Srebp-controlled glucose metabolism is essential for NK cell functional responses

Nat Immunol. 2017 Nov;18(11):1197-1206. doi: 10.1038/ni.3838. Epub 2017 Sep 18.


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.

MeSH terms

  • Animals
  • Cell Proliferation
  • Cytokines / metabolism
  • Flow Cytometry
  • Glucose / metabolism*
  • Glycolysis*
  • Humans
  • Immunoblotting
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • Lipids / biosynthesis
  • Oxidative Phosphorylation
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • Sterol Regulatory Element Binding Protein 2 / metabolism*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism


  • Cytokines
  • Lipids
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Glucose