SPNS1 is a multi-pass lysosomal membrane protein in the major facilitator superfamily and Spinster family. Its core function is proton-gradient-dependent export of lysophospholipids, especially lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), from the lysosomal lumen to the cytosol. The exported lysophospholipids are reused in phospholipid salvage pathways and can support phosphatidylcholine synthesis, neutral-lipid storage, cholesterol homeostasis, and survival under nutrient limitation. SPNS1 deficiency causes lysosomal accumulation of LPC/LPE and related lysolipids, perturbs lysosomal function and lipid homeostasis, and is now linked to human multiorgan disease caused by biallelic loss-of-function variants.
Definition: Enables the coupled transfer of a lysophospholipid and a proton from one side of a membrane to the other, driven by the transmembrane proton gradient.
Justification: The current closest GO molecular-function term for SPNS1 is GO:0051978 lysophospholipid:sodium symporter activity, but SPNS1 is repeatedly described experimentally as proton dependent, not sodium dependent.
Parent term: solute:proton symporter activity
Supporting Evidence:
Definition: The directed movement of lysophospholipids from the lysosomal lumen across the lysosomal membrane to the cytosol.
Justification: Existing GO terms capture lysophospholipid transport and broad lysosomal transport, but do not represent the specific lysosomal export/salvage process established for SPNS1.
Parent term: lysophospholipid transport
Mappings:
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0022857 transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: SPNS1 is a transmembrane transporter, and the broad term is accurate for the currently supported lysosomal lysophospholipid export activity. Reason: Retain the broad transporter term rather than replacing it with GO:0051978, whose sodium-coupled label does not match the proton-gradient-dependent SPNS1 evidence. A proton-specific lysophospholipid symporter term is requested below. Supporting Evidence: PMID:36161949 the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter PMID:39739806 Spns1 mediates the rate-limiting efflux of lysophospholipids from the lysosome to the cytosol |
| GO:0051977 lysophospholipid transport | IBA GO_REF:0000033 | ACCEPT | Summary: This is a core SPNS1 biological process. SPNS1 exports lysosomal LPC and LPE to the cytosol, and loss of SPNS1 causes lysosomal accumulation of these lysophospholipids. Reason: The process accurately captures the conserved cargo-level biology, even though a more precise lysosomal export term would be preferable. Supporting Evidence: PMID:36161949 Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species PMID:37075117 leads to intralysosomal accumulation of lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). |
| GO:0033700 phospholipid efflux | IBA GO_REF:0000033 | ACCEPT | Summary: SPNS1 mediates efflux of lysosomal lysophospholipids that derive from lysosomal phospholipid degradation. These products are exported to the cytosol for re-acylation and broader lipid salvage. Reason: Although the transported substrates are lysophospholipids rather than intact phospholipids, the term is a reasonable process-level description of lysosomal phospholipid catabolite efflux and salvage. Supporting Evidence: PMID:36161949 Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner PMID:40608416 SPNS1 is a lysosomal transporter that mediates the salvage of lysoglycerophospholipids |
| GO:0016020 membrane | IBA GO_REF:0000033 | MODIFY | Summary: SPNS1 is a multi-pass membrane transporter, but generic membrane is too broad. The experimentally and physiologically relevant active location is the lysosomal membrane. Reason: Replace the generic membrane term with the specific lysosomal membrane localization. Proposed replacements: lysosomal membrane Supporting Evidence: file:human/SPNS1/SPNS1-uniprot.txt SUBCELLULAR LOCATION: Lysosome membrane PMID:39739806 While Spns1 primarily localizes to the lysosomal membrane to export its substrates from lysosomal lumen under physiological conditions |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Early HSpin1 work and UniProt note occasional mitochondrial localization, but later biochemical and structural work establishes lysosomal membrane transport as the dominant SPNS1 function. Reason: Keep as a possible non-core/overexpression-associated localization rather than treating it as a defining location for SPNS1 activity. Supporting Evidence: file:human/SPNS1/SPNS1-uniprot.txt Mitochondrion inner membrane {ECO:0000269|PubMed:12815463}; Multi-pass membrane protein {ECO:0000269|PubMed:12815463}. Note=Ocassionally localizes to mitochondria. |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Lysosomal membrane is the core active location for SPNS1. Transport assays, lysosome lipidomics, human disease work, and structural analyses all interpret SPNS1 as a lysosomal membrane lysophospholipid transporter. Reason: Core localization for the lysosomal efflux function. Supporting Evidence: file:human/SPNS1/SPNS1-uniprot.txt SUBCELLULAR LOCATION: Lysosome membrane PMID:40608416 SPNS1, a ubiquitously expressed lysosomal transmembrane protein belonging to the major facilitator superfamily |
