S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate

Tyrakis, Petros A.; Palazón, Asís; Macías, David; Lee, Kian Leong; Phan, Anthony T.; Veliça, Pedro; You, Jia; Chia, Grace Sushin; Sim, Jingwei; Doedens, Andrew L.; Abélanet, Alice; Evans, Colin E.; Griffiths, John R.; Poellinger, Lorenz; Goldrath, Ananda W.; Johnson, Randall S.

doi:10.1038/nature20165

Cited by 347 publications

(331 citation statements)

References 51 publications

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“…The extent to which larvae accumulate L-2HG is striking, as the only other healthy tissues known to accumulate high concentrations of L-2HG are T lymphocytes and cultured human cells that experience hypoxia (20,21). Since we raised larvae under normoxic conditions (Materials and Methods), our results suggested that larvae accumulate L-2HG via a novel metabolic mechanism.…”

Section: Resultsmentioning

confidence: 82%

“…Discussion L-2HG was long considered a metabolic waste product, as eukaryotic genomes lack enzymes devoted to synthesizing this molecule, most cell types quickly degrade L-2HG, and L-2HG accumulation in humans is primarily associated with disease states (3, 12, 15). Recent studies, however, indicate that L-2HG can function as a metabolic signaling molecule and demonstrate a need to better understand the normal cellular functions of this compound (17,20,21). Our findings establish Drosophila as a model for studying L-2HG and provide a genetic framework for conducting in vivo studies of this putative oncometabolite.…”

Section: Resultsmentioning

confidence: 91%

“…which revealed that these immune cells generate L-2HG as a means of controlling cell fate and gene expression (20). Furthermore, both hypoxia and the disruption of mitochondrial metabolism cause human cells to generate high levels of L-2HG, indicating that synthesis of this compound might alleviate oxidative stress (17,(21)(22)(23).…”

Section: Significancementioning

confidence: 99%

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Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth

Chawla

Hurlburt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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L-2-hydroxyglutarate (L-2HG) has emerged as a putative oncometabolite that is capable of inhibiting enzymes involved in metabolism, chromatin modification, and cell differentiation. However, despite the ability of L-2HG to interfere with a broad range of cellular processes, this molecule is often characterized as a metabolic waste product. Here, we demonstrate that Drosophila larvae use the metabolic conditions established by aerobic glycolysis to both synthesize and accumulate high concentrations of L-2HG during normal developmental growth. A majority of the larval L-2HG pool is derived from glucose and dependent on the Drosophila estrogen-related receptor (dERR), which promotes L-2HG synthesis by up-regulating expression of the Drosophila homolog of lactate dehydrogenase (dLdh). We also show that dLDH is both necessary and sufficient for directly synthesizing L-2HG and the Drosophila homolog of L-2-hydroxyglutarate dehydrogenase (dL2HGDH), which encodes the enzyme that breaks down L-2HG, is required for stage-specific degradation of the L-2HG pool. In addition, dLDH also indirectly promotes L-2HG accumulation via synthesis of lactate, which activates a metabolic feedforward mechanism that inhibits dL2HGDH activity and stabilizes L-2HG levels. Finally, we use a genetic approach to demonstrate that dLDH and L-2HG influence position effect variegation and DNA methylation, suggesting that this compound serves to coordinate glycolytic flux with epigenetic modifications. Overall, our studies demonstrate that growing animal tissues synthesize L-2HG in a controlled manner, reveal a mechanism that coordinates glucose catabolism with L-2HG synthesis, and establish the fly as a unique model system for studying the endogenous functions of L-2HG during cell growth and proliferation.ne of the hallmarks of cancer is a dramatic reprograming of cellular metabolism that results in enhanced biosynthesis (1). These metabolic changes are particularly apparent in tumors that use the Warburg effect, also referred to as aerobic glycolysis, a metabolic program characterized by elevated levels of glucose consumption and enhanced lactate production (1, 2). By activating aerobic glycolysis, tumors are able to synthesize macromolecules rapidly from glycolytic intermediates. In addition, elevated levels of lactate dehydrogenase (LDH) activity allow proliferating cells to synthesize lactate and maintain the NAD + levels required for high rates of glucose catabolism and biomass production (1).The metabolic reprogramming of cancer cells, however, extends beyond biosynthesis, as many tumors also generate progrowth metabolites, or oncometabolites, that promote tumor formation via nonmetabolic means. Most notable among these compounds is D-2-hydroxyglutarate (D-2HG), which is associated with cancers such as gliomas and acute myelogenous leukemias (3). Although D-2HG is generated as a normal byproduct of γ-hydroxybutyrate metabolism (4), oncogenic D-2HG production is the result of neomorphic mutations in the active site of isocitrate dehydrogenas...

