Glycolytic rate and lymphomagenesis depend on PARP14, an ADP ribosyltransferase of the B aggressive lymphoma (BAL) family

Cho, Sung Hoon; Ahn, Annie K.; Bhargava, Prerna; Lee, Chih‐Hao; Eischen, Christine M.; McGuinness, Owen P.; Boothby, Mark

doi:10.1073/pnas.1017082108

Cited by 93 publications

(131 citation statements)

References 46 publications

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“…Previous studies have shown that B cells increase glucose import with activation (Caro-Maldonado et al., 2014, Cho et al., 2011, Doughty et al., 2006, Dufort et al., 2007). In agreement, we also measure an increase in import of the fluorescent glucose analog, 2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose (2-NBDG), in CD40/IL4 activated B cells (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Initial B Cell Activation Induces Metabolic Reprogramming and Mitochondrial Remodeling

Waters

Ahsan

Wolf³

et al. 2018

iScience

221

208

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SummaryB lymphocytes provide adaptive immunity by generating antigen-specific antibodies and supporting the activation of T cells. Little is known about how global metabolism supports naive B cell activation to enable an effective immune response. By coupling RNA sequencing (RNA-seq) data with glucose isotopomer tracing, we show that stimulated B cells increase programs for oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and nucleotide biosynthesis, but not glycolysis. Isotopomer tracing uncovered increases in TCA cycle intermediates with almost no contribution from glucose. Instead, glucose mainly supported the biosynthesis of ribonucleotides. Glucose restriction did not affect B cell functions, yet the inhibition of OXPHOS or glutamine restriction markedly impaired B cell growth and differentiation. Increased OXPHOS prompted studies of mitochondrial dynamics, which revealed extensive mitochondria remodeling during activation. Our results show how B cell metabolism adapts with stimulation and reveals unexpected details for carbon utilization and mitochondrial dynamics at the start of a humoral immune response.

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Section: Resultsmentioning

confidence: 99%

Initial B Cell Activation Induces Metabolic Reprogramming and Mitochondrial Remodeling

Waters

Ahsan

Wolf³

et al. 2018

iScience

221

208

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“…Acting alone or in concert, dysregulation of Myc and HIF1α, two key transcription factors that regulate the expression of metabolic genes, plays an essential role in reprograming metabolism to support tumor growth (30,32,42,43). Notably, heightened aerobic glycolysis has also been implicated as a key metabolic feature of many immune cells, such as T cells, B cells, and dendritic cells, upon activation (44)(45)(46). Interestingly, the ligation of the T-cell receptors (TCR) or B-cell receptors (BCR) induces the expression of both Myc and HIF1α in T cells and B cells, respectively (33,34).…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1 α -dependent

