Srebp-controlled glucose metabolism is essential for NK cell functional responses
Open accessAbstract
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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The citrate-malate shuttle performs functions beyond electron shuttling and supports continuous citrate regeneration and TCA cycle intermediate homeostasis.
“More recently, it was demonstrated that the citrate–malate shuttle performs functions beyond that of an electron shuttle and, in fact, supports continuous citrate regeneration and TCA cycle intermediate homeostasis (119, 121).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [119]
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- Authors
- Assmann, N., O'Brien, K. L., Donnelly, R. P., Dyck, L., Zaiatz-Bittencourt, V., Loftus, R. M., Heinrich, P., Oefner, P. J., Lynch, L., Gardiner, C. M., Dettmer, K., & Finlay, D. K.
- Affiliations
- Trinity College Dublin (IE)
- University of Regensburg (DE)
- Corresponding author
- Finlay, David K
- ORCID
- Venue
- Nature Immunology
- Published
- 2017-09-18
- Volume
- 18
- Issue
- 11
- Pages
- 1197-1206
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2755907400
- Cited by
- 375
- References
- 57
- Citations by year
- 2026: 35 · 2025: 54 · 2024: 37 · 2023: 44 · 2022: 53 · 2021: 57 · 2020: 45 · 2019: 25 · 2018: 21 · 2017: 4
- FWCI
- 11.74
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- natural killer cells, SREBP, glucose metabolism, metabolic reprogramming, glycolysis, oxidative phosphorylation, interferon-gamma, NK cell cytotoxicity, cytokine activation, antitumor immunity, viral infection
- MeSH terms
- Animals, Flow Cytometry, Glucose, Glycolysis, Humans, Killer Cells, Natural, Lipids, Oxidative Phosphorylation, Immunoblotting, T-Lymphocyte Subsets, Cytokines, Cell Proliferation, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2
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