ArticleCell death and differentiation2015
Stress-induced ceramide generation and apoptosis via the phosphorylation and activation of nSMase1 by JNK signaling.
Article in Cell death and differentiation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 116 citations in OpenAlex.
- Lipidomic Analysis of Human Plasma and Hippocampus Across Alzheimer's Progression and Preclinical 5xFAD Mouse Model.Molecular neurobiology · 2026Article
- Sphingolipids in Emotional Well-Being.Journal of neurochemistry · 2026Review
- Ceramide as a Biomarker for HFpEF in Women: Menopause, Aging, and Pregnancy.International journal of molecular sciences · 2025Review
- Glycolytic Enzyme HK2 Phosphorylates nSMase1 to Promote Astrocytic Exosomes Biogenesis Contributing to Acute Ischemic Stroke Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- SMPD2 affects the prognosis of cancer patients by mediating lipid metabolism and the immune microenvironment.Discover oncology · 2025Article
- Artesunate Nanoplatform Targets the Serine-MAPK Axis in Cancer-Associated Fibroblasts to Reverse Photothermal Resistance in Triple-Negative Breast Cancer.Advanced materials (Deerfield Beach, Fla.) · 2025Article
- Clicking viruses-with chemistry toward mechanisms in infection.Journal of virology · 2025Review
- Glucosylceramide Synthase, a Key Enzyme in Sphingolipid Metabolism, Regulates Expression of Genes Accounting for Cancer Drug Resistance.International journal of molecular sciences · 2025Article
- Heat Acclimation Enhances Brain Resilience to Acute Thermal Stress inAnimals : an open access journal from MDPI · 2025Article
- The Ceramide-Dependent EV Secretome Differentially Affects Prostate Cancer Cell Migration.Cells · 2025Article
- Increased acid sphingomyelinase levels in saliva as oral mucositis severity predictors.Frontiers in oncology · 2025Article
- Exploring the role and therapeutic potential of lipid metabolism in acute kidney injury.Renal failure · 2024Review
- Radiotherapy-associated Sensorineural Hearing Loss in Pediatric Oncology Patients.Current medicinal chemistry · 2024Review
- Molecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2).Nature communications · 2023Article
- Review
- Article
- HILPDA promotes NASH-driven HCC development by restraining intracellular fatty acid flux in hypoxia.Journal of hepatology · 2023Article
- The relationship among amyloid-β deposition, sphingomyelin level, and the expression and function of P-glycoprotein in Alzheimer's disease pathological process.Neural regeneration research · 2023Article
- Zebra-Sphinx: Modeling Sphingolipidoses in Zebrafish.International journal of molecular sciences · 2023Review
- Sphingolipid metabolism and its relationship with cardiovascular, renal and metabolic diseases.Archivos de cardiologia de Mexico · 2023Review
6 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neutral sphingomyelinase (nSMase) activation in response to environmental stress or inflammatory cytokine stimuli generates the second messenger ceramide, which mediates the stress-induced apoptosis. However, the signaling pathways and activation mechanism underlying this process have yet to be elucidated. Here we show that the phosphorylation of nSMase1 (sphingomyelin phosphodiesterase 2, SMPD2) by c-Jun N-terminal kinase (JNK) signaling stimulates ceramide generation and apoptosis and provide evidence for a signaling mechanism that integrates stress- and cytokine-activated apoptosis in vertebrate cells. An nSMase1 was identified as a JNK substrate, and the phosphorylation site responsible for its effects on stress and cytokine induction was Ser-270. In zebrafish cells, the substitution of Ser-270 for alanine blocked the phosphorylation and activation of nSMase1, whereas the substitution of Ser-270 for negatively charged glutamic acid mimicked the effect of phosphorylation. The JNK inhibitor SP600125 blocked the phosphorylation and activation of nSMase1, which in turn blocked ceramide signaling and apoptosis. A variety of stress conditions, including heat shock, UV exposure, hydrogen peroxide treatment, and anti-Fas antibody stimulation, led to the phosphorylation of nSMase1, activated nSMase1, and induced ceramide generation and apoptosis in zebrafish embryonic ZE and human Jurkat T cells. In addition, the depletion of MAPK8/9 or SMPD2 by RNAi knockdown decreased ceramide generation and stress- and cytokine-induced apoptosis in Jurkat cells. Therefore the phosphorylation of nSMase1 is a pivotal step in JNK signaling, which leads to ceramide generation and apoptosis under stress conditions and in response to cytokine stimulation. nSMase1 has a common central role in ceramide signaling during the stress and cytokine responses and apoptosis.
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