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CRISPR interference reveals that all-trans-retinoic acid promotes macrophage control of Mycobacterium tuberculosis by limiting bacterial access to cholesterol and propionyl-CoA

ABSTRACT: CRISPR interference reveals that all-trans-retinoic acid promotes macrophage control of Mycobacterium tuberculosis by limiting bacterial access to cholesterol and propionyl-CoA

PROVIDER: PRJNA762328 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15841200.fastq.gz	Fastqsanger.gz
	SRR15841201.fastq.gz	Fastqsanger.gz
	SRR15841203.fastq.gz	Fastqsanger.gz
	SRR15841204.fastq.gz	Fastqsanger.gz
	SRR15841205.fastq.gz	Fastqsanger.gz

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CRISPR interference reveals that all-trans-retinoic acid promotes macrophage control of Mycobacterium tuberculosis by limiting bacterial access to cholesterol and propionyl-CoA

Project description:Macrophages are a protective replicative niche for Mycobacterium tuberculosis (Mtb) but can kill the infecting bacterium when appropriately activated. To identify mechanisms of clearance, we compared bacterial restriction by human macrophages after treatment with 26 compounds, including some currently in clinical trials for tuberculosis. All-trans-retinoic acid (ATRA), an active metabolite of vitamin A, drove the greatest increase in Mtb control. Bacterial clearance was transcriptionally and functionally associated with changes in macrophage cholesterol trafficking and lipid metabolism. To determine how these macrophage changes affected bacterial control, we performed the first Mtb CRISPR interference screen in an infection model, identifying Mtb genes specifically required to survive in ATRA-activated macrophages. These data showed that ATRA treatment starves Mtb of cholesterol and the downstream metabolite propionyl-CoA. Supplementation with sources of propionyl-CoA, including cholesterol, abrogated the restrictive effect of ATRA. This work demonstrates that targeting the coupled metabolism of Mtb and the macrophage improves control of infection, and that it is possible to genetically map the mode of bacterial death using CRISPR interference.

2021-12-21 | GSE183912 | GEO

Systemic toxicity in hepatic Propionyl-CoA Carboxylase deficiency

Project description:Inborn errors in Propionyl-CoA Carboxylase (Pcca/b) cause life threatening propionic acidemia. To understand the contribution of mitochondrial propionyl-CoA metabolism to cellular and systemic metabolic dysfunction, we generated inducible and tissue-specific knockout (KO) mouse models of Pcca. Adult inducible loss of Pcca results in acute metabolic decompensation resembling the inborn error. The liver-specific loss of Pcca largely recapitulates this in a sexually dimorphic manner. Propionate and pyruvate converge in the TCA cycle as major anaplerotic substrates. Paradoxically, the simultaneous KO of Pyruvate Carboxylase (Pcx) rescues the lethality of liver-specific Pcca KO male mice. Most metabolites suspected as deleterious in propionic acidemia are exacerbated in Pcca;Pcx double KO mice with the noted exception of methylcitrate suggesting the centrality of this metabolite to systemic toxicity. These data clarify relevant toxic biomarkers and suggest that rebalancing hepatic TCA cycle metabolism as critical to mitigate the adverse effects of alternative propionyl-CoA metabolism.

2026-03-27 | GSE305924 | GEO

Systemic toxicity in hepatic Propionyl-CoA Carboxylase deficiency

Project description:Systemic toxicity in hepatic Propionyl-CoA Carboxylase deficiency

| PRJNA1308458 | ENA

Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol synthesis and storage

Project description:Cholesterol performs multiple essential roles in cells. Enhanced cholesterol synthesis and storage in lipid droplets have been linked to cancer aggressiveness, particularly in lipid-rich and hormone-sensitive cancers such as prostate cancer . Cholesterol anabolism and catabolism are finely regulated in tumor cells in response to various nutritional states. Mitochondria have increasingly been recognized as a signal transduction organelle, particularly concerning metabolites derived from mitochondrial activity. The link between mitochondrial regulation and cholesterol synthesis remains inadequately understood. Here, we show that propionyl-CoA promotes cholesterol synthesis, storage, and further progression in prostate cancer cells. We found that propionyl-CoA, mainly produced by isoleucine and valine metabolism in the mitochondria, can translocate through the mitochondrial membrane and serves as a substrate for modifying cleaved SREBP2, stabilizing it and thereby promoting cholesterol synthesis and storage in lipid droplets. This process facilitates cancer metastasis and castration resistant partially through enhancing androgen synthesis in prostate cancer cells. Our results demonstrate that branched-chain amino acid (BCAA) catabolism and propionate metabolism in mitochondria are involved in the regulation of cholesterol synthesis and utilization through metabolite-mediated protein modification. We anticipate that our findings provide a critical link between amino acid metabolism and cholesterol anabolism, highlighting a mechanism that plays a crucial role in the development of castration resistance in prostate cancer patients. This study offers a theoretical rationale for targeting the production of propionyl-CoA, particularly through the metabolism of isoleucine and valine, as an effective strategy to inhibit cholesterol synthesis and its related diseases.

