.
    action: ACCEPT
    reason: Direct experimental ganglioside binding; consistent with lipid-binding function.
    supported_by:
    - reference_id: PMID:1454804
      supporting_text: formed stable complexes with 13 different gangliosides
- term:
    id: GO:0005543
    label: phospholipid binding
  evidence_type: IDA
  original_reference_id: PMID:14674747
  qualifier: enables
  review:
    summary: Saposin C binds phospholipid vesicles/membranes in a pH-dependent, reversible manner (NMR
      study), directly demonstrating phospholipid binding. Membrane binding is essential for saposin C to
      activate lysosomal lipid degradation.
    action: ACCEPT
    reason: Direct experimental evidence for saposin C phospholipid/membrane binding, integral to the
      activator/lipid-transfer function.
    supported_by:
    - reference_id: PMID:14674747
      supporting_text: the binding of saposin C to phospholipid vesicles is a
        pH-controlled reversible process
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:18462685
  qualifier: enables
  review:
    summary: Crystal structures show saposin C forming domain-swapped homodimers and saposin D forming a
      defined homodimer (confirmed in solution), directly supporting protein homodimerization activity.
      Saposin B likewise functions as a homodimer.
    action: ACCEPT
    reason: Direct structural evidence for saposin homodimerization; consistent with the functional
      dimeric lipid-binding shells of the saposins.
    supported_by:
    - reference_id: PMID:18462685
      supporting_text: two crystal structures of human saposin C in an
        "open" configuration with unusual domain swapped homodimers
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22431521
  qualifier: enables
  review:
    summary: Bare protein binding IPI reflecting the prosaposin-sortilin (SORT1) interaction examined in
      the CLN5/endosomal-sorting study; unlike prosaposin, CLN5 does not require sortilin for lysosomal
      localization. The generic term is uninformative, though the underlying PSAP-sortilin interaction is
      real and relevant to lysosomal targeting.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare protein binding term; the biologically meaningful PSAP-SORT1 interaction
      (lysosomal targeting) is documented in UniProt SUBUNIT and better captured functionally elsewhere.
    supported_by:
    - reference_id: PMID:22431521
      supporting_text: CLN5, unlike prosaposin, does not require sortilin to localize to the
        lysosomal compartment
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IDA
  original_reference_id: PMID:22431521
  qualifier: located_in
  review:
    summary: Prosaposin is used as a sortilin-dependent lysosomal cargo in this study; its lysosomal
      localization is directly observed. Confirms the core lysosomal localization.
    action: ACCEPT
    reason: Experimental confirmation of core lysosomal localization.
    supported_by:
    - reference_id: PMID:22431521
      supporting_text: CLN5, unlike prosaposin, does not require sortilin to localize to the
        lysosomal compartment
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798739
  qualifier: located_in
  review:
    summary: Plasma membrane localization from a Reactome neutrophil-degranulation (azurophil granule
      exocytosis) reaction. Reflects transient association during secretion of granule contents rather than
      a stable functional plasma-membrane pool.
    action: KEEP_AS_NON_CORE
    reason: Reactome degranulation pathway localization; peripheral/transient, non-core.
- term:
    id: GO:0035577
    label: azurophil granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798739
  qualifier: located_in
  review:
    summary: Azurophil granule membrane localization from a Reactome neutrophil-degranulation reaction,
      reflecting prosaposin cargo in neutrophil secretory granules. Non-core.
    action: KEEP_AS_NON_CORE
    reason: Neutrophil granule localization from the degranulation pathway; non-core.
- term:
    id: GO:0010506
    label: regulation of autophagy
  evidence_type: TAS
  original_reference_id: PMID:22949512
  qualifier: involved_in
  review:
    summary: In saposin C-deficient fibroblasts, autophagic degradation is impaired (delayed
      autolysosome degradation, reduced cathepsins B/D). This links PSAP/saposin C to autophagy, but as a
      downstream consequence of impaired lysosomal function rather than a direct autophagy-regulatory role.
    action: KEEP_AS_NON_CORE
    reason: Autophagy phenotype is a secondary consequence of saposin C deficiency and lysosomal
      dysfunction; genuine but indirect and non-core.
    supported_by:
    - reference_id: PMID:22949512
      supporting_text: Reduced cathepsins B and D cause impaired autophagic degradation
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of prosaposin in exosomes (prostatic secretions).
