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

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

doi:10.1038/s41467-018-04719-2

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

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 (Lead / Corresponding author)

Cell Signalling and Immunology

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 cMyc protein levels are acutely regulated by amino acids; cMyc protein is lost rapidly when glutamine is withdrawn or when system L-amino acid transport is blocked.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

Original language	English
Article number	2341
Pages (from-to)	1-15
Number of pages	15
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04719-2
Publication status	Published - 14 Jun 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Final published version, 2.13 MBLicence: CC BY

Multidimensional Proteomic Analysis of Metabolic Stress & Cellular Phenotypes (Strategic Grant)
Cantrell, D. (Investigator) & Lamond, A. (Investigator)
1/01/15 → 31/12/19
Project: Research
Serine Kinase Pathways that Determine T Lymphocyte Activation and Cell Fate Choices (Principal Research Fellowship renewal)
Cantrell, D. (Investigator)
1/10/12 → 1/10/24
Project: Research

Cantrell, Doreen
- Cell Signalling and Immunology - Wellcome Trust Principal Research Fellow of Immunology
Person: Academic

Cite this

Loftus, R. M., Assmann, N., Kedia-Mehta, N., O'Brien, K. L., Garcia, A., Gillespie, C., Hukelmann, J. L., Oefner, P. J., Lamond, A. I., Gardiner, C. M., Dettmer, K., Cantrell, D. A., Sinclair, L. V., & Finlay, D. K. (2018). Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice. Nature Communications, 9(1), 1-15. Article 2341. https://doi.org/10.1038/s41467-018-04719-2

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

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.",

author = "Loftus, {R{\'o}is{\'i}n M.} and Nadine Assmann and Nidhi Kedia-Mehta and O'Brien, {Katie L.} and Arianne Garcia and Conor Gillespie and Hukelmann, {Jens L.} and Oefner, {Peter J.} and Lamond, {Angus I.} and Gardiner, {Clair M.} and Katja Dettmer and Cantrell, {Doreen A.} and Sinclair, {Linda V.} and Finlay, {David K.}",

note = "This work was supported by the Science Foundation Ireland (12/IP/1286 and 13/CDA/2161) and Marie Sk{\l}odowska-Curie Actions (PCIG11-GA-2012-321603), German Research Foundation (KFO262). K.L.O. is supported by an Irish Cancer Society Research Scholarship (CRS15OBR) including support from the Children{\textquoteright}s Leukaemia Research Project.",

year = "2018",

month = jun,

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doi = "10.1038/s41467-018-04719-2",

language = "English",

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Loftus, RM, Assmann, N, Kedia-Mehta, N, O'Brien, KL, Garcia, A, Gillespie, C, Hukelmann, JL, Oefner, PJ, Lamond, AI, Gardiner, CM, Dettmer, K, Cantrell, DA , Sinclair, LV & Finlay, DK 2018, 'Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice', Nature Communications, vol. 9, no. 1, 2341, pp. 1-15. https://doi.org/10.1038/s41467-018-04719-2

TY - JOUR

T1 - Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice

AU - Loftus, Róisín M.

AU - Assmann, Nadine

AU - Kedia-Mehta, Nidhi

AU - O'Brien, Katie L.

AU - Garcia, Arianne

AU - Gillespie, Conor

AU - Hukelmann, Jens L.

AU - Oefner, Peter J.

AU - Lamond, Angus I.

AU - Gardiner, Clair M.

AU - Dettmer, Katja

AU - Cantrell, Doreen A.

AU - Sinclair, Linda V.

AU - Finlay, David K.

N1 - This work was supported by the Science Foundation Ireland (12/IP/1286 and 13/CDA/2161) and Marie Skłodowska-Curie Actions (PCIG11-GA-2012-321603), German Research Foundation (KFO262). K.L.O. is supported by an Irish Cancer Society Research Scholarship (CRS15OBR) including support from the Children’s Leukaemia Research Project.

PY - 2018/6/14

Y1 - 2018/6/14

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-018-04719-2

DO - 10.1038/s41467-018-04719-2

M3 - Article

C2 - 29904050

SN - 2041-1723

VL - 9

SP - 1

EP - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2341

ER -

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

Abstract

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Projects

Multidimensional Proteomic Analysis of Metabolic Stress & Cellular Phenotypes (Strategic Grant)

Serine Kinase Pathways that Determine T Lymphocyte Activation and Cell Fate Choices (Principal Research Fellowship renewal)

Profiles

Cantrell, Doreen

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