Abstract

Activated natural killer (NK) cells engage in a robust metabolic response that is required for normal effector function. Using genetic, pharmacological and metabolic analyses, we demonstrated an essential role for Srebp transcription factors in cytokine-induced metabolic reprogramming of NK cells that was independent of their conventional role in the control of lipid synthesis. Srebp was required for elevated glycolysis and oxidative phosphorylation and promoted a distinct metabolic pathway configuration in which glucose was metabolized to cytosolic citrate via the citrate–malate shuttle. Preventing the activation of Srebp or direct inhibition of the citrate–malate shuttle inhibited production of interferon-γ and NK cell cytotoxicity. Thus, Srebp controls glucose metabolism in NK cells, and this Srebp-dependent regulation is critical for NK cell effector function.

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Acknowledgements

We thank the Comparative Medicine Unit, Trinity College Dublin for use of their facilities. Supported by Science Foundation Ireland (12/IP/1286 and 13/CDA/2161 for the D.K.F. laboratory); Irish Cancer Society (research scholarship CRS15OBR to K.L.O'B. which includes support from the Children's Leukaemia Research Project), Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil (research scholarship BEX 13446134 to V.Z.B.) and Deutsche Forschungsgemeinschaft (KFO-262 for K.D.).

Author information

Author notes

    • Katie L O'Brien
    •  & Raymond P Donnelly

    These authors contributed equally to this work.

Affiliations

  1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.

    • Nadine Assmann
    • , Katie L O'Brien
    • , Raymond P Donnelly
    • , Lydia Dyck
    • , Vanessa Zaiatz-Bittencourt
    • , Róisín M Loftus
    • , Lydia Lynch
    • , Clair M Gardiner
    •  & David K Finlay
  2. Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.

    • Paul Heinrich
    • , Peter J Oefner
    •  & Katja Dettmer
  3. School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.

    • David K Finlay

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Contributions

Conceptualization, N.A., R.P.D. and D.K.F.; methodology, N.A., R.P.D., L.D., V.Z.-B., C.M.G., K.D. and D.K.F.; investigation, N.A., K.L.O'B. R.P.D., L.D., V.Z.-B., R.M.L., K.D. and P.H.; writing (original draft), N.A. and D.K.F.; writing (review and editing), N.A., K.L.O'B., P.J.O., C.M.G. and D.K.F.; and supervision, P.J.O., L.L., C.M.G. and D.K.F.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David K Finlay.

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https://doi.org/10.1038/ni.3838

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