Effect of deletion of SPTLC1 on gene expression and differentiation of mouse Th17 cells in vitro
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE254602 | GEO | 2024/03/21
REPOSITORIES: GEO
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Project description:Part 3/5: It includes quantitative targeted measurements of sphingolipids (ceramides and glycosphingolipids)in Th17 cells before(scrambled / control)and after the triple knockdown of SPTLC1,2,3 genes (SPT de novo pathway: sphingolipid metabolism).
2021-01-31 | ST001677 | MetabolomicsWorkbench
Project description:Sphingolipids are structural membrane components that also function in cellular stress responses. The serine palmitoyl-transferase (SPT) catalyzes the rate limiting step in sphingolipid biogenesis. Its activity is tightly regulated through multiple bind-ing partners, including Tsc3, Orm proteins, ceramides, and the phosphatidylinositol-4-phosphate (PI4P) phosphatase Sac1. The structural organization and regulatory mechanisms of this complex are not yet understood. Here, we report the high-resolution cryo-EM structures of the yeast SPT in complex with Tsc3 and Orm1 (SPOT) as dimers and monomers and a monomeric complex further carrying Sac1 (SPOTS). In all complexes, the tight interaction of the down-stream metabolite ceramide and Orm1 reveals the ceramide dependent inhibition. Additionally, observation of ceramide and ergosterol binding suggests a co-regulation of sphingolipid biogenesis and sterol metabolism within the SPOTS com-plex.
2023-10-24 | PXD044586 | Pride
Project description:ABSTRACT: Sphingolipid synthesis is initiated by condensation of serine with palmitoyl-CoA to produce 3-ketodihydrosphinganine (3-KDS), which is subsequently reduced by a 3-KDS reductase to dihydrosphinganine (DHS). Serine palmitoyltransferase was recently shown to be essential for plant viability, but the 3-KDS reductase step of sphingolipid synthesis has not been investigated in plants. Arabidopsis thaliana contains two genes (At3g06060/TSC10A and At5g19200/TSC10B) that encode proteins with significant homology to the yeast 3-KDS reductase, Tsc10p. Heterologous expression, in yeast, of either A. thaliana gene restored 3-KDS reductase activity to the yeast tsc10Δ mutant, thereby identifying both as bona fide 3-KDS reductase genes. Consistent with previous evidence that sphingolipids have essential functions in plants, double mutant progeny lacking both genes were not recovered. Although the 3-KDS reductase genes are functionally redundant and ubiquitously expressed in A. thaliana, 3-KDS reductase activity was reduced to approximately 10% of wild-type levels in the loss-of-function tsc10a mutant, leading to an altered sphingolipid profile compared to wild-type plants. Interestingly, this perturbation of sphingolipid biosynthesis in the A. thaliana tsc10a mutant leads to significant alterations in the leaf ionome, including increases in Na, K and Rb (a K analogue), and decreases in Mg, Ca, Fe, and Mo. Reciprocal grafting revealed that these changes in the leaf ionome are driven by the root, and are associated with both increases in root suberin, and elevation of expression in the root of genes involved in Fe homoeostasis, including the Fe-transporter IRT1. Keywords: genomic hybridization bulked segregant analysis
2011-05-26 | GSE22163 | GEO
Project description:ABSTRACT: Sphingolipid synthesis is initiated by condensation of serine with palmitoyl-CoA to produce 3-ketodihydrosphinganine (3-KDS), which is subsequently reduced by a 3-KDS reductase to dihydrosphinganine (DHS). Serine palmitoyltransferase was recently shown to be essential for plant viability, but the 3-KDS reductase step of sphingolipid synthesis has not been investigated in plants. Arabidopsis thaliana contains two genes (At3g06060/TSC10A and At5g19200/TSC10B) that encode proteins with significant homology to the yeast 3-KDS reductase, Tsc10p. Heterologous expression, in yeast, of either A. thaliana gene restored 3-KDS reductase activity to the yeast tsc10Δ mutant, thereby identifying both as bona fide 3-KDS reductase genes. Consistent with previous evidence that sphingolipids have essential functions in plants, double mutant progeny lacking both genes were not recovered. Although the 3-KDS reductase genes are functionally redundant and ubiquitously expressed in A. thaliana, 3-KDS reductase activity was reduced to approximately 10% of wild-type levels in the loss-of-function tsc10a mutant, leading to an altered sphingolipid profile compared to wild-type plants. Interestingly, this perturbation of sphingolipid biosynthesis in the A. thaliana tsc10a mutant leads to significant alterations in the leaf ionome, including increases in Na, K and Rb (a K analogue), and decreases in Mg, Ca, Fe, and Mo. Reciprocal grafting revealed that these changes in the leaf ionome are driven by the root, and are associated with both increases in root suberin, and elevation of expression in the root of genes involved in Fe homoeostasis, including the Fe-transporter IRT1. Keywords: genomic hybridization bulked segregant analysis Hybridizations from a set of Bulk Segregant analysis. An F2 population from 7113 in the col-0 background crossed to Ler-0 was analyzed. This series contains the 3 hybs from Ler used to identify Single Feature Polymorphisms, the 3 hybs of Col-0 they were compared to, and 1 hyb for each pool from the BSA mapping(low Ca/Mg Pool and wild type pools).