| GO:0006869 lipid transport | IEA GO_REF:0000117 | MODIFY | Summary: SPNS1 is involved in lipid transport, but the reviewed literature defines the more specific process as lysosomal lysophospholipid transport and phospholipid-catabolite efflux. Reason: The broad lipid transport term should be replaced by more informative lysophospholipid transport and phospholipid efflux terms. Proposed replacements: lysophospholipid transport phospholipid efflux Supporting Evidence: PMID:36161949 Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 |
| GO:0022857 transmembrane transporter activity | IEA GO_REF:0000002 | ACCEPT | Summary: The InterPro-derived transporter annotation is broad but accurate for SPNS1 lysosomal lysophospholipid export activity. Reason: Retain the broad transporter term rather than replacing it with GO:0051978, whose sodium-coupled label does not match the proton-gradient-dependent SPNS1 evidence. A proton-specific lysophospholipid symporter term is requested below. Supporting Evidence: PMID:39739806 Our results reveal molecular insights into lysosomal LPC transport and the proton-sensing mechanism by Spns1. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: SPNS1 mediates transmembrane movement, but the specific process is lysosomal lysophospholipid export/salvage. Reason: Replace the broad transmembrane transport term with the specific lysophospholipid transport process. Proposed replacements: lysophospholipid transport Supporting Evidence: PMID:37075117 SPNS1 functions to export LPC species from the lysosomal lumen to the cytosol for reacylation to PC |
| GO:0005515 protein binding | IPI PMID:12815463 HSpin1, a transmembrane protein interacting with Bcl-2/Bcl-x... | MARK AS OVER ANNOTATED | Summary: The early HSpin1 study reported interaction with BCL2 and BCL2L1, but GO:0005515 is uninformative and does not describe SPNS1's core molecular function. Reason: Avoid protein binding as a retained functional annotation. The interaction may be valid as interaction data, but it should not define SPNS1 function. Supporting Evidence: PMID:12815463 HSpin1 bound to Bcl-2 and apoptosis regulator Bcl-X (Bcl-xL) |
| GO:0005764 lysosome | IEA GO_REF:0000107 | ACCEPT | Summary: SPNS1 acts in lysosomes as a lysophospholipid exporter. This orthology transfer is consistent with direct human and model-organism evidence. Reason: Core active cellular location. Supporting Evidence: PMID:36161949 The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. PMID:40608416 SPNS1 is a lysosomal transporter that mediates the salvage of lysoglycerophospholipids |
| GO:0051977 lysophospholipid transport | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology-based lysophospholipid transport is directly supported by human SPNS1 transport assays, lysosome flux experiments, and disease variant studies. Reason: Core biological process. Supporting Evidence: PMID:36161949 Taken together, these data indicate that endogenous Spns1 mediates the transport of LPCs and LPEs out of lysosomes PMID:40608416 lysophospholipids transported by SPNS1 into the cytosol quantitatively contributed to triglyceride synthesis |
| GO:0005764 lysosome | IDA PMID:36161949 Spns1 is a lysophospholipid transporter mediating lysosomal ... | ACCEPT | Summary: The 2022 PNAS study directly investigated SPNS1 function in lysosomes and isolated lysosome-enriched fractions showing substrate accumulation in SPNS1-deficient cells. Reason: Core active location. Supporting Evidence: PMID:36161949 Lysosomes isolated from [14C]-choline-labeled Spns1 KO cells showed accumulation of [14C]-LPC |
| GO:0051977 lysophospholipid transport | IDA PMID:36161949 Spns1 is a lysophospholipid transporter mediating lysosomal ... | ACCEPT | Summary: This is one of the central conclusions of the 2022 PNAS study. SPNS1 transports LPC and LPE out of lysosomes and enables their reuse in phospholipid pools. Reason: Core biological process supported by direct assays and flux data. Supporting Evidence: PMID:36161949 data from our flux analysis support the conclusion that LPCs are transported out of lysosomes by Spns1 and re-acylated into PC pools |