      Consistent with the secreted prosaposin form; non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Proteomics-based exosome detection of the secreted form; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:16502470
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of prosaposin in human colostrum/milk aqueous phase,
      consistent with the secreted prosaposin form (prosaposin is abundant in milk). Non-core.
    action: KEEP_AS_NON_CORE
    reason: Proteomics-based extracellular detection of the secreted form; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-380073
  qualifier: located_in
  review:
    summary: Extracellular region from a Reactome Gi-GPCR signalling reaction, reflecting secreted
      prosaposin acting as an extracellular GPCR ligand (GPR37/GPR37L1). Non-core.
    action: KEEP_AS_NON_CORE
    reason: Extracellular localization tied to the secreted prosaposin GPCR-ligand role; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5336182
  qualifier: located_in
  review:
    summary: Extracellular region from the Reactome reaction GPR37 binds prosaptide, i.e. secreted
      prosaposin/prosaptide engaging its GPCR. Non-core.
    action: KEEP_AS_NON_CORE
    reason: Extracellular localization for the secreted prosaposin GPCR-ligand role; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5336184
  qualifier: located_in
  review:
    summary: Extracellular region from the Reactome reaction GPR37L binds prosaposin, reflecting
      secreted prosaposin engaging GPR37L1. Non-core.
    action: KEEP_AS_NON_CORE
    reason: Extracellular localization for the secreted prosaposin GPCR-ligand role; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-749454
  qualifier: located_in
  review:
    summary: Extracellular region from a Reactome Gi-GPCR complex-dissociation reaction, part of the
      secreted-prosaposin GPCR signalling pathway. Non-core.
    action: KEEP_AS_NON_CORE
    reason: Extracellular localization for the secreted prosaposin GPCR-ligand role; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-749456
  qualifier: located_in
  review:
    summary: Extracellular region from a Reactome ligand-GPCR-Gi binding reaction, part of the secreted
      prosaposin GPCR signalling pathway. Non-core.
    action: KEEP_AS_NON_CORE
    reason: Extracellular localization for the secreted prosaposin GPCR-ligand role; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of prosaposin in urinary exosomes. Consistent with the
      secreted prosaposin form; non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Proteomics-based exosome detection of the secreted form; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20709014
  qualifier: enables
  review:
    summary: Bare protein binding IPI capturing the prosaposin-fibrocystin/polyductin (FPC, PKHD1
      product; P08F94) interaction identified by yeast two-hybrid and confirmed by GST pull-down/co-IP. The
      interaction is real and proposed to modulate cell proliferation/apoptosis, but the generic term is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative bare protein binding term; the specific PSAP-fibrocystin interaction is
      documented but its molecular function for prosaposin is not captured by this generic term. Flagged,
      not removed (experimental IPI).
    supported_by:
    - reference_id: PMID:20709014
      supporting_text: we confirmed the interaction between FPC and prosaposin
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-351341
  qualifier: located_in
  review:
    summary: Extracellular region from the Reactome Exocytosis of Proactivator polypeptide reaction,
      reflecting secretion of prosaposin. Consistent with the secreted form; non-core.
    action: KEEP_AS_NON_CORE
    reason: Extracellular localization from the prosaposin-exocytosis reaction; non-core.
    supported_by:
    - reference_id: file:human/PSAP/PSAP-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: [Prosaposin]: Secreted"
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1605591
  qualifier: located_in
  review:
    summary: Lysosomal membrane localization from the Reactome reaction GBA1:SAPC hydrolyzes GlcCer,
      where saposin C acts at the lysosomal membrane to present glucosylceramide to glucocerebrosidase.
