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TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation
Open accessAbstract
The ligation of Toll-like receptors (TLRs) leads to rapid activation of dendritic cells (DCs). However, the metabolic requirements that support this process remain poorly defined. We found that DC glycolytic flux increased within minutes of exposure to TLR agonists and that this served an essential role in supporting the de novo synthesis of fatty acids for the expansion of the endoplasmic reticulum and Golgi required for the production and secretion of proteins that are integral to DC activation. Signaling via the kinases TBK1, IKKɛ and Akt was essential for the TLR-induced increase in glycolysis by promoting the association of the glycolytic enzyme HK-II with mitochondria. In summary, we identified the rapid induction of glycolysis as an integral component of TLR signaling that is essential for the anabolic demands of the activation and function of DCs.
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“The increased degradation of key enzymes, such as SUCLA2, ALDH2 and ACO2, is consistent with a reported shift in LPS-stimulated DCs from oxidative phosphorylation and oxygen consumption to glycolysis, glucose consumption and lactate production (39–42).”
From Dynamic profiling of the protein life cycle in response to pathogens (2015) · cites this paper as [42]
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“Metabolic state is directly manipulated by cytokine and pattern-recognition receptors, and elevated glycolytic activity has been tied to immune cell activation (Everts et al., 2014; O’Neill and Pearce, 2016).”
From Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain (2018) · cites this paper as Everts et al., 2014
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Metadata
- Authors
- Everts, B., Amiel, E., Huang, S. C.-C., Smith, A. M., Chang, C.-H., Lam, W. Y., Redmann, V., Freitas, T. C., Blagih, J., van der Windt, G. J. W., Artyomov, M. N., Jones, R. G., Pearce, E. L., & Pearce, E. J.
- Affiliations
- Washington University in St. Louis (US)
- University of Vermont (US)
- Trudeau Institute (US)
- McGill University (CA)
- Corresponding author
- Pearce, Erika L
- Pearce, Edward J
- ORCID
- Venue
- Nature Immunology
- Published
- 2014-02-23
- Volume
- 15
- Issue
- 4
- Pages
- 323-332
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC4358322
- OpenAlex
- W2054828149
- Cited by
- 1,064
- References
- 48
- Citations by year
- 2026: 75 · 2025: 84 · 2024: 89 · 2023: 99 · 2022: 93 · 2021: 119 · 2020: 127 · 2019: 97 · 2018: 81 · 2017: 72 · 2016: 61 · 2015: 44 · 2014: 21
- FWCI
- 30.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Institutes of Health
- National Cancer Institute (CA158823, CA164062, R21CA158823, R01CA164062)
- National Institute of Allergy and Infectious Diseases (R01AI091965, AI049823, T32AI049823, R01AI053825, AI53825)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- dendritic cell activation, glycolytic reprogramming, Toll-like receptor signaling, TBK1, IKKε, Akt, hexokinase 2, fatty acid synthesis, mitochondrial association, endoplasmic reticulum expansion, Golgi apparatus, dendritic cell metabolism, oxidative phosphorylation
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Dendritic Cells, Fatty Acids, Glycolysis, Hexokinase, Lipopolysaccharides, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Transgenic, T-Lymphocytes, Signal Transduction, Protein Serine-Threonine Kinases, Mice, Knockout, RNA, Small Interfering, Proto-Oncogene Proteins c-akt, Toll-Like Receptors, Mice, I-kappa B Kinase
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