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发挥肿瘤抑制功能的核心机制。本研究证实，丙酰辅酶A（propionyl-CoA）代谢重塑与表观遗传变化，通过调节性T细胞（Treg细胞）介导了p53对自身免疫的抑制作用。通过对自身免疫病患者的临床样本分析，我们发现Treg细胞中p53的表达水平显著降低，且与B细胞淋巴瘤因子6（BCL-6）的异常升高呈负相关。p53缺失会导致免疫稳态失调，并在体内外削弱Treg细胞的功能。从机制层面来看，p53可通过转录激活乙醛脱氢酶6A1（ALDH6A1）的表达与丙酰辅酶A合成代谢，经由组蛋白丙酰化（histone propionylation）上调功能性Treg细胞的基因表达。Treg细胞特异性敲除ALDH6A1可模拟p53缺失引发的自身免疫反应，而补充丙酰辅酶A可在p53或ALDH6A1缺失的小鼠模型中大幅恢复Treg细胞的功能。临床研究中，我们在强直性脊柱炎（AS）与系统性红斑狼疮（SLE）患者体内观察到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显著相关。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——该通路受p53调控，且对Treg细胞功能与免疫耐受维持至关重要。