Glycogen has long been considered to have a function in energy metabolism. However, our recent study indicated that glycogen metabolism, directed by cytosolic phosphoenolpyruvate carboxykinase Pck1, controls the formation and maintenance of CD8+ memory T (Tmem) cells by regulating redox homeostasis1. This unusual metabolic program raises the question of how Pck1 is upregulated in CD8+ Tmem cells. Here, we show that mitochondrial acetyl coenzyme A is diverted to the ketogenesis pathway, which indirectly regulates Pck1 expression. Mechanistically, ketogenesis-derived β-hydroxybutyrate is present in CD8+ Tmem cells; β-hydroxybutyrate epigenetically modifies Lys 9 of histone H3 (H3K9) of Foxo1 and Ppargc1a (which encodes PGC-1α) with β-hydroxybutyrylation, upregulating the expression of these genes. As a result, FoxO1 and PGC-1α cooperatively upregulate Pck1 expression, therefore directing the carbon flow along the gluconeogenic pathway to glycogen and the pentose phosphate pathway. These results reveal that ketogenesis acts as an unusual metabolic pathway in CD8+ Tmem cells, linking epigenetic modification required for memory development.

中文翻译：

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生酮生成的 β-羟基丁酸是 CD8+ T 细胞记忆发育的表观遗传调节剂。

长期以来，糖原被认为具有能量代谢的功能。然而，我们最近的研究表明，由胞质磷酸烯醇丙酮酸羧激酶 Pck1 指导的糖原代谢通过调节氧化还原稳态来控制 CD8+ 记忆 T (Tmem) 细胞的形成和维持。这种不寻常的代谢程序提出了一个问题，即 CD8+ Tmem 细胞中 Pck1 是如何上调的。在这里，我们显示线粒体乙酰辅酶 A 被转移到酮生成途径，间接调节 Pck1 表达。从机制上讲，生酮衍生的 β-羟基丁酸存在于 CD8+ Tmem 细胞中；β-羟基丁酸通过 β-羟基丁酰化对 Foxo1 和 Ppargc1a（编码 PGC-1α）的组蛋白 H3 (H3K9) 的 Lys 9 进行表观遗传修饰，上调这些基因的表达。因此，FoxO1 和 PGC-1α 协同上调 Pck1 表达，因此引导碳沿着糖异生途径流向糖原和磷酸戊糖途径。这些结果表明，生酮在 CD8+ Tmem 细胞中充当一种不寻常的代谢途径，将记忆发育所需的表观遗传修饰联系起来。