2. Academic Validation
  3. Phosphoglycerate dehydrogenase activates PKM2 to phosphorylate histone H3T11 and attenuate cellular senescence

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

  • Nat Commun. 2023 Mar 10;14(1):1323. doi: 10.1038/s41467-023-37094-8.
Yinsheng Wu # 1,  Lixu Tang # 2,  Han Huang 1,  Qi Yu 1,  Bicheng Hu 3,  Gang Wang 1,  Feng Ge 4,  Tailang Yin 5,  Shanshan Li 6,  Xilan Yu 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, Hubei, 430062, China.
  • 2 School of Martial Arts, Wuhan Sports University, Wuhan, Hubei, 430079, China.
  • 3 The Central Laboratory, Wuhan No.1 Hospital, Wuhan, Hubei, 430022, China.
  • 4 Key Laboratory of Algal Biology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei, 430072, China.
  • 5 Reproductive Medicine Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China. reproductive@whu.edu.cn.
  • 6 State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, Hubei, 430062, China. shl@hubu.edu.cn.
  • 7 State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, Hubei, 430062, China. yuxilan@hubu.edu.cn.
  • # Contributed equally.
PMID: 36899022 DOI: 10.1038/s41467-023-37094-8
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.

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