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Acute proteome responses to de novo sphingolipid synthesis inhibition suggest cancer combination therapies

ABSTRACT: Sphingolipids are essential structural and signaling lipids that support membrane integrity and govern cell fate decisions. Whereas the consequences of chronic sphingolipid inhibition have been extensively explored, the immediate cellular responses to reduced sphingolipid levels remain poorly defined. Here, we performed mass spectrometry analysis of subcellular fractions to examine proteome alterations 4 hours after myriocin treatment, which inhibits de novo sphingolipid synthesis. We have identified changes in the abundance of 1307 proteins across the membrane, cytosolic, and nuclear fractions.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Zhiping Wu

LAB HEAD: Junmin Peng

PROVIDER: PXD079016 | Pride | 2026-06-08

REPOSITORIES: Pride

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			Action	DRS
	Du_Sph_Cytosol_DMSO_1_1.raw	Raw
	Du_Sph_Cytosol_DMSO_1_2.raw	Raw
	Du_Sph_Cytosol_DMSO_2_1.raw	Raw
	Du_Sph_Cytosol_DMSO_2_2.raw	Raw
	Du_Sph_Cytosol_DMSO_3_1.raw	Raw

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Transcriptional suppression of sphingolipid catabolism controls pathogen resistance in C. elegans [RNA-Seq]

Project description:Sphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance.

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Transcriptional suppression of sphingolipid catabolism controls pathogen resistance in C. elegans [ChIP-Seq]

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sphingo-1-Identification of Sphingolipid regulated genes in cold stress response. Sphingolipids regulated genes.

Project description:rs07-05_sphingolipids-cold - sphingo-1 - The cold choc response seems to be partly triggered by Sphingolipid species. To date no gene response as been associated to sphingolipid signaling pathway in plant. Our aim is to identify among the cold induced genes the ones regulated by sphingolipids and to try to define a sphingolipid pathway specific group of genes. - 7ml of 5 days-old cells suspensions were incubated in presence of different sphingolipid pathway inhibitors, 30 min to 2 hours depending in the coumpound (all were resuspended in DMSO and control were done with DMSO). Then a 30 min cold choc was applied before cells were harvested and frozen in cold nitrogen. RNA were then extracted. FB1 and DMS were from Alexis , Myr from Cayman, TSP from matreya. 6 dye-swap - treated vs untreated comparison

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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.

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Effects of inhibiting sphingolipid synthesis and TOR signaling on the Candida albicans transcriptome

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.

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Reduced sphingolipid biosynthesis modulates proteostasis networks to enhance longevity

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Gene expression by myriocin treatment

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2014-09-22 | E-GEOD-41362 | biostudies-arrayexpress

Rewiring endothelial cell sphingolipid metabolism to favor S1P over ceramide signaling protects from coronary atherosclerosis

Project description:Growing evidence correlated changes in bioactive sphingolipids, particularly sphingosine-1-phosphate (S1P) and ceramides, with coronary artery diseases. Furthermore, specific plasma ceramide species can predict major cardiovascular events. Dysfunction of the endothelium lining lesion-prone areas plays a pivotal role in the initiation and progression of atherosclerosis. Yet, how sphingolipid metabolism and signaling change and contribute to endothelial dysfunction and atherosclerosis remain poorly understood. By using a mouse model of coronary atherosclerosis, we demonstrated that hemodynamic stress induces an early metabolic rewiring of endothelial sphingolipid de novo biosynthesis favoring S1P signaling over ceramide as protective response. Furthermore, our data are paradigm shift from the current believe that ceramide accrual contributes to endothelial dysfunction. The de novo biosynthesis of sphingolipids is commenced by serine palmitoyltransferase (SPT), and is downregulated by NOGO-B, an ER membrane protein. We showed that Nogo-B is upregulated by hemodynamic stress in myocardial endothelial cells (EC) of ApoE-/- mice and is expressed in the endothelium lining coronary lesions in mice and human. We demonstrated that mice lacking Nogo-B specifically in EC (Nogo-A/BECKOApoE-/-) were resistant to coronary atherosclerosis development and progression, and mortality. Fibrous cap thickness was significantly increased in Nogo-A/BECKOApoE-/- mice and correlated with reduced necrotic core and macrophage infiltration. Mechanistically, the deletion of Nogo-B in EC sustained the rewiring of sphingolipid metabolism towards S1P, imparting an atheroprotective transcriptional signature that refrain coronary atherogenesis and its progression. These findings also set forth the foundation for sphingolipid-based therapeutics to reduce the treat this condition.

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