Phosphoenolpyruvate regulates the Th17 transcriptional program and inhibits autoimmunity
Phosphoenolpyruvate regulates the Th17 transcriptional program and inhibits autoimmunity
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DOI：
10.1016/j.celrep.2023.112205
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发表时间：
2023-02-28
期刊：
影响因子：
8.8
通讯作者：
Ishikawa，Hiroki
中科院分区：
文献类型：
--
作者：
Huang，Tsung-Yen;Hirota，Masato;Ishikawa，Hiroki
有氧糖酵解是效应 T 细胞存活和增殖所必需的代谢途径，可调节自身免疫 T 辅助细胞 (Th) 17 细胞的分化，但这种调节背后的机制在很大程度上尚不清楚。在这里，我们确定了一种糖酵解中间代谢物磷酸烯醇丙酮酸 (PEP)，作为 Th17 分化的负调节剂。在分化的 Th17 细胞中补充 PEP 或抑制下游糖酵解酶会增加细胞内 PEP 水平并抑制白介素 (IL)-17A 表达。 PEP 补充剂可抑制 Th17 和 Th2 细胞特征分子的表达，但不会显着影响糖酵解、细胞增殖或 T 辅助细胞的存活。从机制上讲，PEP 与 JunB 结合并抑制 JunB/碱性亮氨酸拉链转录因子 ATF 样 (BATF)/干扰素调节因子 4 (IRF4) 复合物的 DNA 结合，从而调节 Th17 转录程序。此外，每天给小鼠施用 PEP 可以抑制 Th17 细胞的生成，并改善 Th17 依赖性自身免疫性脑脊髓炎。这些数据表明 PEP 将有氧糖酵解与 Th17 转录程序联系起来，表明 PEP 对自身免疫性疾病的治疗潜力。
Aerobic glycolysis, a metabolic pathway essential for effector T cell survival and proliferation, regulates differentiation of autoimmune T helper (Th) 17 cells, but the mechanism underlying this regulation is largely unknown. Here, we identify a glycolytic intermediate metabolite, phosphoenolpyruvate (PEP), as a negative regulator of Th17 differentiation. PEP supplementation or inhibition of downstream glycolytic enzymes in differentiating Th17 cells increases intracellular PEP levels and inhibits interleukin (IL)-17A expression. PEP supplementation inhibits expression of signature molecules for Th17 and Th2 cells but does not significantly affect glycolysis, cell proliferation, or survival of T helper cells. Mechanistically, PEP binds to JunB and inhibits DNA binding of the JunB/basic leucine zipper transcription factor ATF-like (BATF)/interferon regulatory factor 4 (IRF4) complex, thereby modulating the Th17 transcriptional program. Furthermore, daily administration of PEP to mice inhibits generation of Th17 cells and ameliorates Th17-dependent autoimmune encephalomyelitis. These data demonstrate that PEP links aerobic glycolysis to the Th17 transcriptional program, suggesting the therapeutic potential of PEP for autoimmune diseases.