ArticleJCI insight2024
Lack of SPNS1 results in accumulation of lysolipids and lysosomal storage disease in mouse models.
Article in JCI insight, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 16 citations in OpenAlex.
- Structure and mechanism of human sphingosine-1-phosphate transporter MFSD2B.Nature communications · 2026Article
- Proton-coupled alternating access in a versatile mycobacterial Spns drug transporter.Research square · 2026Article
- Proton-coupled alternating access in a versatile mycobacterial Spns drug transporter.bioRxiv : the preprint server for biology · 2026Article
- LPLAT7 reutilizes unsaturated 1-lysophospholipids formed during lysosomal phospholipid degradation.Journal of lipid research · 2026Article
- Structure and mechanism of human sphingosine-1-phosphate transporter MFSD2B.bioRxiv : the preprint server for biology · 2026Article
- Non-invasive assessment of embryo development and ploidy: morphokinetics predict blastulation, and exploratory metabolomics identifies candidate metabolic signatures for euploidy.Frontiers in cell and developmental biology · 2026Article
- Genome-wide Association Studies of the Pathogenic Sphingosine-1-Phosphate Gene in Ulcerative ColitisEndocrine, metabolic & immune disorders drug targets · 2026Article
- SPNS1 is an essential cellular factor for EV-A71 by acting as a transporter of viral pocket factor.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Enzyme Activity-Based Genome-wide Screening for Modifiers of Lysosomal Glucocerebrosidase Uncovers Candidate Risk Factors for Parkinson's Disease.ACS central science · 2025Article
- Peripheral immune cell-specific genes in Parkinson's disease uncovered by multi-omics with therapeutic implications.NPJ Parkinson's disease · 2025Article
- The SLC-ome of membrane transport: From molecular discovery to physiology and clinical applications.Physiological reviews · 2025Review
- SPNS1 variants cause multiorgan disease and implicate lysophospholipid transport as critical for mTOR-regulated lipid homeostasis.The Journal of clinical investigation · 2025Article
- Molecular basis of Spns1-mediated lysophospholipid transport from the lysosome.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cellular and organismal function of choline metabolism.Nature metabolism · 2025Review
- Spns1 is an iron transporter essential for megalin-dependent endocytosis.American journal of physiology. Renal physiology · 2024Article
- Regulation of cellular and systemic sphingolipid homeostasis.Nature reviews. Molecular cell biology · 2024Review
Corrections and comments
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Authors and funding
18 authors at 5 institutions in 8 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter, functions as a transporter for lysolipids from the lysosome. We generated Spns1-KO cells and mice and employed lipidomic and metabolomic approaches to reveal SPNS1 ligand identity. Global KO of Spns1 caused embryonic lethality between E12.5 and E13.5 and an accumulation of sphingosine, lysophosphatidylcholines (LPC), and lysophosphatidylethanolamines (LPE) in the fetal livers. Similarly, metabolomic analysis of livers from postnatal Spns1-KO mice presented an accumulation of sphingosines and lysoglycerophospholipids including LPC and LPE. Subsequently, biochemical assays showed that SPNS1 is required for LPC and sphingosine release from lysosomes. The accumulation of these lysolipids in the lysosomes of Spns1-KO mice affected liver functions and altered the PI3K/AKT signaling pathway. Furthermore, we identified 3 human siblings with a homozygous variant in the SPNS1 gene. These patients suffer from developmental delay, neurological impairment, intellectual disability, and cerebellar hypoplasia. These results reveal a critical role of SPNS1 as a promiscuous lysolipid transporter in the lysosomes and link its physiological functions with lysosomal storage diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.