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Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 91%

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Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth

Chawla

Hurlburt

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In the current issue of Nature, Tyrakis et al 6 report on the physiological role of S-2HG in T cells. T cells display a high degree of metabolic flexibility as their needs change during periods of rapid proliferation and cytolytic activity, and these metabolic changes are required for T-cell function and the formation of durable memory cell populations.…”

mentioning

confidence: 99%

S-2HG is an immunometabolite that shapes the T-cell response

Cairns

Mak

2016

Cell Death Differ

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The field of immunometabolism has expanded rapidly over the past several years, and it is now clear that specific alterations to the metabolism of immune cells occur in response to endogenous and exogenous stimuli in order to tailor the biochemistry of cells to their functional requirements and microenvironmental context. 1 Major findings in T cells have shown that, upon activation, a metabolic response is engaged, resulting in a dramatic increase in glycolysis to support rapid proliferation. Subsequently, during the formation of memory T cells, metabolism shifts away from glycolysis and back towards oxidative phosphorylation fueled by fatty acid oxidation. The mechanisms responsible for this change overlap significantly with the adaptive response to changes in oxygen concentration, but the details are not completely understood.The two chiral forms of the metabolite 2-hydroxyglutarate, R-2HG and S-2HG, are produced in mammalian cells, and are usually maintained at low levels in cells and body fluids via the activity of dedicated dehydrogenase enzymes that convert these compounds to ɑ-ketoglutarate (ɑ-KG). Gain-of-function mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) lead to the inappropriate production and accumulation of R-2HG, which is thought to contribute to tumorigenesis in several tissues by altering epigenetic state and metabolism. 2 The discovery of these mutations has led to a concerted effort to understand the tumorigenic mechanisms underlying R-2HG accumulation. However, little is known about the physiological roles of R-2HG or S-2HG. The ability of these molecules to inhibit a broad class of 2-oxoglutarate-dependent dioxygenases, including key epigenetic regulatory enzymes, suggests that they may have roles in altering the function and fate of specific cells.It has been shown previously that S-2HG increases upon exposure of cells to hypoxia or in situations where mitochondria are dysfunctional. [3][4][5] Under these conditions, S-2HG can be produced by malate dehydrogenase (MDH), lactate dehydrogenase A (LDHA), and even wild-type IDH in certain cell types. These previous studies suggest that accumulation of S-2HG plays a role in the process of hypoxic adaptation by causing epigenetic alterations that are necessary for appropriate reprogramming of metabolism. Interestingly, these previous reports found only a minor role for the HIF transcription factor, often considered the master regulator of the hypoxic response, in mediating the observed increases in S-2HG.In the current issue of Nature, Tyrakis et al. 6 report on the physiological role of S-2HG in T cells. T cells display a high degree of metabolic flexibility as their needs change during periods of rapid proliferation and cytolytic activity, and these metabolic changes are required for T-cell function and the formation of durable memory cell populations. In addition, these cells operate in a diverse array of microenvironmental conditions, including the hypoxic regions of solid tumors, healing wounds, and inflamed tissue, placing ...

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“…I will always remember our last conversation; he came to my office to share his excitement over a new aspect of hypoxia, S-2-hydroxyglutarate, and how this affects cells in the immune system; a paper that was just recently published in Nature. 4 Lorenz will be missed by many friends and colleagues in Sweden and abroad.…”

mentioning

confidence: 99%