Acetyl-CoA carboxylase inhibition regulates microtubule dynamics and intracellular transport in cystic fibrosis epithelial cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA486100 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7695540_1.fastq.gz | Fastqsanger.gz | |||
| SRR7695540_2.fastq.gz | Fastqsanger.gz | |||
| SRR7695541_1.fastq.gz | Fastqsanger.gz | |||
| SRR7695541_2.fastq.gz | Fastqsanger.gz | |||
| SRR7695542_1.fastq.gz | Fastqsanger.gz |
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Project description:In this study, we hypothesize that acetyl CoA carboxylase (ACC) is an important intermediate in Cystic fibrosis (CF) inflammatory signaling cascade. Here, we demonstrate that ACC inhibition mimics the cellular effects of ibuprofen promoting both redistribution of intracellular cholesterol and increased rates of microtubule reformation, while decreasing RhoA expression in CF epithelial cell models. Inhibiting ACC polymerization with citrate increases RhoA expression and decreases microtubule reformation rates in wild-type epithelial cells, suggesting pro-inflammatory signaling. Together, these findings demonstrate a novel mechanism of high-dose ibuprofen efficacy and point to a potential new therapeutic target for anti-inflammatory drugs in CF.
2019-03-18 | GSE118567 | GEO
Project description:Acetyl-CoA Carboxylase Obstructs CD8+ T-Cell Lipid Utilization in the Tumor Microenvironment
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Project description:The use of high-dose ibuprofen as an anti-inflammatory therapy in cystic fibrosis (CF) has been shown to be an effective intervention although use is limited due to potential adverse events. Identifying the mechanism of ibuprofen efficacy would aid in the development of new therapies that avoid these adverse events. Previous findings demonstrated that ibuprofen treatment restores the regulation of microtubule dynamics in CF epithelial cells through a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent mechanism. The goal of this study is to define the AMPK pathway that leads to microtubule regulation. Here, it is identified that inhibition of acetyl-CoA carboxylase (ACC) is the key step in mediating the AMPK effect. ACC inhibition with 5-(tetradecyloxy)-2-furoic acid (TOFA) increases microtubule reformation rates in cultured and primary CF epithelial cells to wild-type (WT) rates. TOFA treatment also restores microtubule-dependent distribution of cholesterol and Rab7-positive organelles, as well as reduces expression of the proinflammatory signaling molecule RhoA to WT levels. ACC activation with citrate replicates these CF phenotypes in WT cells further supporting the role of AMPK signaling through ACC as a key mediator in CF cell signaling. It is concluded that ACC inhibition is the key step in the efficacy of AMPK activation at the cellular level and could represent a novel site of therapeutic intervention to address inflammation in CF.
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Project description:The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor infiltrating T cells (TILs) hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control.However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. Using patient samples and mouse models, we reveal that the solid TME imposes perpetual acetyl-CoA carboxylase (ACC) activity, invoking lipid biogenesis and storage in TILs that directly opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC rewires T cell metabolism, enabling energy maintenance in TME stress. Moreover, limiting ACC activity potentiates a gene and phenotypic program indicative of T cell longevity, engendering T cells with increased survival and polyfunctionality, with the ability to control solid cancer.
2024-03-05 | GSE254000 | GEO
Project description:Cytosolic acetyl-coenzyme A is a precursor for many biotechnologically relevant compounds produced by Saccharomyces cerevisiae. In this yeast, cytosolic acetyl-CoA synthesis and growth strictly depend on expression of either the Acs1 or Acs2 isoenzyme of acetyl-CoA synthetase (ACS). Since hydrolysis of ATP to AMP and pyrophosphate in the ACS reaction constrains maximum yields of acetyl-CoA-derived products, this study explores replacement of ACS by two ATP-independent pathways for acetyl-CoA synthesis. After evaluating expression of different bacterial genes encoding acetylating acetaldehyde dehydrogenase (A-ALD) and pyruvate-formate lyase (PFL), acs1M-NM-^T acs2M-NM-^T S. cerevisiae strains were constructed in which A-ALD or PFL successfully replaced ACS. In A-ALD-dependent strains, aerobic growth rates of up to 0.27 h-1 were observed, while anaerobic growth rates of PFL-dependent S. cerevisiae (0.21 h-1) were stoichiometrically coupled to formate production. In glucose-limited chemostat cultures, intracellular metabolite analysis did not reveal major differences between A-ALD-dependent and reference strains. However, biomass yields on glucose of A-ALD- and PFL-dependent strains were lower than those of the reference strain. Transcriptome analysis suggested that reduced biomass yields were caused by acetaldehyde and formate in A-ALD- and PFL-dependent strains, respectively. Transcript profiles also indicated that a previously proposed role of Acs2 in histone acetylation is probably linked to cytosolic acetyl-CoA levels rather than to direct involvement of Acs2 in histone acetylation. While, for the first time, demonstrating that yeast ACS can be fully replaced by alternative reactions, this study demonstrates that further modifications are needed to achieve optimal in vivo efficiencies of the supply of acetyl-CoA as product precursor. To investigate the impact of introduced changes in native pathway of cytosolic acetyl-CoA formation in S. cerevisiae, a DNA microarray-based transcriptome analysis was performed on aerobic or anaerobic, glucose-limited chemostat cultures.