      Consistent with saposin C membrane association during the core activator reaction.
    action: ACCEPT
    reason: Correct - saposin C associates with the lysosomal (intralysosomal) membrane to present
      substrate to GBA1; consistent with the pH-dependent membrane-binding of saposin C.
    supported_by:
    - reference_id: PMID:14674747
      supporting_text: Saposin C binds to membranes to activate lipid degradation in lysosomes
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9840334
  qualifier: located_in
  review:
    summary: Lysosomal membrane localization from the Reactome reaction PSAP is cleaved, reflecting the
      membrane-associated processing/action of prosaposin and saposins in the lysosome. Consistent with the
      lysosomal site of function.
    action: ACCEPT
    reason: Correct lysosomal-membrane localization consistent with the intralysosomal membrane-associated
      saposin function.
    supported_by:
    - reference_id: PMID:14674747
      supporting_text: Saposin C binds to membranes to activate lipid degradation in lysosomes
references:
- id: file:human/PSAP/PSAP-uniprot.txt
  title: UniProtKB P07602 (SAP_HUMAN) prosaposin entry
  findings: []
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF: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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:1454804
  title: Binding and transport of gangliosides by prosaposin.
  findings: []
- id: PMID:14674747
  title: 'Solution structure of human saposin C: pH-dependent interaction with phospholipid
    vesicles.'
  findings: []
- id: PMID:16502470
  title: 'Human colostrum: identification of minor proteins in the aqueous phase by
    proteomics.'
  findings: []
- id: PMID:16713569
  title: A protein-protein interaction network for human inherited ataxias and disorders
    of Purkinje cell degeneration.
  findings: []
- id: PMID:18462685
  title: 'Crystal structures of human saposins C andD: implications for lipid recognition
    and membrane interactions.'
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:20551380
  title: Proteomics characterization of extracellular space components in the human
    aorta.
  findings: []
- id: PMID:20709014
  title: Regulation of cell proliferation and apoptosis through fibrocystin-prosaposin
    interaction.
  findings: []
- id: PMID:22261194
  title: Proteomics analysis of cardiac extracellular matrix remodeling in a porcine
    model of ischemia/reperfusion injury.
  findings: []
- id: PMID:22431521
  title: The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) in endosomal
    sorting.
  findings: []
- id: PMID:22949512
  title: Reduced cathepsins B and D cause impaired autophagic degradation that can
    be almost completely restored by overexpression of these two proteases in Sap
    C-deficient fibroblasts.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
- id: PMID:23555801
  title: BANK1 and BLK act through phospholipase C gamma 2 in B-cell signaling.
  findings: []
  reference_review:
    relevance: NONE
    correctness: MISCITED
    review_notes: Cited as support for a PSAP scaffold protein binding (GO:0097110) annotation, but
      the paper is about BANK1/BLK/PLCg2 in B-cell signalling and does not mention prosaposin, PSAP or
      saposins anywhere in the cached full text. The annotation cannot be verified from this reference
      and is likely a citation/interactor mismatch; the associated annotation is marked over-annotated.
- id: PMID:24872419
  title: 'Mesotrypsin and caspase-14 participate in prosaposin processing: potential
    relevance to epidermal permeability barrier formation.'
  findings: []
- id: PMID:26370502
  title: Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin.
  findings: []
- id: PMID:27068509
  title: 'Extracellular matrix remodelling in response to venous hypertension: proteomics
    of human varicose veins.'
  findings: []
- id: PMID:27356620
  title: Prosaposin is a regulator of progranulin levels and oligomerization.
  findings: []
- id: PMID:27559042
  title: Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in
    Human Atrial Fibrillation.
  findings: []
- id: PMID:28541286
  title: Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration
    due to progranulin mutations.
