ArticleThe Biochemical journal2015
Neutral sphingomyelinase-2 is a redox sensitive enzyme: role of catalytic cysteine residues in regulation of enzymatic activity through changes in oligomeric state.
Article in The Biochemical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Hypertensive stretch regulates endothelial cell inflammation and apoptosis through ceramide metabolism.American journal of physiology. Cell physiology · 2026Article
- Sphingolipid Metabolism in Obesity: Bidirectional Regulation and Comparative Perspectives on Plant Sphingolipids.Nutrients · 2026Review
- Impact of HepG2 Cells Glutathione Depletion on Neutral Sphingomyelinases mRNA Levels and Activity.Current issues in molecular biology · 2023Article
- Cross-Regulation of the Cellular Redox System, Oxygen, and Sphingolipid Signalling.Metabolites · 2023Review
- Increased hepatic interleukin-1, arachidonic acid, and reactive oxygen species mediate the protective potential of peptides shared by gut cysteine peptidases against Schistosoma mansoni infection in mice.PLoS neglected tropical diseases · 2023Article
- Lipid metabolism and Alzheimer's disease: clinical evidence, mechanistic link and therapeutic promise.The FEBS journal · 2023Review
- Stress induces major depressive disorder by a neutral sphingomyelinase 2-mediated accumulation of ceramide-enriched exosomes in the blood plasma.Journal of molecular medicine (Berlin, Germany) · 2022Article
- Neutral sphingomyelinase-2 and cardiometabolic diseases.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2021Review
- Dietary inulin decreases circulating ceramides by suppressing neutral sphingomyelinase expression and activity in mice.Journal of lipid research · 2020Article
- Hyaluronan synthase-2 upregulation protects smpd3-deficient fibroblasts against cell death induced by nutrient deprivation, but not against apoptosis evoked by oxidized LDL.Redox biology · 2015Article
- Ceramides in Alzheimer's Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and Aβ Accumulation.Oxidative medicine and cellular longevity · 2015Review
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Authors and funding
3 authors.
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Abstract
Neutral sphingomyelinase-2 (nSMase-2) is the major sphingomyelinase activated in response to pro-inflammatory cytokines and during oxidative stress. It is a membrane-bound 655 amino acid protein containing 22 cysteine residues. In this study, we expressed recombinant mouse nSMase-2 protein in Escherichia coli, and investigated whether nSMase-2 is a redox sensitive enzyme. Our results demonstrate that nSMase-2 exists as both monomers and multimers that are associated with high and low enzymatic activity respectively. Mutational analysis of nSMase-2 identified within its C-terminal catalytic domain several oxidant-sensitive cysteine residues that were shown to be involved in enzyme oligomerization. Changing Cys(617) to Ser for example is a gain-of-function mutation associated with a decreased propensity for oligomerization. Alternatively, nSMase-2 expression in a bacterial strain that lacks endogenous thioredoxin, Rosetta-gami2, results in increased oligomer formation and lower enzyme activity. Phenotypic rescue was accomplished by treating nSMase-2 lysates with recombinant human thioredoxin. This indicates that nSMase-2 may be a novel substrate for thioredoxin. FRET analysis confirmed the presence of nSMase-2 multimers in mammalian HEK cells and their localization to the plasma membrane. In conclusion, our results identify nSMase-2 as a redox-sensitive enzyme, whose basal activity is influenced by thioredoxin-mediated changes in its oligomeric state.
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