Skip to main content

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

Publication ,  Journal Article
Stone, OA; El-Brolosy, M; Wilhelm, K; Liu, X; Romão, AM; Grillo, E; Lai, JKH; Günther, S; Jeratsch, S; Kuenne, C; Lee, I-C; Braun, T ...
Published in: Nat Commun
October 9, 2018

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

October 9, 2018

Volume

9

Issue

1

Start / End Page

4077

Location

England

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transcription Factor RelB
  • Thyroid Hormones
  • Thyroid Hormone-Binding Proteins
  • Signal Transduction
  • Pyruvate Kinase
  • Neovascularization, Physiologic
  • Mitochondria
  • Mice, Inbred C57BL
  • Membrane Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Stone, O. A., El-Brolosy, M., Wilhelm, K., Liu, X., Romão, A. M., Grillo, E., … Stainier, D. Y. R. (2018). Loss of pyruvate kinase M2 limits growth and triggers innate immune signaling in endothelial cells. Nat Commun, 9(1), 4077. https://doi.org/10.1038/s41467-018-06406-8
Stone, Oliver A., Mohamed El-Brolosy, Kerstin Wilhelm, Xiaojing Liu, Ana M. Romão, Elisabetta Grillo, Jason K. H. Lai, et al. “Loss of pyruvate kinase M2 limits growth and triggers innate immune signaling in endothelial cells.Nat Commun 9, no. 1 (October 9, 2018): 4077. https://doi.org/10.1038/s41467-018-06406-8.
Stone OA, El-Brolosy M, Wilhelm K, Liu X, Romão AM, Grillo E, et al. Loss of pyruvate kinase M2 limits growth and triggers innate immune signaling in endothelial cells. Nat Commun. 2018 Oct 9;9(1):4077.
Stone, Oliver A., et al. “Loss of pyruvate kinase M2 limits growth and triggers innate immune signaling in endothelial cells.Nat Commun, vol. 9, no. 1, Oct. 2018, p. 4077. Pubmed, doi:10.1038/s41467-018-06406-8.
Stone OA, El-Brolosy M, Wilhelm K, Liu X, Romão AM, Grillo E, Lai JKH, Günther S, Jeratsch S, Kuenne C, Lee I-C, Braun T, Santoro MM, Locasale JW, Potente M, Stainier DYR. Loss of pyruvate kinase M2 limits growth and triggers innate immune signaling in endothelial cells. Nat Commun. 2018 Oct 9;9(1):4077.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

October 9, 2018

Volume

9

Issue

1

Start / End Page

4077

Location

England

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Transcription Factor RelB
  • Thyroid Hormones
  • Thyroid Hormone-Binding Proteins
  • Signal Transduction
  • Pyruvate Kinase
  • Neovascularization, Physiologic
  • Mitochondria
  • Mice, Inbred C57BL
  • Membrane Proteins