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

• DOI: 10.1038/s41467-018-04719-2
• Publication Date: 2018-06-08T09:44:16Z
• Authors: Róisín M. Loftus; Nadine Assmann; Nidhi Kedia-Mehta; Katie L. O’Brien; Arianne Garcia; Conor Gillespie; Jens L. Hukelmann; Peter J. Oefner; Angus I. Lamond; Clair M. Gardiner; Katja Dettmer; Doreen A. Cantrell; Linda V. Sinclair; David K. Finlay
• Keywords: Male; Proteomics; Science; Glutamine; 610 Medizin; Mechanistic Target of Rapamycin Complex 1; Article; Oxidative Phosphorylation; Large Neutral Amino Acid-Transporter 1; Proto-Oncogene Proteins c-myc; Glycogen Synthase Kinase 3; Mice; 03 medical and health sciences; 0302 clinical medicine; Animals; Humans; Amino Acids; ddc:610; Q; Tricarboxylic Acids; Lymphocyte Subsets; Killer Cells, Natural; Mice, Inbred C57BL; Cytokines; K562 Cells; Glycolysis

AbstractNatural 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 cMyc protein levels are acutely regulated by amino acids; cMyc protein is lost rapidly when glutamine is withdrawn or when system l-amino acid transport is blocked.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.