ArticleNature communications2023
Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 43 citations in OpenAlex.
- Sphingolipid Metabolism in Obesity: Bidirectional Regulation and Comparative Perspectives on Plant Sphingolipids.Nutrients · 2026Review
- Characterization of novel and recurrentJournal of neuromuscular diseases · 2026Article
- Redirection of sphingolipid metabolism drives cytoskeletal defects in SPLIS and reveals ROCK inhibition as therapy.The Journal of clinical investigation · 2026Article
- ORMDL Proteins Turnover via Proteasome and Autophagy Is Cell-Type Dependent and Tied to Ceramide Homeostasis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Distinct Gene Expression Patterns Reveal the Acclimatization Strategies To High-Salinity Stress in Gills of Mozambique Tilapia (Oreochromis mossambicus).Marine biotechnology (New York, N.Y.) · 2026Article
- Inhibition of de novo ceramide synthesis mitigates alpha-synuclein pathology in a Parkinson's disease mouse model.NPJ Parkinson's disease · 2026Article
- Metabolic licensing at the dendritic cell-NK cells immune synapse in viral asthma exacerbations.Frontiers in immunology · 2026Review
- The individual isoforms of ORMDL, the regulatory subunit of serine palmitoyltransferase, have distinctive sensitivities to ceramide.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2025Article
- Article
- Intricate Regulation of Sphingolipid Biosynthesis: An In-Depth Look Into ORMDL-Mediated Regulation of Serine Palmitoyltransferase.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Sphingolipid synthesis maintains nuclear membrane integrity and genome stability during cell division.The Journal of cell biology · 2025Article
- Cardiovascular dysfunction and altered lysosomal signaling in a murine model of acid sphingomyelinase deficiency.Journal of molecular medicine (Berlin, Germany) · 2025Article
- Cross-Trait Genome-Wide Association Study Identifies Shared Genetic Risk Loci Between COPD and Five Autoimmune Diseases.International journal of chronic obstructive pulmonary disease · 2025Article
- Human genetic defects of sphingolipid synthesis.Journal of inherited metabolic disease · 2025Review
- ER stress in D1-MSNs mediates cocaine-induced behavioral plasticityFrontiers in pharmacology · 2025Article
- The Dsc complex and its role in Golgi quality control.Biochemical Society transactions · 2024Review
- A sphingolipid rheostat controls apoptosis versus apical cell extrusion as alternative tumour-suppressive mechanisms.Cell death & disease · 2024Article
- Innovations in Antifungal Drug Discovery among Cell Envelope Synthesis Enzymes through Structural Insights.Journal of fungi (Basel, Switzerland) · 2024Review
- Fine-tuned protein-lipid interactions in biological membranes: exploration and implications of the ORMDL-ceramide negative feedback loop in the endoplasmic reticulum.Frontiers in cell and developmental biology · 2024Article
- Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.Journal of neuromuscular diseases · 2024Review
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
Abstract
The ORM/ORMDL family proteins function as regulatory subunits of the serine palmitoyltransferase (SPT) complex, which is the initiating and rate-limiting enzyme in sphingolipid biosynthesis. This complex is tightly regulated by cellular sphingolipid levels, but the sphingolipid sensing mechanism is unknown. Here we show that purified human SPT-ORMDL complexes are inhibited by the central sphingolipid metabolite ceramide. We have solved the cryo-EM structure of the SPT-ORMDL3 complex in a ceramide-bound state. Structure-guided mutational analyses reveal the essential function of this ceramide binding site for the suppression of SPT activity. Structural studies indicate that ceramide can induce and lock the N-terminus of ORMDL3 into an inhibitory conformation. Furthermore, we demonstrate that childhood amyotrophic lateral sclerosis (ALS) variants in the SPTLC1 subunit cause impaired ceramide sensing in the SPT-ORMDL3 mutants. Our work elucidates the molecular basis of ceramide sensing by the SPT-ORMDL complex for establishing sphingolipid homeostasis and indicates an important role of impaired ceramide sensing in disease development.
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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.