mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity
Open accessAbstract
A BLUEPRINT of immune cell development: To determine the epigenetic mechanisms that direct blood cells to develop into the many components of our immune system, the BLUEPRINT consortium examined the regulation of DNA and RNA transcription to dissect the molecular traits that govern blood cell differentiation. By inducing immune responses, Saeed et al. document the epigenetic changes in the genome that underlie immune cell differentiation. Cheng et al. demonstrate that trained monocytes are highly dependent on the breakdown of sugars in the presence of oxygen, which allows cells to produce the energy needed to mount an immune response. Chen et al. examine RNA transcripts and find that specific cell lineages use RNA transcripts of different length and composition (isoforms) to form proteins. Together, the studies reveal how epigenetic effects can drive the development of blood cells involved in the immune system. Science , this issue 10.1126/science.1251086 , 10.1126/science.1250684 , 10.1126/science.1251033
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AKT/mTOR/HIF1α signaling plays critical roles in promoting glycolysis and lactate production and thus in the metabolic reprogramming of cancer cells.
“AKT/mTOR/HIF1α signaling has been suggested to play critical roles in promoting glycolysis and lactate production and thus in the “metabolic reprogramming” of cancer cells24–28.”
From RETRACTED ARTICLE: Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression (2020) · cites this paper as [28]
mTOR is a conserved serine/threonine kinase that plays a key role in integrating multiple physiological stimuli to regulate cell growth and metabolic pathways.
“mTOR is a conserved serine/threonine kinase that plays a key role in integrating multiple physiological stimuli to regulate cell growth and metabolic pathways27,28,40,48.”
From RETRACTED ARTICLE: Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression (2020) · cites this paper as [28]
mTOR activates glycolysis through modulating HIF-1α, indirectly upregulating transcription of almost all glycolytic genes in tumor cells.
“mTOR activates glycolysis through modulating the expression of the transcription factor HIF-1α, indirectly upregulating the transcription of almost all glycolytic genes in tumor cell5,28,56.”
From RETRACTED ARTICLE: Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression (2020) · cites this paper as [28]
SirT5 has potent desuccinylase and demalonylase activity.
“SirT5, which was previously thought to function primarily as a deacetylase has been shown to have potent desuccinylase activity 44.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [44]
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- Authors
- Cheng, S.-C., Quintin, J., Cramer, R. A., Shepardson, K. M., Saeed, S., Kumar, V., Giamarellos-Bourboulis, E. J., Martens, J. H. A., Rao, N. A., Aghajanirefah, A., Manjeri, G. R., Li, Y., Ifrim, D. C., Arts, R. J. W., van der Veer, B. M. J. W., Deen, P. M. T., Logie, C., O’Neill, L. A., Willems, P., van de Veerdonk, F. L., van der Meer, J. W. M., Ng, A., Joosten, L. A. B., Wijmenga, C., Stunnenberg, H. G., Xavier, R. J., & Netea, M. G.
- Affiliations
- Radboud University Medical Center (NL)
- Dartmouth College (US)
- Radboud University Nijmegen (NL)
- University Medical Center Groningen (NL)
- 4th Department of Internal Medicine, University of Athens Medical School, 12462 Athens, Greece.
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
- Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands.
- Broad Institute (US)
- Corresponding author
- Netea, Mihai G.
- ORCID
- Venue
- Science
- Published
- 2014-09-26
- Volume
- 345
- Issue
- 6204
- Pages
- 1250684-1250684
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4226238
- OpenAlex
- W2067031028
- Cited by
- 2,224
- References
- 45
- Citations by year
- 2026: 266 · 2025: 262 · 2024: 242 · 2023: 199 · 2022: 227 · 2021: 235 · 2020: 199 · 2019: 139 · 2018: 145 · 2017: 111 · 2016: 107 · 2015: 81 · 2014: 10 · 2013: 1
- FWCI
- 46.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- HAL (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Leona M. and Harry B. Helmsley Charitable Trust (DK097485)
- European Commission (322698, 2007–2013, 310372, FP/2007-2013)/ERC, FP/2007/2013)
- National Institute of General Medical Sciences (P30GM106394, P30GM103415)
- National Institute of Allergy and Infectious Diseases (R01AI081838)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 097485, R01DK097485, DK 43351, P30DK043351)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- trained immunity, aerobic glycolysis, mTOR, HIF-1α, Akt signaling, myeloid cells, monocytes, epigenetic reprogramming, β-glucan, Candida albicans, NAD+/NADH ratio, lactic acid production, metformin, AMPK, innate immunity, sepsis, fungal infection
- MeSH terms
- Aerobiosis, Animals, Candida albicans, Candidiasis, Disease Models, Animal, Female, Glucose, Glycolysis, Humans, Immunity, Innate, Immunologic Memory, Male, Mice, Inbred C57BL, Monocytes, Staphylococcal Infections, Staphylococcus aureus, Sepsis, Epigenesis, Genetic, beta-Glucans, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases, Transcriptome
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