Exosomes released from embryonic hippocampal cells under ceramide treatment carry a specific miRNA signature for sphingolipid pathway and cell differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA947939 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23947917.fastq.gz | Fastqsanger.gz | |||
| SRR23947918.fastq.gz | Fastqsanger.gz | |||
| SRR23947919.fastq.gz | Fastqsanger.gz | |||
| SRR23947920.fastq.gz | Fastqsanger.gz | |||
| SRR23947921.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Identification of the miRNA signature carried by the exosomes released from embryonic hippocampal cells under ceramide treatment Outcome: We investigated the role of ceramide in amplifying the differentiation signal of HN9.10 cells. Treatment of HN9.10 cells with ceramide caused the release of exosomes carrying neutral sphingomyelinase and neutral ceramidase. The analysis of exosomal miRNAs showed that 38 miRNAs were differentially expressed in a statistically significant manner, with some overexpressed miRNAs regulating genes encoding for proteins involved in biological, homeostatic, biosynthetic and small molecule metabolic processes, embryo development and cell differentiation, all phenomena that could be relevant for HN9.10 cell differentiation.
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Project description:The bioactive sphingolipid ceramide, generated by ceramide synthase, is an adaptive stress effector induced in response to various stress stimuli such as aging. In fact, ceramide synthase (CerS) was first discovered in yeast as a longevity assurance gene (LAG1), as the reduced ceramide generation consequent to LAG1 deletion increased longevity. There are six homologues of mammalian LAG1/ceramide synthases (CerS1-6) that generate ceramides with different fatty acid chain lengths with distinct functions and hydrophobicity. Ceramide can be metabolized by sphingosine kinase 1 or 2 for the generation of pro-survival sphingosine 1-phosphate (S1P), which enhances immune cell egress to the blood stream, activating immune function. Ceramide is known to induce mitophagy and cell death. Here we investigated the role of this sphingolipid pathway in immune function, specifically T cell functions, via high throughput expression profiling.
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Project description:Metabolic disorders and obesity increase the risk for cardiovascular (CV) disease, including hypertension, atherosclerosis, and myocardial infarction. Systemic endothelial dysfunction, a well-established response to CV risk factors, precedes the development of CV diseases. However, growing evidence suggest that endothelial dysregulation also contributes to metabolic disorders, underlying a centric role of the endothelium in cardiometabolic diseases. The accrual of the sphingolipid ceramide, bioactive molecule, has been causally implicated in endothelial dysfunction in vitro. However, direct in vivo evidence supporting the accrual of ceramide in the endothelium, underlying mechanisms, and pathological implications are lacking. Here, we showed that the suppression rather than the accrual of ceramides is causally linked to endothelial dysfunction, and imparts a pro-inflammatory and pro-atherosclerotic phenotype, contributing to both vascular and metabolic disorders. Mechanistically, the upregulation of Nogo-B and ORMDLs proteins, inhibitors of the first and rate limiting enzyme of the de novo biosynthesis, in the endothelium of obese and diabetic mice suppresses sphingolipid signaling, particularly ceramides and sphingosine-1-phosphate, resulting in vascular and metabolic dysfunctions. Systemic and endothelial specific deletion of Nogo-B restores sphingolipid signaling and functions of the endothelium, improves hypertension and lowers hepatic glucose production. Our results demonstrating that Nogo-B-mediated suppression of sphingolipid metabolism and signaling in the endothelium has pathological implication in cardiometabolic disorders and set a framework for the development of therapeutic strategies to treat these conditions.
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Project description:Ceramide is synthesized via the ceramide synthases (CerSs), six of which have been identified in mammalian cells, with each using a unique subset of acyl-CoAs for ceramide synthesis. The CerSs are part of a larger gene family, the Tram-Lag-CLN8 (TLC) domain family. We now identify a unique, C-terminal motif, the DxRSDxE motif, which is only found in CerS and not in other TLC family members. Deletion of this motif in either CerS2-HA or in CerS6-Flag did not affect the ability of either to generate ceramide using both an in vitro assay and upon metabolic labeling, but deletion of this motif did affect the activity of CerS2-HA when co-expressed with CerS6-Flag. Surprisingly, transfection of cells with either CerS2-HA or CerS6-Flag lacking the motif did not result in changes in cellular ceramide levels. CerS2-HA and CerS6-Flag interact with each other, as shown by immunoprecipitation, but deletion of the DxRSDxE motif impedes this interaction. Moreover, proteomics analysis of cells transfected with CerS6Δ338-344-Flag indicated that deletion of the C-terminal motif impacted cellular protein expression, and in particular, levels of ORMDL1, a negative regulator of sphingolipid synthesis. We suggest that this novel C-terminus motif regulates CerS dimer formation and thereby impacts ceramide synthesis.
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