Phosphoglycerate dehydrogenase activates PKM2 to phosphorylate histone H3T11 and attenuate cellular senescence

Yinsheng Wu, Lixu Tang, Han Huang, Qi Yu, Bicheng Hu, Gang Wang, Feng Ge, Tailang Yin (), Shanshan Li () and Xilan Yu ()
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Yinsheng Wu: Hubei University
Lixu Tang: Wuhan Sports University
Han Huang: Hubei University
Qi Yu: Hubei University
Bicheng Hu: Wuhan No.1 Hospital
Gang Wang: Hubei University
Feng Ge: Chinese Academy of Sciences
Tailang Yin: Renmin Hospital of Wuhan University
Shanshan Li: Hubei University
Xilan Yu: Hubei University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Vascular endothelial cells (ECs) senescence correlates with the increase of cardiovascular diseases in ageing population. Although ECs rely on glycolysis for energy production, little is known about the role of glycolysis in ECs senescence. Here, we report a critical role for glycolysis-derived serine biosynthesis in preventing ECs senescence. During senescence, the expression of serine biosynthetic enzyme PHGDH is significantly reduced due to decreased transcription of the activating transcription factor ATF4, which leads to reduction of intracellular serine. PHGDH prevents premature senescence primarily by enhancing the stability and activity of pyruvate kinase M2 (PKM2). Mechanistically, PHGDH interacts with PKM2, which prevents PCAF-catalyzed PKM2 K305 acetylation and subsequent degradation by autophagy. In addition, PHGDH facilitates p300-catalyzed PKM2 K433 acetylation, which promotes PKM2 nuclear translocation and stimulates its activity to phosphorylate H3T11 and regulate the transcription of senescence-associated genes. Vascular endothelium-targeted expression of PHGDH and PKM2 ameliorates ageing in mice. Our findings reveal that enhancing serine biosynthesis could become a therapy to promote healthy ageing.

Date: 2023
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DOI: 10.1038/s41467-023-37094-8

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