| GO:0051978 lysophospholipid:sodium symporter activity | IDA PMID:36161949 Spns1 is a lysophospholipid transporter mediating lysosomal ... | MODIFY | Summary: This term captures lysophospholipid transport, but its sodium-symporter label is mechanistically incorrect for SPNS1 because SPNS1 is proton-gradient dependent. Reason: Replace with the broad transmembrane transporter activity term pending a proton-specific lysophospholipid symporter term, which is requested below. Proposed replacements: transmembrane transporter activity Supporting Evidence: PMID:36161949 The uptake of [14C]-LPC-oleate by Spns1 was concentration dependent and saturable, with a pH optimum between pH 5.0 and 6.0 PMID:39739806 we identify a five-residue network that is crucial for proton-sensing by Spns1 |
| GO:0005764 lysosome | IDA PMID:25365221 Spastic paraplegia proteins spastizin and spatacsin mediate ... | ACCEPT | Summary: The seeded original reference is an autophagic lysosome reformation paper focused on spastizin and spatacsin rather than direct SPNS1 evidence. Nevertheless, lysosomal localization of SPNS1 is strongly supported by later direct SPNS1 studies and UniProt. Reason: Accept the term because it is correct, while noting that PMID:25365221 is not the best primary evidence for SPNS1 itself. Supporting Evidence: file:human/SPNS1/SPNS1-uniprot.txt SUBCELLULAR LOCATION: Lysosome membrane PMID:39739806 Spns1 is located on the lysosomal membrane and mediates lysophospholipid efflux depending on the proton gradient |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | ACCEPT | Summary: High-throughput lysosomal membrane proteomics is consistent with the established SPNS1 lysosomal membrane localization, but the direct transporter papers are stronger support. Reason: Accurate cellular component annotation consistent with core function. Supporting Evidence: PMID:17897319 We searched for novel proteins in lysosomal membranes, tentatively participating in molecular transport across the membrane file:human/SPNS1/SPNS1-uniprot.txt SUBCELLULAR LOCATION: Lysosome membrane |
| GO:0007041 lysosomal transport | IDA PMID:36161949 Spns1 is a lysophospholipid transporter mediating lysosomal ... | NEW | Summary: Proposed new annotation from the Proteostasis Network context. SPNS1 exports lysosomal degradation products across the lysosomal membrane, placing its specific lysophospholipid salvage activity within the broader process of lysosomal transport. Reason: GOA already captures lysophospholipid transport and phospholipid efflux, but not the broader lysosomal-transport context highlighted by the PN entry. This should be added conservatively as a broad process annotation; a more precise lysosomal lysophospholipid export term would be better. Supporting Evidence: PMID:36161949 Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 PMID:37075117 SPNS1 functions to export LPC species from the lysosomal lumen to the cytosol for reacylation to PC file:human/SPNS1/SPNS1-notes.md The Proteostasis Network places SPNS1 under `Autophagy-Lysosome Pathway|Autophagic lysosome reformation|Efflux of autophagy products`. |
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Download this section (compressed HTML)Q: Should GO:0051978 be renamed or should a proton-dependent lysophospholipid symporter child term be added for SPNS1-like lysosomal transporters?
Suggested experts: David L. Silver, Li X
Q: Should SPNS1 receive a broad GO:0007041 lysosomal transport annotation now, or should curation wait for a more precise lysosomal lysophospholipid export biological-process term?
Suggested experts: Menglan He, Susanna G. Scharenberg
Q: How much of SPNS1-associated disease is driven by lysophospholipid salvage, ether-lysophospholipid/plasmalogen salvage, cholesterol egress, or secondary autophagy defects in specific tissues?
Suggested experts: Menglan He, David L. Silver
Experiment: Reconstitute purified human SPNS1 into proteoliposomes with controlled proton and sodium gradients and measure transport of LPC, LPE, LPG, and lysoplasmalogen substrates.
Hypothesis: SPNS1 is a lysophospholipid:proton symporter rather than a sodium-coupled lysophospholipid transporter.
Type: transport_reconstitution
Experiment: Use autophagy-induced lysosomal cargo flux assays in SPNS1 knockout and rescue cells to measure export of autolysosome-derived lysophospholipids after starvation and recovery.
Hypothesis: SPNS1 mediates lysosomal export of autophagy-derived lysophospholipid catabolites during lysosome recovery and lipid salvage.
Type: lipidomics/genetic_rescue
Experiment: Compare wild-type SPNS1, disease variants, and transport-site mutants for lysosomal LPC/LPE accumulation, cholesterol egress, triglyceride synthesis, and autophagy markers under mTOR inhibition.
Hypothesis: Disease variants cause partial loss of lysosomal lysophospholipid export that secondarily disrupts cholesterol egress and nutrient-stress lipid storage.
Type: disease_variant_functional_assay
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