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

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

Author information

1
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany. oliver.stone@dpag.ox.ac.uk.
2
Department of Physiology, Anatomy and Genetics, BHF Centre of Research Excellence, University of Oxford, Oxford, OX1 3PT, UK. oliver.stone@dpag.ox.ac.uk.
3
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany.
4
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany.
5
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
6
Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany.
7
Department of Oncology, KUL, Herestraat 49, 3000, Leuven, Belgium.
8
Mechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore.
9
ECCPS Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany.
10
Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231, Bad Nauheim, Germany.
11
Department of Biology, University of Padua, Viale Giuseppe Colombo 3, 10141, Padua, Italy.

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.

PMID:
30301887
PMCID:
PMC6177464
DOI:
10.1038/s41467-018-06406-8
[Indexed for MEDLINE]
Free PMC Article

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