  findings: []
- id: PMID:28835281
  title: Lysosomal processing of progranulin.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: Reactome:R-HSA-1605591
  title: GBA1:SAPC hydrolyzes GlcCer
  findings: []
- id: Reactome:R-HSA-1605624
  title: Beta-galactosidases hydrolyse mobilized GM1 to mobilized GM2
  findings: []
- id: Reactome:R-HSA-1605632
  title: bHEXA,bHEXB hydrolyze PSAP(195-273):Gb4Cer:PE
  findings: []
- id: Reactome:R-HSA-1605724
  title: NEU1,4 hydrolyze PSAP(195-273):GM3:PE
  findings: []
- id: Reactome:R-HSA-1605736
  title: GLA hydrolyzes PSAP(195-273):Gb3Cer:PE
  findings: []
- id: Reactome:R-HSA-1606312
  title: GLB1 hydrolyzes SapB/C:LacCer
  findings: []
- id: Reactome:R-HSA-1606807
  title: ARSA removes sulfate from PSAP(195-273):Sulfatide
  findings: []
- id: Reactome:R-HSA-351341
  title: Exocytosis of Proactivator polypeptide
  findings: []
- id: Reactome:R-HSA-380073
  title: Liganded Gi-activating GPCR acts as a GEF for Gi
  findings: []
- id: Reactome:R-HSA-5336182
  title: GPR37 binds prosaptide
  findings: []
- id: Reactome:R-HSA-5336184
  title: GPR37L binds prosaposin
  findings: []
- id: Reactome:R-HSA-6798739
  title: Exocytosis of azurophil granule membrane proteins
  findings: []
- id: Reactome:R-HSA-749454
  title: The Ligand:GPCR:Gi complex dissociates
  findings: []
- id: Reactome:R-HSA-749456
  title: Liganded Gi-activating GPCRs bind inactive heterotrimeric G-protein Gi
  findings: []
- id: Reactome:R-HSA-9840334
  title: PSAP is cleaved
  findings: []
- id: Reactome:R-HSA-9840470
  title: PSAP(195-273) dimer:PE binds and mobilizes ligands
  findings: []
- id: Reactome:R-HSA-9840488
  title: PSAP(195-273) forms a dimer
  findings: []
- id: Reactome:R-HSA-9841189
  title: GLA hydrolyzes PSAP(195-273):Gal2Cer:PE
  findings: []
- id: Reactome:R-HSA-9842115
  title: PSAP(195-273) dimer binds PE
  findings: []
core_functions:
- description: As the precursor of saposins A-D, prosaposin provides non-enzymatic sphingolipid-activator
    protein cofactors that stimulate lysosomal sphingolipid-degrading hydrolases (galactosylceramidase,
    arylsulfatase A, beta-galactosidase, alpha-galactosidase A, acid beta-glucosylceramidase, acid
    ceramidase and sphingomyelinase), driving glycosphingolipid catabolism in the lysosome.
  molecular_function:
    id: GO:0030290
    label: sphingolipid activator protein activity
  directly_involved_in:
  - id: GO:0046479
    label: glycosphingolipid catabolic process
  locations:
  - id: GO:0005764
    label: lysosome
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: file:human/PSAP/PSAP-uniprot.txt
    supporting_text: Saposins are specific low-molecular mass non-enzymatic
      glycoproteins that act as activator proteins for lysosomal
      sphingolipid-degrading enzymes
- description: The saposins act as lipid-binding/lipid-transfer proteins that extract or solubilise
    membrane glycosphingolipids (including gangliosides and sulfatide) and phospholipids and present them
    to their cognate acid hydrolases, enabling sphingolipid catabolism in the lysosome.
  molecular_function:
    id: GO:0008289
    label: lipid binding
  directly_involved_in:
  - id: GO:0030149
    label: sphingolipid catabolic process
  locations:
  - id: GO:0005764
    label: lysosome
  - id: GO:0043202
    label: lysosomal lumen
  supported_by:
  - reference_id: file:human/PSAP/PSAP-uniprot.txt
    supporting_text: extracting lipid substrates from membranes and
      presenting them to their respective enzymes
  - reference_id: PMID:1454804
    supporting_text: Prosaposin and saposins transferred gangliosides from donor
      liposomes to erythrocyte ghost membranes