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Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development.

Abstract：

: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.

journal_name

Nat Cell Biol

journal_title

Nature cell biology

authors

Zhang H,Tang K,Ma J,Zhou L,Liu J,Zeng L,Zhu L,Xu P,Chen J,Wei K,Liang X,Lv J,Xie J,Liu Y,Wan Y,Huang B

doi

10.1038/s41556-019-0440-0

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

18-25

issue

1

eissn

1465-7392

issn

1476-4679

pii

10.1038/s41556-019-0440-0

journal_volume

22

pub_type

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