id: Q9H2V7 gene_symbol: SPNS1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- 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. alternative_products: - name: '1' id: Q9H2V7-1 - name: '2' id: Q9H2V7-2 sequence_note: VSP_028196 - name: 3 (CRA_d) id: Q9H2V7-3 sequence_note: VSP_028195, VSP_028196 - name: '4' id: Q9H2V7-4 sequence_note: VSP_028194 - name: '5' id: Q9H2V7-5 sequence_note: VSP_036389 existing_annotations: - term: id: GO:0022857 label: transmembrane transporter activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: >- SPNS1 is a transmembrane transporter, and the broad term is accurate for the currently supported lysosomal lysophospholipid export activity. action: ACCEPT 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. supported_by: - reference_id: PMID:36161949 supporting_text: >- the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter - reference_id: PMID:39739806 supporting_text: >- Spns1 mediates the rate-limiting efflux of lysophospholipids from the lysosome to the cytosol - term: id: GO:0051977 label: lysophospholipid transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: ACCEPT reason: >- The process accurately captures the conserved cargo-level biology, even though a more precise lysosomal export term would be preferable. supported_by: - reference_id: PMID:36161949 supporting_text: >- Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species - reference_id: PMID:37075117 supporting_text: >- leads to intralysosomal accumulation of lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). - term: id: GO:0033700 label: phospholipid efflux evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: ACCEPT 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. supported_by: - reference_id: PMID:36161949 supporting_text: >- 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 - reference_id: PMID:40608416 supporting_text: >- SPNS1 is a lysosomal transporter that mediates the salvage of lysoglycerophospholipids - term: id: GO:0016020 label: membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: 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. action: MODIFY reason: >- Replace the generic membrane term with the specific lysosomal membrane localization. proposed_replacement_terms: - id: GO:0005765 label: lysosomal membrane supported_by: - reference_id: file:human/SPNS1/SPNS1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Lysosome membrane' - reference_id: PMID:39739806 supporting_text: >- While Spns1 primarily localizes to the lysosomal membrane to export its substrates from lysosomal lumen under physiological conditions - term: id: GO:0005743 label: mitochondrial inner membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: 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. action: KEEP_AS_NON_CORE reason: >- Keep as a possible non-core/overexpression-associated localization rather than treating it as a defining location for SPNS1 activity. supported_by: - reference_id: file:human/SPNS1/SPNS1-uniprot.txt supporting_text: >- Mitochondrion inner membrane {ECO:0000269|PubMed:12815463}; Multi-pass membrane protein {ECO:0000269|PubMed:12815463}. Note=Ocassionally localizes to mitochondria. - term: id: GO:0005765 label: lysosomal membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: 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. action: ACCEPT reason: Core localization for the lysosomal efflux function. supported_by: - reference_id: file:human/SPNS1/SPNS1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Lysosome membrane' - reference_id: PMID:40608416 supporting_text: >- SPNS1, a ubiquitously expressed lysosomal transmembrane protein belonging to the major facilitator superfamily - term: id: GO:0006869 label: lipid transport evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: >- SPNS1 is involved in lipid transport, but the reviewed literature defines the more specific process as lysosomal lysophospholipid transport and phospholipid-catabolite efflux. action: MODIFY reason: >- The broad lipid transport term should be replaced by more informative lysophospholipid transport and phospholipid efflux terms. proposed_replacement_terms: - id: GO:0051977 label: lysophospholipid transport - id: GO:0033700 label: phospholipid efflux supported_by: - reference_id: PMID:36161949 supporting_text: >- Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 - term: id: GO:0022857 label: transmembrane transporter activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: >- The InterPro-derived transporter annotation is broad but accurate for SPNS1 lysosomal lysophospholipid export activity. action: ACCEPT 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. supported_by: - reference_id: PMID:39739806 supporting_text: >- Our results reveal molecular insights into lysosomal LPC transport and the proton-sensing mechanism by Spns1. - term: id: GO:0055085 label: transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: >- SPNS1 mediates transmembrane movement, but the specific process is lysosomal lysophospholipid export/salvage. action: MODIFY reason: >- Replace the broad transmembrane transport term with the specific lysophospholipid transport process. proposed_replacement_terms: - id: GO:0051977 label: lysophospholipid transport supported_by: - reference_id: PMID:37075117 supporting_text: >- SPNS1 functions to export LPC species from the lysosomal lumen to the cytosol for reacylation