Reduced sphingolipid biosynthesis modulates proteostasis networks to enhance longevity
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE199904 | GEO | 2023/01/01
REPOSITORIES: GEO
Similar Datasets
Project description:Goal: We employed RNA-seq to detect changes in the transcriptome of the yeast Candida albicans in response to the addition of myriocin, a sphingolipid synthesis inhibitor, or caffeine, a drug that blocks the TOR kinase. The effects of the drugs were studied in wild-type cells and in the rtg3 mutant strain.
2019-04-01 | GSE125332 | GEO
Project description:Studies of aging and longevity are revealing how diseases that shorten life can be controlled to improve the quality of life and lifespan itself. Two strategies under intense study to accomplish this goal are rapamycin treatment and calorie restriction. New strategies are being discovered including one that uses low-dose myriocin treatment. Myriocin inhibits the first enzyme in sphingolipid synthesis in all eukaryotes and we showed recently that low-dose myriocin treatment increases yeast lifespan at least in part by down-regulating the sphingolipid-controlled Pkh1/2-Sch9 (ortholog of mammalian S6 kinase) signaling pathway. Here we show that myriocin treatment has global influences and modulates the evolutionarily conserved Snf1/AMPK, PKA and TORC1 signaling pathways to enhance yeast lifespan. These extensive affects of myriocin rival those of rapamycin and calorie restriction. Our studies in yeast along with other studies in mammals reveal the potential of myriocin or related compounds to lower the incidence of age-related diseases in humans. No-myriocin-treated cells and myriocin-treated cells; three biological replicates in each treatment
2014-09-22 | E-GEOD-41362 | biostudies-arrayexpress
Project description:Studies of aging and longevity are revealing how diseases that shorten life can be controlled to improve the quality of life and lifespan itself. Two strategies under intense study to accomplish this goal are rapamycin treatment and calorie restriction. New strategies are being discovered including one that uses low-dose myriocin treatment. Myriocin inhibits the first enzyme in sphingolipid synthesis in all eukaryotes and we showed recently that low-dose myriocin treatment increases yeast lifespan at least in part by down-regulating the sphingolipid-controlled Pkh1/2-Sch9 (ortholog of mammalian S6 kinase) signaling pathway. Here we show that myriocin treatment has global influences and modulates the evolutionarily conserved Snf1/AMPK, PKA and TORC1 signaling pathways to enhance yeast lifespan. These extensive affects of myriocin rival those of rapamycin and calorie restriction. Our studies in yeast along with other studies in mammals reveal the potential of myriocin or related compounds to lower the incidence of age-related diseases in humans.
2014-09-22 | GSE41362 | GEO
Project description:In animals, maternal diet and environment can influence the health of offspring. Whether and how maternal dietary choice impacts the nervous system across multiple generations is not well understood. Here, we show that feeding Caenorhabditis elegans with ursolic acid (UA), a natural plant product, reduces adult-onset neurodegeneration intergenerationally. UA provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate (S1P) - a bioactive sphingolipid. Intestine-to-oocyte S1P transfer is required for intergenerational neuroprotection and is dependent on the RME-2 lipoprotein yolk receptor. S1P acts intergenerationally by upregulating transcription of the acid ceramidase-1 (asah-1) gene in the intestine. Spatially regulating sphingolipid metabolism is critical as inappropriate asah-1 expression in neurons causes developmental axon outgrowth defects. Our results show that sphingolipid homeostasis impacts the development and intergenerational health of the nervous system. The ability of specific lipid metabolites to act as messengers between generations may have broad implications for dietary choice during reproduction.