2013-11-21 | E-GEOD-47983 | biostudies-arrayexpress
Project description:Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-CoA carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. It is discovered that a malonylation-mimic mutant in ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.
2023-03-05 | GSE226139 | GEO
Project description:Cytosolic acetyl-coenzyme A is a precursor for many biotechnologically relevant compounds produced by Saccharomyces cerevisiae. In this yeast, cytosolic acetyl-CoA synthesis and growth strictly depend on expression of either the Acs1 or Acs2 isoenzyme of acetyl-CoA synthetase (ACS). Since hydrolysis of ATP to AMP and pyrophosphate in the ACS reaction constrains maximum yields of acetyl-CoA-derived products, this study explores replacement of ACS by two ATP-independent pathways for acetyl-CoA synthesis. After evaluating expression of different bacterial genes encoding acetylating acetaldehyde dehydrogenase (A-ALD) and pyruvate-formate lyase (PFL), acs1Δ acs2Δ S. cerevisiae strains were constructed in which A-ALD or PFL successfully replaced ACS. In A-ALD-dependent strains, aerobic growth rates of up to 0.27 h-1 were observed, while anaerobic growth rates of PFL-dependent S. cerevisiae (0.21 h-1) were stoichiometrically coupled to formate production. In glucose-limited chemostat cultures, intracellular metabolite analysis did not reveal major differences between A-ALD-dependent and reference strains. However, biomass yields on glucose of A-ALD- and PFL-dependent strains were lower than those of the reference strain. Transcriptome analysis suggested that reduced biomass yields were caused by acetaldehyde and formate in A-ALD- and PFL-dependent strains, respectively. Transcript profiles also indicated that a previously proposed role of Acs2 in histone acetylation is probably linked to cytosolic acetyl-CoA levels rather than to direct involvement of Acs2 in histone acetylation. While, for the first time, demonstrating that yeast ACS can be fully replaced by alternative reactions, this study demonstrates that further modifications are needed to achieve optimal in vivo efficiencies of the supply of acetyl-CoA as product precursor.
2013-11-21 | GSE47983 | GEO
Project description:The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor infiltrating T cells (TILs) hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control. However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. Using patient samples and mouse models, we reveal that the solid TME imposes perpetual acetyl-CoA carboxylase (ACC) activity, invoking lipid biogenesis and storage in TILs that directly opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC rewires T cell metabolism, enabling energy maintenance in TME stress. Moreover, limiting ACC activity potentiates a gene and phenotypic program indicative of T cell longevity, engendering T cells with increased survival and polyfunctionality, with the ability to control solid cancer.
2024-05-20 | PXD048393 | Pride
Project description:Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drug targeting the catalytic activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the DNL process, has been approved by FDA. Whether cytosolic ACC1 can be regulated spatially is unknown. Herein, we found that streptavidin, which is a bacterium derived tetrameric protein, forms cytosolic condensates and efficiently induce a spatial re-localization of ACC1 in liver cells, concomitant with inhibited lipid accumulation. Both SA tetrameric structure and multivalent protein interaction are required for condensates formation. Interestingly, the condensates are further characterized as gel-like membraneless organelle (SAGMO) and significantly restrict the cytosolic dispersion of ACC1 and fatty acid synthase (FASN). Notably, AAV mediated delivery of SA partially blocks mice liver DNL and ameliorate NASH without eliciting hypertriglyceridemia. In summary, our study demonstrates that insulating lipogenesis-related proteins by SAGMO might be effective for NASH treatment.
2023-10-25 | GSE245797 | GEO
Project description:Acetyl-Coenzyme A (acetyl-CoA) is a central metabolite and the acetyl source for protein acetylation, particularly histone acetylation that promotes gene expression. However, the effect of acetyl-CoA levels on histone acetylation status in plants remains unknown. Here, we show that malfunctioned cytosolic acetyl-CoA carboxylase1 (ACC1) in Arabidopsis leads to elevated levels of acetyl-CoA and promotes histone hyperacetylation predominantly at lysine 27 of histone H3 (H3K27). The increase of H3K27 acetylation (H3K27ac) is dependent on ATP-citrate lyase which cleaves citrate to acetyl-CoA in the cytoplasm, and requires histone acetyltransferase GCN5. A comprehensive analysis of the transcriptome and metabolome in combination with the genome-wide H3K27ac profiles of acc1 mutants, demonstrate the dynamic changes of H3K27ac, gene transcripts and metabolites occurring in the cell by the increased levels of acetyl-CoA. This study suggests that H3K27ac is an important link between cytosolic acetyl-CoA level and gene expression in response to the dynamic metabolic environments in plants.
2017-09-25 | GSE79524 | GEO