Review
Series: Superlative Sequels
Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription

https://doi.org/10.1016/j.tibs.2016.05.013Get rights and content

Trends

Many cytoplasmic metabolic enzymes (including all essential glycolytic enzymes) and mitochondrial enzymes moonlight in the nucleus.

Their nuclear function includes canonical (production of the metabolite they normally produce) and non-canonical functions, independent of catalytic activity, such as kinase activity or DNA binding to regulate gene transcription and DNA repair.

The nuclear production of metabolites is important. For example, acetyl-CoA is produced in mitochondria and is crucially needed for histone acetylation in the nucleus, but is not permeable through mitochondrial membranes and, owing to its high-energy status and instability, needs to be produced close to where it is needed.

These nuclear metabolic enzymes provide the basis of an emerging metabolism–gene transcription axis, which includes epigenetic regulation (histone acetylation, histone and DNA methylation).

Growing evidence suggests that this axis optimizes adaptive responses linking metabolic stress to cellular functions such as proliferation or differentiation.

During evolution, cells acquired the ability to sense and adapt to varying environmental conditions, particularly in terms of fuel supply. Adaptation to fuel availability is crucial for major cell decisions and requires metabolic alterations and differential gene expression that are often epigenetically driven. A new mechanistic link between metabolic flux and regulation of gene expression is through moonlighting of metabolic enzymes in the nucleus. This facilitates delivery of membrane-impermeable or unstable metabolites to the nucleus, including key substrates for epigenetic mechanisms such as acetyl-CoA which is used in histone acetylation. This metabolism–epigenetics axis facilitates adaptation to a changing environment in normal (e.g., development, stem cell differentiation) and disease states (e.g., cancer), providing a potential novel therapeutic target.

Section snippets

Moonlighting Metabolic Enzymes and Adaptive Cellular Metabolism Homeostasis

Moonlighting proteins perform multiple autonomous and often unrelated functions, increasing functional options for the cell, without increasing the number of genes that need to be replicated and transcribed. The first example of a moonlighting protein was described by Hendriks et al. who showed that ɛ-crystallin, a structural protein of the duck lens, was actually the metabolic enzyme lactate dehydrogenase (LDH) [1]. Since then, multiple moonlighting proteins have been described in many species

Glycolytic Enzymes in the Nucleus

The first reports of glycolytic enzymes present in the nucleus date to the late 1950s 8, 9, 10, but all essential glycolytic enzymes have now been observed in the nucleus [11] (Figure 1). Glycolysis produces pyruvate from glucose using the oxidative potential of NAD+ which is converted to NADH. In the absence of oxygen or healthy mitochondria, lactate dehydrogenase (LDH) converts pyruvate into lactic acid and uses NADH to regenerate NAD+. Otherwise, PDC converts pyruvate into acetyl-CoA in the

Mitochondrial Krebs Cycle Enzymes in the Nucleus

Unlike the enzymes of glycolysis that are all present in the nucleus, only some of the mitochondrial enzymes that support the Krebs cycle have been found in the nucleus (Figure 1 and Table 1).

Acetyl-CoA-Producing Enzymes (ACPEs) and Histone Acetylation in the Nucleus

Acetylation and phosphorylation are the two most common protein post-translational modifications. Acetylation of lysine residues can alter the function or cellular localization of many proteins, including metabolic enzymes, and plays a crucial role in epigenetic regulation through the acetylation of histones. As many as 4600 total acetylation [68] and over 60 histone acetylation [69] sites have now been described. The acetylation of histones promotes gene transcription through neutralization of

Methylation in the Nucleus

DNA and histone methylation/demethylation occur in the nucleus through the metabolite SAM (the sole methyl group donor for all methylation reactions), methyltransferases, and demethylases. As with acetylation, there is also evidence that methylation can occur at specific sub-nuclear domains. For example, methionine adenosyl-transferase IIa (MATIIa) is recruited to specific MafK sites and synthesizes SAM locally [76], which can then be used for localized histone methylation through interactions

Nuclear Metabolic Enzymes and Major Cell Decisions

That nuclear methylation and acetylation are reciprocally regulated [84] suggests a very complex network, partially regulated by the translocation and choreography of specific metabolic enzyme groups in the nucleus. It is intriguing to speculate that this choreography of nuclear metabolic enzymes is a part of a comprehensive mechanism to drive gene transcription toward specific cell decisions, particularly those relating to or driven by the supply/demand of fuels and nutrients, including

Metabolic Enzyme Trafficking

The nuclear translocation mechanism of metabolic enzymes remains largely unknown, and many of them lack nuclear localization sequences. One can provocatively hypothesize that groups of these enzymes can translocate together as a ‘package’, following a common stimulus, as part of a program linked to a specific cell decision. For example, direct acetylation of the glycolytic enzymes GAPDH 99, 100 and PKM2 [101] by the acetyltransferase p300 promotes their nuclear translocation and their

Concluding Remarks: Translational Implications

The nuclear translocation of metabolic enzymes is exploited by cancer cells, and thus may also be explored therapeutically (see Outstanding Questions). (i) There is a rapidly growing interest in targeting many metabolic enzymes in cancer. Metabolic modulators of several enzymes are being studied as potential cancer therapies (Box 2). Such drugs can have epigenetic effects, altering the levels of many gene products, thereby amplifying their effect beyond what would be predicted from their

References (134)

  • Z. Ronai

    Aldolase–DNA interactions in a SEWA cell system

    Biochim. Biophys. Acta

    (1992)
  • P. Mamczur

    Nuclear localization of aldolase A correlates with cell proliferation

    Biochim. Biophys. Acta

    (2013)
  • E.C. Yego et al.