2011-05-25 | E-GEOD-22163 | biostudies-arrayexpress
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.
2024-02-12 | GSE254426 | GEO
Project description:We report the application of bulk RNA sequencing to RNA extracted from lung tissue and magnetic bead isolated EpCAM+ lung epithelial cells and CD45+ lung immune cells from mice. Heterozygous serine palmitory transferase subunit 2 , Sptlc2+/- (SPT) and Sptlc2+/+ controls (WT) mice were included. Differential gene expression analysis reveals genes within the sphingolipid synthesis pathway are similarly expressed in the lung and lung epithelial cells of RV infected WT mice and SPT mice (both infected and uninfected).
2021-11-20 | GSE189056 | GEO
Project description:We identified 1-deoxysphingosine as a ligand for NR2F1 and NR2F2. To prove physiological relevance after in vitro binding assay we used different strategies to manipulate levels of 1-deoxysphingosines and canonical sphingosines in cardiomyocytes derived from human embrynonic stem cells. These manipulations included treating cells with sphingolipid biosynthesis inhibitors (myriocin), adding 1-deoxysphingosines to culture media or induced expression of the Sptlc1 HSAN mutant C133W to enhance 1-deoxysphingosine synthesis by cardiomyocytes.
2021-10-21 | GSE184913 | GEO
Project description:Sphingolipids and their metabolic pathways have been implicated in disease development and therapeutic response; however, the detailed mechanisms remain unclear. Using a sphingolipid network focused CRISPR/Cas9 library screen, we identified an endoplasmic reticulum (ER) enzyme, 3-Ketodihydrosphingosine reductase (KDSR), to be essential for leukemia cell maintenance. Loss of KDSR led to apoptosis, cell cycle arrest, and aberrant ER structure. Transcriptomic analysis revealed the indispensable role of KDSR in maintaining the unfolded protein response (UPR) in ER. High-density CRISPR tiling scan and sphingolipid mass spectrometry pinpointed the critical role of KDSR’s catalytic function in leukemia. Meanwhile, depletion of KDSR resulted in accumulated 3-ketodihydrosphingosine (KDS) and dysregulated UPR checkpoint proteins PERK, ATF6, and ATF4. Finally, our study revealed the synergism between KDSR suppression and pharmacologically induced ER-stress, underscoring a therapeutic potential of combinatorial targeting sphingolipid metabolism and ER homeostasis in leukemia treatment.
2021-07-24 | GSE167688 | GEO
Project description:Background: Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children.Objective: To determine if nasal allergen challenge (NAC) responses to cockroach allergen would improve following one year of SCIT.Methods: Urban children with asthma, cockroach-sensitized (skin prick test [SPT] and serum specific IgE) and reactive on NAC, participated in a yearlong randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean total nasal symptoms scores (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, SPT wheal size, serum allergen-specific antibody production and T-cell responses to cockroach allergen were assessed.Results: Changes in mean NAC TNSS did not differ between SCIT-assigned (n=28) versus placebo-assigned (n=29) participants (p=0.63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach sIgE decreased to a similar extent in both groups, while decreased cockroach SPT wheal size was greater among SCIT participants (p=0.04). A 200-fold increase in cockroach sIgG4 was observed among subjects receiving SCIT (p<0.001) but was unchanged in the placebo group. T-cell interleukin-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (p=0.002), while no effect was observed for interleukin-10 or interferon-gamma.Conclusion: A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum sIgG4 production and down-modulation of allergen stimulated T-cell responses.
2024-12-18 | GSE250580 | GEO
Project description:Purpose: The purpose of this study is to find the binding partner of IRF4 in the context of Th17- cell differentiation. To this end, we have used ChIPseq analysis followed by de novo motif search around genome-wide binding sites to identify BATF as the binding partner for IRF4 in the context of not only Th17 cells but other immune cell types as well.
2012-09-13 | GSE40727 | GEO