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

ABSTRACT: 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.

ORGANISM(S): Mus Musculus

SUBMITTER: Peng Jiang

PROVIDER: PXD071798 | iProX | Wed Dec 10 00:00:00 GMT 2025

REPOSITORIES: iProX

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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.

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

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