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

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