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

Author

Listed:
  • Róisín M. Loftus

    (Trinity College Dublin)

  • Nadine Assmann

    (Trinity College Dublin)

  • Nidhi Kedia-Mehta

    (Trinity College Dublin)

  • Katie L. O’Brien

    (Trinity College Dublin)

  • Arianne Garcia

    (Trinity College Dublin)

  • Conor Gillespie

    (Trinity College Dublin)

  • Jens L. Hukelmann

    (School of Life Sciences, University of Dundee
    University of Dundee)

  • Peter J. Oefner

    (University of Regensburg)

  • Angus I. Lamond

    (School of Life Sciences, University of Dundee)

  • Clair M. Gardiner

    (Trinity College Dublin)

  • Katja Dettmer

    (University of Regensburg)

  • Doreen A. Cantrell

    (University of Dundee)

  • Linda V. Sinclair

    (University of Dundee)

  • David K. Finlay

    (Trinity College Dublin
    Trinity College Dublin)

Abstract

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 cMyc protein levels are acutely regulated by amino acids; cMyc protein is lost rapidly when glutamine is withdrawn or when system l-amino acid transport is blocked.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

Suggested Citation

  • 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 , 2018. "Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04719-2
    DOI: 10.1038/s41467-018-04719-2
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    Cited by:

    1. Zenan Wang & Binghao Li & Shan Li & Wenlong Lin & Zhan Wang & Shengdong Wang & Weida Chen & Wei Shi & Tao Chen & Hao Zhou & Eloy Yinwang & Wenkan Zhang & Haochen Mou & Xupeng Chai & Jiahao Zhang & Zhi, 2022. "Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Nicholas L. Dooley & Tinashe G. Chabikwa & Zuleima Pava & Jessica R. Loughland & Julianne Hamelink & Kiana Berry & Dean Andrew & Megan S. F. Soon & Arya SheelaNair & Kim A. Piera & Timothy William & B, 2023. "Single cell transcriptomics shows that malaria promotes unique regulatory responses across multiple immune cell subsets," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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