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

Oliver A. Stone (), Mohamed El-Brolosy, Kerstin Wilhelm, Xiaojing Liu, Ana M. Romão, Elisabetta Grillo, Jason K. H. Lai, Stefan Günther, Sylvia Jeratsch, Carsten Kuenne, I-Ching Lee, Thomas Braun, Massimo M. Santoro, Jason W. Locasale, Michael Potente and Didier Y. R. Stainier
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Oliver A. Stone: Max Planck Institute for Heart and Lung Research
Mohamed El-Brolosy: Max Planck Institute for Heart and Lung Research
Kerstin Wilhelm: Max Planck Institute for Heart and Lung Research
Xiaojing Liu: Duke University School of Medicine
Ana M. Romão: Max Planck Institute for Heart and Lung Research
Elisabetta Grillo: KUL
Jason K. H. Lai: Max Planck Institute for Heart and Lung Research
Stefan Günther: Max Planck Institute for Heart and Lung Research
Sylvia Jeratsch: Max Planck Institute for Heart and Lung Research
Carsten Kuenne: Max Planck Institute for Heart and Lung Research
I-Ching Lee: Max Planck Institute for Heart and Lung Research
Thomas Braun: Max Planck Institute for Heart and Lung Research
Massimo M. Santoro: University of Padua
Jason W. Locasale: Duke University School of Medicine
Michael Potente: Max Planck Institute for Heart and Lung Research
Didier Y. R. Stainier: Max Planck Institute for Heart and Lung Research

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06406-8

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