Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice

Nat Commun. 2018 Jun 14;9(1):2341. doi: 10.1038/s41467-018-04719-2.


Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cytokine activation of NK cell glycolysis and oxidative phosphorylation (OXPHOS) are essential for robust NK cell responses. However, the mechanisms leading to this metabolic phenotype are unclear. Here we show that the transcription factor cMyc is essential for IL-2/IL-12-induced metabolic and functional responses in mice. cMyc protein levels are acutely regulated by amino acids; cMyc protein is lost rapidly when glutamine is withdrawn or when system L-amino acid transport is blocked. We identify SLC7A5 as the predominant system L-amino acid transporter in activated NK cells. Unlike other lymphocyte subsets, glutaminolysis and the tricarboxylic acid cycle do not sustain OXPHOS in activated NK cells. Glutamine withdrawal, but not the inhibition of glutaminolysis, results in the loss of cMyc protein, reduced cell growth and impaired NK cell responses. These data identify an essential role for amino acid-controlled cMyc for NK cell metabolism and function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Animals
  • Cytokines / metabolism
  • Glutamine / chemistry
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycolysis
  • Humans
  • K562 Cells
  • Killer Cells, Natural / cytology*
  • Killer Cells, Natural / metabolism
  • Large Neutral Amino Acid-Transporter 1 / metabolism
  • Lymphocyte Subsets / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Phosphorylation
  • Proteomics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Tricarboxylic Acids / chemistry


  • Amino Acids
  • Cytokines
  • Large Neutral Amino Acid-Transporter 1
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Tricarboxylic Acids
  • Glutamine
  • Mechanistic Target of Rapamycin Complex 1
  • Glycogen Synthase Kinase 3