Loss of pyruvate kinase M2 limits growth and triggers innate immune signaling in endothelial cells

Nat Commun. 2018 Oct 9;9(1):4077. doi: 10.1038/s41467-018-06406-8.

Abstract

Despite their inherent proximity to circulating oxygen and nutrients, endothelial cells (ECs) oxidize only a minor fraction of glucose in mitochondria, a metabolic specialization that is poorly understood. Here we show that the glycolytic enzyme pyruvate kinase M2 (PKM2) limits glucose oxidation, and maintains the growth and epigenetic state of ECs. We find that loss of PKM2 alters mitochondrial substrate utilization and impairs EC proliferation and migration in vivo. Mechanistically, we show that the NF-κB transcription factor RELB is responsive to PKM2 loss, limiting EC growth through the regulation of P53. Furthermore, S-adenosylmethionine synthesis is impaired in the absence of PKM2, resulting in DNA hypomethylation, de-repression of endogenous retroviral elements (ERVs) and activation of antiviral innate immune signalling. This work reveals the metabolic and functional consequences of glucose oxidation in the endothelium, highlights the importance of PKM2 for endothelial growth and links metabolic dysfunction with autoimmune activation in ECs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Cell Proliferation
  • DNA Methylation
  • Endogenous Retroviruses / metabolism
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism*
  • Gene Deletion
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Neovascularization, Physiologic
  • Pyruvate Kinase / metabolism*
  • Signal Transduction*
  • Thyroid Hormones / metabolism*
  • Transcription Factor RelB / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Carrier Proteins
  • Membrane Proteins
  • RELB protein, human
  • Thyroid Hormones
  • Tumor Suppressor Protein p53
  • thyroid hormone-binding proteins
  • Transcription Factor RelB
  • Pkm protein, mouse
  • Pyruvate Kinase