to PC - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12815463 qualifier: enables review: 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. action: MARK_AS_OVER_ANNOTATED reason: >- Avoid protein binding as a retained functional annotation. The interaction may be valid as interaction data, but it should not define SPNS1 function. supported_by: - reference_id: PMID:12815463 supporting_text: >- HSpin1 bound to Bcl-2 and apoptosis regulator Bcl-X (Bcl-xL) - term: id: GO:0005764 label: lysosome evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: >- SPNS1 acts in lysosomes as a lysophospholipid exporter. This orthology transfer is consistent with direct human and model-organism evidence. action: ACCEPT reason: Core active cellular location. supported_by: - reference_id: PMID:36161949 supporting_text: >- The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. - reference_id: PMID:40608416 supporting_text: >- SPNS1 is a lysosomal transporter that mediates the salvage of lysoglycerophospholipids - term: id: GO:0051977 label: lysophospholipid transport evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: >- Orthology-based lysophospholipid transport is directly supported by human SPNS1 transport assays, lysosome flux experiments, and disease variant studies. action: ACCEPT reason: Core biological process. supported_by: - reference_id: PMID:36161949 supporting_text: >- Taken together, these data indicate that endogenous Spns1 mediates the transport of LPCs and LPEs out of lysosomes - reference_id: PMID:40608416 supporting_text: >- lysophospholipids transported by SPNS1 into the cytosol quantitatively contributed to triglyceride synthesis - term: id: GO:0005764 label: lysosome evidence_type: IDA original_reference_id: PMID:36161949 qualifier: is_active_in review: summary: >- The 2022 PNAS study directly investigated SPNS1 function in lysosomes and isolated lysosome-enriched fractions showing substrate accumulation in SPNS1-deficient cells. action: ACCEPT reason: Core active location. supported_by: - reference_id: PMID:36161949 supporting_text: >- Lysosomes isolated from [14C]-choline-labeled Spns1 KO cells showed accumulation of [14C]-LPC - term: id: GO:0051977 label: lysophospholipid transport evidence_type: IDA original_reference_id: PMID:36161949 qualifier: involved_in review: 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. action: ACCEPT reason: Core biological process supported by direct assays and flux data. supported_by: - reference_id: PMID:36161949 supporting_text: >- data from our flux analysis support the conclusion that LPCs are transported out of lysosomes by Spns1 and re-acylated into PC pools - term: id: GO:0051978 label: lysophospholipid:sodium symporter activity evidence_type: IDA original_reference_id: PMID:36161949 qualifier: enables review: summary: >- This term captures lysophospholipid transport, but its sodium-symporter label is mechanistically incorrect for SPNS1 because SPNS1 is proton-gradient dependent. action: MODIFY reason: >- Replace with the broad transmembrane transporter activity term pending a proton-specific lysophospholipid symporter term, which is requested below. proposed_replacement_terms: - id: GO:0022857 label: transmembrane transporter activity supported_by: - reference_id: PMID:36161949 supporting_text: >- The uptake of [14C]-LPC-oleate by Spns1 was concentration dependent and saturable, with a pH optimum between pH 5.0 and 6.0 - reference_id: PMID:39739806 supporting_text: >- we identify a five-residue network that is crucial for proton-sensing by Spns1 - term: id: GO:0005764 label: lysosome evidence_type: IDA original_reference_id: PMID:25365221 qualifier: located_in review: 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. action: ACCEPT reason: >- Accept the term because it is correct, while noting that PMID:25365221 is not the best primary evidence for SPNS1 itself. supported_by: - reference_id: file:human/SPNS1/SPNS1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Lysosome membrane' - reference_id: PMID:39739806 supporting_text: >- Spns1 is located on the lysosomal membrane and mediates lysophospholipid efflux depending on the proton gradient - term: id: GO:0005765 label: lysosomal membrane evidence_type: HDA original_reference_id: PMID:17897319 qualifier: located_in review: summary: >- High-throughput lysosomal membrane proteomics is consistent with the established SPNS1 lysosomal membrane localization, but the direct transporter papers are stronger support. action: ACCEPT reason: Accurate cellular component annotation consistent with core function. supported_by: - reference_id: PMID:17897319 supporting_text: >- We searched for novel proteins in lysosomal membranes, tentatively participating in molecular transport across the membrane - reference_id: file:human/SPNS1/SPNS1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Lysosome membrane' - term: id: GO:0007041 label: lysosomal transport evidence_type: IDA original_reference_id: PMID:36161949 qualifier: involved_in review: 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. action: NEW 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. supported_by: - reference_id: PMID:36161949 supporting_text: >- Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 - reference_id: PMID:37075117 supporting_text: >- SPNS1 functions to export LPC species from the lysosomal lumen to the cytosol for reacylation to PC - reference_id: file:human/SPNS1/SPNS1-notes.md supporting_text: >- The Proteostasis Network places SPNS1 under `Autophagy-Lysosome Pathway|Autophagic lysosome reformation|Efflux of autophagy products`. core_functions: - description: >- Proton-gradient-dependent export of lysophospholipids from the lysosomal lumen to the cytosol. SPNS1 transports LPC and LPE, and also transports LPG and lysoplasmalogen species in reported assays. This lysosomal efflux enables phospholipid salvage through downstream re-acylation and supports lipid homeostasis under nutrient stress. molecular_function: id: GO:0022857 label: transmembrane transporter activity directly_involved_in: - id: GO:0051977 label: lysophospholipid transport - id: GO:0033700 label: phospholipid efflux - id: GO:0007041 label: lysosomal transport locations: - id: GO:0005765 label: lysosomal membrane - id: GO:0005764 label: lysosome supported_by: - reference_id: PMID:36161949 supporting_text: >- major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter - reference_id: PMID:37075117 supporting_text: >- SPNS1 functions to export LPC species from the lysosomal lumen to the cytosol for reacylation to PC - reference_id: PMID:39739806 supporting_text: >- Our results reveal molecular insights into lysosomal LPC transport and the proton-sensing mechanism by Spns1. - reference_id: PMID:40608416 supporting_text: >- lysophospholipids transported by SPNS1 into the cytosol quantitatively contributed to triglyceride synthesis proposed_new_terms: - proposed_name: lysophospholipid:proton symporter activity proposed_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. proposed_parent: id: GO:0015295 label: solute:proton symporter activity supported_by: - reference_id: PMID:36161949 supporting_text: >- The uptake of [14C]-LPC-oleate by Spns1 was concentration dependent and saturable, with a pH optimum between pH 5.0 and 6.0 - reference_id: PMID:39739806 supporting_text: >- we identify a five-residue network that is crucial for proton-sensing by Spns1 - proposed_name: lysosomal lysophospholipid export proposed_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. proposed_parent: id: GO:0051977 label: lysophospholipid transport proposed_mappings: - predicate: skos:relatedMatch target_term: id: GO:0007041 label: lysosomal transport supported_by: - reference_id: PMID:36161949 supporting_text: >- Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 - reference_id: PMID:37075117 supporting_text: >- SPNS1 functions to export LPC species from the lysosomal lumen to the cytosol for reacylation to PC suggested_questions: - question: >- Should GO:0051978 be renamed or should a proton-dependent lysophospholipid symporter child term be added for SPNS1-like lysosomal transporters? experts: - David L. Silver - Li X - question: >- 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? experts: - Menglan He - Susanna G. Scharenberg - question: >- How much of SPNS1-associated disease is driven by lysophospholipid salvage, ether-lysophospholipid/plasmalogen salvage, cholesterol egress, or secondary autophagy defects in specific tissues? experts: - Menglan He - David L. Silver suggested_experiments: - description: >- Reconstitute purified human SPNS1 into proteoliposomes with controlled proton and sodium gradients and measure transport of LPC, LPE, LPG, and lysoplasmalogen substrates. experiment_type: transport_reconstitution hypothesis: >- SPNS1 is a lysophospholipid:proton symporter rather than a sodium-coupled lysophospholipid transporter. - description: >- Use autophagy-induced lysosomal cargo flux assays in SPNS1 knockout and rescue cells to measure export of autolysosome-derived lysophospholipids after starvation and recovery. experiment_type: lipidomics/genetic_rescue hypothesis: >- SPNS1 mediates lysosomal export of autophagy-derived lysophospholipid catabolites during lysosome recovery and lipid salvage. - description: >- 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. experiment_type: disease_variant_functional_assay hypothesis: >- Disease variants cause partial loss of lysosomal lysophospholipid export that secondarily disrupts cholesterol egress and nutrient-stress lipid storage. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:12815463 title: HSpin1, a transmembrane protein interacting with Bcl-2/Bcl-xL, induces a caspase-independent autophagic cell death. findings: [] - id: PMID:17897319 title: Integral and associated lysosomal membrane proteins. findings: [] - id: PMID:25365221 title: Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation. findings: [] - id: PMID:36161949 title: Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage. findings: [] - id: PMID:37075117 title: An SPNS1-dependent lysosomal lipid transport pathway that enables cell survival under choline limitation. findings: [] - id: PMID:39739806 title: Molecular basis of Spns1-mediated lysophospholipid transport from the lysosome. findings: [] - id: PMID:40608416 title: SPNS1 variants cause multiorgan disease and implicate lysophospholipid transport as critical for mTOR-regulated lipid homeostasis. findings: [] - id: file:human/SPNS1/SPNS1-uniprot.txt title: UniProt record for human SPNS1 findings: [] - id: file:human/SPNS1/SPNS1-notes.md title: SPNS1 curation notes findings: [] - id: file:projects/PROTEOSTASIS/mappings/autophagy_lysosome_pathway.yaml title: Proteostasis Network autophagy-lysosome pathway mappings findings: []