2023-06-26 | GSE214425 | GEO
Project description:ORMDL proteins are essential negative regulators of the serine palmitoyltransferase (SPT) complex, thereby controlling the rate of de novo sphingolipid synthesis. Although mammalian ORMDL proteins undergo rapid turnover, the mechanisms regulating their stability are not completely understood, with conflicting observations reported across several studies. Here, we combined lipidomics, proteomics, and biochemical assays to investigate the regulation of ORMDL proteins in HEK293 cells and primary mouse bone marrow–derived mast cells (BMMCs). Inhibition of the SPT complex by myriocin or of ceramide synthases by fumonisin B1 (FB1) profoundly altered sphingolipid composition but induced minimal global proteomic changes, while consistently reducing amounts of ORMDL proteins. In contrast, overexpression of a single-chain SPT increased ORMDL proteins levels alongside elevated sphingolipids, an effect abolished by myriocin or FB1 treatment. Loss of ORMDL proteins closely correlated with ceramide depletion and, in HEK293 cells, could be prevented by proteasome inhibition, whereas autophagy had no effect. In BMMCs, both pathways contributed to the regulation of ORMDL proteins, consistent with high basal autophagic activity reflected by elevated LC3-II levels. Mutation of conserved asparagines (N11/N13) in ORMDL3, which mediate ceramide binding and stabilization of the inhibitory conformation, disrupted association with SPTLC1 and SPTLC2, mimicking myriocin-induced complex dissociation, while FB1 had a weaker effect. These findings identify ceramide depletion as the primary trigger for ORMDL proteins degradation in BMMCs and HEK293 cells, and reveal a proteasome-dependent pathway that can be supplemented by autophagy in cell types with high basal autophagic activity.
2026-03-16 | PXD067431 | Pride
Project description:To delineate cellular pathways underlying cell growth in the absence of sphingolipid syntehsis, we performed a genome-wide CRISPRi screen to identify genetic modifiers of myriocin sensitivity in human K562 cells.
2020-07-09 | GSE154045 | GEO
Project description:We sequenced mRNA from three independent pairs of mock and c-SRC transformed mouse embryonic fibroblasts and examined changes in expression of sphingolipid metabolism genes
2013-10-17 | GSE46340 | GEO
Project description:Ectopic lipid deposition and altered mitochondrial dynamics contribute to the development of obesity and insulin resistance. However, the mechanistic link between both processes remains unclear. Here we demonstrate that abrogation of ceramide synthase (CerS)6, which generates C16:0-sphingolipids, but not of the alternative C16:0-sphingolipid synthetizing CerS5 protects from obesity and insulin resistance, and both enzymes regulate C16:0-sphingolipid synthesis in distinct intracellular compartments. Moreover, we identify proteins, which specifically interact with C16:0-sphingolipids derived from CerS5 or CerS6. Here, only CerS6-derived C16:0-sphingolipids bind the mitochondrial fission factor (Mff). CerS6- and Mff-deficiency protects from fatty acid-induced mitochondrial fragmentation in vitro, and both proteins genetically interact in vivo in obesity-induced mitochondrial fragmentation and development of insulin resistance. Our experiments reveal an unprecedented specificity of sphingolipid-signaling depending on specific synthetizing enzymes, provide a mechanistic link between lipid deposition and mitochondrial dynamics in obesity, and define the CerS6/sphingolid/Mff interaction as a therapeutic target for obesity and diabetes.
2019-05-20 | PXD007158 | Pride
Project description:Stem cells are fundamental units of tissue remodeling, whose functions are dictated by lineage-specific transcription factors. Home to epidermal stem cells and their upward stratifying progenies, skin relies upon its secretory functions to form the outmost protective barrier, of which a transcriptional orchestrator has been elusive. KLF5 is a Krüppel-like transcription factor broadly involved in development and regeneration, whose lineage specificity, if any, remains unclear. Here we report KLF5 specifically marks the epidermis, and its deletion leads to skin barrier dysfunction in vivo. Lipid envelopes and secretory lamellar bodies are defective in KLF5-deficient skin, accompanied by preferential loss of complex sphingolipids. KLF5 binds to and transcriptionally regulates genes encoding rate-limiting sphingolipid metabolism enzymes. Remarkably, skin barrier defects elicited by KLF5 ablation can be rescued by dietary interventions. Finally, we found KLF5 is widely suppressed in human diseases with disrupted epidermal secretion, and its regulation of sphingolipid metabolism is conserved in human skin. Altogether, we establish KLF5 as a disease-relevant transcription factor governing sphingolipid metabolism and barrier function in the skin, likely representing a long-sought secretory lineage defining factor across tissue types.
2022-08-18 | GSE168600 | GEO
Project description:We sequenced mRNA from three independent pairs of mock and c-SRC transformed mouse embryonic fibroblasts and examined changes in expression of sphingolipid metabolism genes Three independent cultures of NIH3T3 MEFs were retrovirally transduced with either pBabe-Puro, og pBabe-Puro containing c-srcY527F. After a 7 day of selection in puromycine the three vector and three src transduced pools were propagated for RNA sequencing.
2013-10-17 | E-GEOD-46340 | biostudies-arrayexpress