    Siah-1 Protein is necessary for high glucose-induced glyceraldehyde-3-phosphate dehydrogenase nuclear accumulation and cell death in Muller cells

    J. Biol. Chem.

    (2010)
  • L. Zheng

    S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component

    Cell

    (2003)
  • K.P. Sundararaj

    Rapid shortening of telomere length in response to ceramide involves the inhibition of telomere binding activity of nuclear glyceraldehyde-3-phosphate dehydrogenase

    J. Biol. Chem.

    (2004)
  • O. Popanda

    Modulation of DNA polymerases alpha, delta and epsilon by lactate dehydrogenase and 3-phosphoglycerate kinase

    Biochim. Biophys. Acta

    (1998)
  • H. Qiu

    Assignment and expression patterns of porcine muscle-specific isoform of phosphoglycerate mutase gene

    J. Genet. Genomics

    (2008)
  • S. Feo

    ENO1 gene product binds to the c-myc promoter and acts as a transcriptional repressor: relationship with Myc promoter-binding protein 1 (MBP-1)

    FEBS Lett.

    (2000)
  • X. Gao

    Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase

    Mol. Cell

    (2012)
  • Y. Jiang

    PKM2 regulates chromosome segregation and mitosis progression of tumor cells

    Mol. Cell

    (2014)
  • A.M. Hosios

    Lack of evidence for PKM2 protein kinase activity

    Mol. Cell

    (2015)
  • W. Luo

    Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1

    Cell

    (2011)
  • J. Lee

    Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription

    Int. J. Biochem. Cell Biol.

    (2008)
  • S. Li

    Serine and SAM responsive complex SESAME regulates histone modification crosstalk by sensing cellular metabolism

    Mol. Cell

    (2015)
  • Z. Castonguay

    Nuclear lactate dehydrogenase modulates histone modification in human hepatocytes

    Biochem. Biophys. Res. Commun.

    (2014)
  • B.S. McEwen

    Studies on energy-yielding reactions in thymus nuclei. II. Pathways of aerobic carbohydrate catabolism

    J. Biol. Chem.

    (1963)
  • P. De et al.

    Evidence of nucleolar succinic dehydrogenase activity

    Exp. Cell Res.

    (1962)
  • S.J. Jung

    Essential function of Aco2, a fusion protein of aconitase and mitochondrial ribosomal protein bL21, in mitochondrial translation in fission yeast

    FEBS Lett.

    (2015)
  • Y. Chen

    Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways

    Mol. Cell. Proteomics

    (2012)
  • H. Huang

    SnapShot: histone modifications

    Cell

    (2014)
  • F.Y. Chueh

    Nuclear localization of pyruvate dehydrogenase complex-E2 (PDC-E2), a mitochondrial enzyme, and its role in signal transducer and activator of transcription 5 (STAT5)-dependent gene transcription

    Cell. Signal.

    (2011)
  • Y. Katoh

    Methionine adenosyltransferase II serves as a transcriptional corepressor of Maf oncoprotein

    Mol. Cell

    (2011)
  • Y. Kera

    Methionine adenosyltransferase II-dependent histone H3K9 methylation at the COX-2 gene locus

    J. Biol. Chem.

    (2013)
  • W. Xu

    Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases

    Cancer Cell

    (2011)
  • C. Lu et al.

    Metabolic regulation of epigenetics

    Cell Metab.

    (2012)
  • P. Wang

    Oncometabolite D-2-hydroxyglutarate inhibits ALKBH DNA repair enzymes and sensitizes IDH mutant cells to alkylating agents

    Cell Rep.

    (2015)
  • L. Cai

    Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes

    Mol. Cell

    (2011)
  • A. Moussaieff

    Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells

    Cell Metab.

    (2015)
  • D.C. Berwick

    The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes

    J. Biol. Chem.

    (2002)
  • J.V. Lee

    Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation

    Cell Metab.

    (2014)
  • T. Li

    Glyceraldehyde-3-phosphate dehydrogenase is activated by lysine 254 acetylation in response to glucose signal

    J. Biol. Chem.

    (2014)
  • M. Ventura

    Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase is regulated by acetylation

    Int. J. Biochem. Cell Biol.

    (2010)
  • W. Hendriks

    Duck lens epsilon-crystallin and lactate dehydrogenase B4 are identical: a single-copy gene product with two distinct functions

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

    (1988)
  • D.L. Nelson et al.

    Lehninger: Principles of Biochemistry

    (2013)
  • S. Matsuda

    Nuclear pyruvate kinase M2 complex serves as a transcriptional coactivator of arylhydrocarbon receptor

    Nucleic Acids Res.

    (2015)
  • G. Siebert

    Bestimmung von Glykolyse-Metaboliten in isolierten Zellkernen

    Experientia

    (1958)
  • G. Siebert et al.

    Enzymology of the nucleus

    Adv. Enzymol. Relat. Areas Mol. Biol.

    (1965)
  • A.W. Konings

    On the dependence of nuclear oxidative phosphorylation on glycolysis in isolated rat thymus nuclei

    Experientia

    (1969)
  • G. Guillemain

    The large intracytoplasmic loop of the glucose transporter GLUT2 is involved in glucose signaling in hepatic cells

    J. Cell Sci.

    (2000)
  • M. Pantaleon

    An unusual subcellular localization of GLUT1 and link with metabolism in oocytes and preimplantation mouse embryos

    Biol. Reprod.

    (2001)
  • Cited by (0)

    These authors contributed equally.

    View full text