Liu

Martinez

et al. 2016

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

192

171

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As a phenotypically plastic cellular population, macrophages change their physiology in response to environmental signals. Emerging evidence suggests that macrophages are capable of tightly coordinating their metabolic programs to adjust their immunological and bioenergetic functional properties, as needed. Upon mitogenic stimulation, quiescent macrophages enter the cell cycle, increasing their bioenergetic and biosynthetic activity to meet the demands of cell growth. Proinflammatory stimulation, however, suppresses cell proliferation, while maintaining a heightened metabolic activity imposed by the production of bactericidal factors. Here, we report that the mitogenic stimulus, colony-stimulating factor 1 (CSF-1), engages a myelocytomatosis viral oncogen (Myc)-dependent transcriptional program that is responsible for cell cycle entry and the up-regulation of glucose and glutamine catabolism in bone marrow-derived macrophages (BMDMs). However, the proinflammatory stimulus, lipopolysaccharide (LPS), suppresses Myc expression and cell proliferation and engages a hypoxia-inducible factor alpha (HIF1α)-dependent transcriptional program that is responsible for heightened glycolysis. The acute deletion of Myc or HIF1α selectively impaired the CSF-1-or LPS-driven metabolic activities in BMDM, respectively. Finally, inhibition of glycolysis by 2-deoxyglucose (2-DG) or genetic deletion of HIF1α suppressed LPS-induced inflammation in vivo. Our studies indicate that a switch from a Myc-dependent to a HIF1α-dependent transcriptional program may regulate the robust bioenergetic support for an inflammatory response, while sparing Myc-dependent proliferation.T he cells of the immune system are constantly exposed to environmental challenges and are capable of tailoring their metabolic programs to meet distinct physiological needs. Macrophages, like other immune cells, rapidly change their physiology in response to various environmental cues. Macrophages undergo proliferation in response to mitogenic stimuli, such as colony-stimulating factor 1 (CSF-1) [also known as macrophage CSF (M-CSF)], and this cellular turnover is essential for macrophage homeostasis and may occur in mature macrophages, bypassing the need for self-renewing progenitors (1, 2). Proliferating macrophages consume considerable amounts of energy and require de novo synthesis of macromolecules to support their growth and proliferation (3-6). Therefore, macrophages must coordinately regulate metabolic programs to meet their bioenergetic and biosynthetic demand during proliferation. Despite the emerging view that extracellular signaling events dictate cell growth, proliferation, and death, in part by modulating metabolic activities in cancer cells and T lymphocytes, the precise mechanisms and crucial players of reprogramming metabolism during macrophage proliferation are incompletely understood.Upon encountering an invading microorganism, the bioenergetic potential in macrophages quickly shifts away from fulfilling the needs of cell proliferation to mount a robust...

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“…For example, PARP-14 regulates the class distribution, affinity repertoire, and recall capacity of antibody responses, which require efficient differentiation and interactions among B cells, Th cells, and dendritic cells (Cho et al 2013). Furthermore, PARP-14 is required for IL-4-dependent enhancement of glycolysis in B cells as well as Myc-induced oncogenesis (Cho et al 2011). PARP-14 inhibits STAT1 phosphorylation and proinflammatory gene expression in IFNγ-stimulated macrophages while enhancing STAT6 phosphorylation and anti-inflammatory gene expression in IL-4-stimulated macrophages, in part by antagonizing the actions of PARP-9 and by ADP-ribosylating STAT1 (Iwata et al 2016).…”

Section: Parp-14mentioning

confidence: 99%

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

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The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.ADP-ribosylation is a reversible post-translational modification (PTM) of proteins resulting in the covalent attachment of a single ADP-ribose unit [i.e., mono(ADP-ribose) (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ribose) (PAR)] on a variety of amino acid residues on target proteins (Gibson and Kraus 2012;Daniels et al. 2015a). This modification is mediated by a diverse group of ADPribosyl transferase (ADPRT) enzymes that use ADP-ribose units derived from β-NAD + to catalyze the ADP-ribosylation reaction. These enzymes include bacterial ADPRTs (e.g., cholera toxin and diphtheria toxin) as well as members of three different protein families in yeast and animals: (1) arginine-specific ecto-enzymes (ARTCs), (2) sirtuins, and (3) PAR polymerases (PARPs) . Surprisingly, a recent study showed that the bacterial toxin DarTG can ADP-ribosylate DNA . How this fits into the broader picture of cellular ADP-ribosylation has yet to be determined.In this review, we focus on the mono(ADP-ribosyl)ation (MARylation) and poly(ADP-ribosyl)ation (PARylation) of glutamate, aspartate, and lysine residues by PARP family members. While many reviews have been written on PARPs in the past decade, we highlight the current trends and ideas in the field, in particular those discoveries that have been published in the past 2-3 years.

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Glycolytic rate and lymphomagenesis depend on PARP14, an ADP ribosyltransferase of the B aggressive lymphoma (BAL) family

Cited by 93 publications

References 46 publications

Initial B Cell Activation Induces Metabolic Reprogramming and Mitochondrial Remodeling

Initial B Cell Activation Induces Metabolic Reprogramming and Mitochondrial Remodeling

Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1 α -dependent

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

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