2025-07-11 | GSE272086 | GEO

Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation

Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which induces diverse biological and toxic effects, including the reprograming of intermediate metabolism, mediated by the aryl hydrocarbon receptor (AHR). Targeted LC-MS analysis of hepatic extracts from mice gavaged with TCDD every 4 days for 28 days detected an increase in S-(2-carboxyethyl)-L-cysteine, a conjugate produced following the spontaneous reaction between the sulfhydryl group of cysteine and highly reactive acrylyl-CoA, an intermediate in the cobalamin (Cbl)-independent β–oxidation-like metabolism of propionyl-CoA. In addition to repressing genes in both the canonical Cbl-dependent carboxylase and the alternate Cbl-independent β–oxidation-like pathways at 30 µg/kg TCDD, methylmalonyl-CoA mutase (MUT) activity was inhibited at lower doses. Moreover, TCDD decreased serum Cbl levels and hepatic cobalt levels while eliciting negligible effects on gene expression associated with Cbl absorption, transport, trafficking, or the derivatization to 5’-deoxy-adenosylcobalamin (AdoCbl), the required MUT cofactor. In addition to inducing Acod1 that encodes for aconitate decarboxylase 1, the enzyme responsible for the decarboxylation cis-aconitate to itaconate, TCDD also dose-dependently increased itaconate levels in hepatic extracts. MUT inhibition is consistent with itaconate activation to itaconyl-CoA, a MUT suicide inactivator that adducts AdoCbl, that in turn, inhibits MUT activity and reduces Cbl levels. Collectively, these results suggest the decrease in MUT activity is due to Cbl depletion following TCDD treatment that redirected propionyl-CoA metabolism to the alternate Cbl-independent β–oxidation-like pathway. The resulting hepatic accumulation of acrylyl-CoA likely contributes to TCDD-elicited hepatotoxicity and the multi-hit progression of steatosis to steatohepatitis with fibrosis.

2022-08-05 | GSE203302 | GEO

Proteome data of the Saccharopolyspora spinosa propionyl-CoA carboxylase engineered strain

Project description:To enhance spinosad biosynthesis, we investigated the propionyl-CoA carboxylase (PCC) complex responsible for precursor synthesis. Through CRISPR interference (CRISPRi) and overexpression strategies, we constructed six engineered strains to systematically regulate the core PCC subunits encoded by pccA, pccB1, and pccB2. Upregulation of these genes enhanced PCC activity, improved energy and precursor utilization, and activated metabolic pathways, ultimately increasing spinosad production.

2025-04-02 | PXD062497 |

Loss of p53 exacerbates autoimmunity by reprogramming propionyl-CoA metabolism and epigenetics in Treg cells

Project description:<p>Metabolic regulation is central to the tumor suppressor function of p53. Here we report that propionyl-CoA metabolic remodeling and epigenetic changes underpin p53-mediated restraint of autoimmunity through regulatory T (Treg) cells. By analyzing the human patients with autoimmune diseases, we found p53 expression was significantly reduced in Treg cells negatively correlating with abnormally elevated BCL-6 levels. p53 loss causes dysregulated immune homeostasis and dampens Tregs function in vitro and in vivo. Mechanistically, p53 transcriptionally activates ALDH6A1 expression and propionyl-CoA anabolism to upregulate functional Treg gene expression via histone propionylation. Treg-specific knockout of ALDH6A1 phenocopies the autoimmune responses of p53 deficiency, and propionyl-CoA restoration recovers Treg cell function in mice lacking p53 or ALDH6A1. Clinically, impaired p53-ALDH6A1-histone propionylation signaling is observed in AS and SLE patients and correlates with poor efficacy of first-line therapies in autoimmune patients. Together, these findings reveal a directly connection between propionyl-CoA metabolism and epigenetic changes, which is governed by p53 and is crucial for Treg cell function and immune tolerance suppression.</p>

2026-02-06 | MTBLS13473 | MetaboLights

Loss of p53 exacerbates autoimmunity by reprogramming propionyl-CoA metabolism and epigenetics in Treg cells

Project description:Metabolic regulation is central to the tumor suppressor function of p53. Here we report that propionyl-CoA metabolic remodeling and epigenetic changes underpin p53-mediated restraint of autoimmunity through regulatory T (Treg) cells. By analyzing the human patients with autoimmune diseases, we found p53 expression was significantly reduced in Treg cells negatively correlating with abnormally elevated BCL-6 levels. p53 loss causes dysregulated immune homeostasis and dampens Tregs function in vitro and in vivo. Mechanistically, p53 transcriptionally activates ALDH6A1 expression and propionyl-CoA anabolism to upregulate functional Treg gene expression via histone propionylation. Treg-specific knockout of ALDH6A1 phenocopies the autoimmune responses of p53 deficiency, and propionyl-CoA restoration recovers Treg cell function in mice lacking p53 or ALDH6A1. Clinically, impaired p53-ALDH6A1-histone propionylation signaling is observed in AS and SLE patients and correlates with poor efficacy of first-line therapies in autoimmune patients. Together, these findings reveal a directly connection between propionyl-CoA metabolism and epigenetic changes, which is governed by p53 and is crucial for Treg cell function and immune tolerance suppression.

2025-12-10 | PXD071798 |

Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol synthesis and storage

Project description:Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol synthesis and storage

| PRJNA1135101 | ENA

Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation

Project description:Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation

| PRJNA839389 | ENA

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