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

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 largely 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.代谢调控是p53抑癌功能的核心机制。本研究发现，丙酰辅酶A（propionyl-CoA）代谢重塑与表观遗传变化，共同支撑了p53通过调节性T细胞（Treg细胞）介导的自身免疫抑制作用。通过分析自身免疫病患者样本，我们发现Treg细胞中p53的表达显著下调，且与BCL-6水平异常升高呈负相关。p53缺失会导致免疫稳态失衡，并在体内外削弱Treg细胞的功能。机制层面，p53通过转录激活ALDH6A1的表达与丙酰辅酶A合成代谢，经由组蛋白丙酰化修饰上调功能性Treg细胞的基因表达。特异性敲除Treg细胞中的ALDH6A1，可模拟p53缺失引发的自身免疫应答；而补充丙酰辅酶A可在p53或ALDH6A1缺失的小鼠中，大幅恢复Treg细胞的功能。临床研究显示，在强直性脊柱炎（AS）与系统性红斑狼疮（SLE）患者体内，均可观察到p53-ALDH6A1-组蛋白丙酰化信号通路受损，且该通路异常与自身免疫病患者一线治疗疗效不佳相关。综上，本研究揭示了丙酰辅酶A代谢与表观遗传变化之间的直接关联，该通路由p53调控，对Treg细胞功能与免疫耐受维持至关重要。