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      Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation

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          Summary

          Epstein-Barr virus (EBV) causes Burkitt, Hodgkin, and post-transplant B cell lymphomas. How EBV remodels metabolic pathways to support rapid B cell outgrowth remains largely unknown. To gain insights, primary human B cells were profiled by tandem-mass-tag-based proteomics at rest and at nine time points after infection; >8,000 host and 29 viral proteins were quantified, revealing mitochondrial remodeling and induction of one-carbon (1C) metabolism. EBV-encoded EBNA2 and its target MYC were required for upregulation of the central mitochondrial 1C enzyme MTHFD2, which played key roles in EBV-driven B cell growth and survival. MTHFD2 was critical for maintaining elevated NADPH levels in infected cells, and oxidation of mitochondrial NADPH diminished B cell proliferation. Tracing studies underscored contributions of 1C to nucleotide synthesis, NADPH production, and redox defense. EBV upregulated import and synthesis of serine to augment 1C flux. Our results highlight EBV-induced 1C as a potential therapeutic target and provide a new paradigm for viral onco-metabolism.

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          Highlights

          • •

            Global analysis of EBV proteome and metabolism remodeling in B cell transformation

          • •

            EBV induces mitochondrial 1C metabolic enzyme expression and flux

          • •

            EBNA2 is a viral master regulator of B cell metabolic reprogramming

          • •

            1C drives nucleotide, mitochondrial NADPH, and glutathione production

          Abstract

          Global unbiased proteomic analysis reveals key metabolic pathways induced by Epstein-Barr virus critical for B cell growth transformation. In this issue of Cell Metabolism, Wang et al. utilized multiplexed proteomics to identify key virus-induced metabolic pathways important for outgrowth of newly infected primary human B cells. The authors describe virus-activated mitochondrial one-carbon metabolism as being crucial for nucleotide and glutathione syntheses, as well as generation of intramitochondrial NADPH.

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          Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis.

          Jason Locasale, Alexandra R. Grassian, Tamar Melman … (2011)
          Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.
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            Increasing the multiplexing capacity of TMTs using reporter ion isotopologues with isobaric masses.

            Graeme C McAlister, Edward L. Huttlin, Wilhelm Haas … (2012)
            Quantitative mass spectrometry methods offer near-comprehensive proteome coverage; however, these methods still suffer with regards to sample throughput. Multiplex quantitation via isobaric chemical tags (e.g., TMT and iTRAQ) provides an avenue for mass spectrometry-based proteome quantitation experiments to move away from simple binary comparisons and toward greater parallelization. Herein, we demonstrate a straightforward method for immediately expanding the throughput of the TMT isobaric reagents from 6-plex to 8-plex. This method is based upon our ability to resolve the isotopic shift that results from substituting a (15)N for a (13)C. In an accommodation to the preferred fragmentation pathways of ETD, the TMT-127 and -129 reagents were recently modified such that a (13)C was exchanged for a (15)N. As a result of this substitution, the new TMT reporter ions are 6.32 mDa lighter. Even though the mass difference between these reporter ion isotopologues is incredibly small, modern high-resolution and mass accuracy analyzers can resolve these ions. On the basis of our ability to resolve and accurately measure the relative intensity of these isobaric reporter ions, we demonstrate that we are able to quantify across eight samples simultaneously by combining the (13)C- and (15)N-containing reporter ions. Considering the structure of the TMT reporter ion, we believe this work serves as a blueprint for expanding the multiplexing capacity of the TMT reagents to at least 10-plex and possibly up to 18-plex.
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              A PHGDH inhibitor reveals coordination of serine synthesis and 1-carbon unit fate

              Michael E Pacold, Kyle R. Brimacombe, Sze Chan … (2016)
              Serine is a both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical glucose-derived serine synthesis pathway, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic towards PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we use a quantitative high-throughput screen to identify small molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and suggest that one-carbon unit wasting may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.
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                Author and article information

                Contributors
                Michael P. Weekes
                Benjamin E. Gewurz
                Journal
                Journal ID (nlm-ta): Cell Metab
                Journal ID (iso-abbrev): Cell Metab
                Title: Cell Metabolism
                Publisher: Cell Press
                ISSN (Print): 1550-4131
                ISSN (Electronic): 1932-7420
                Publication date PMC-release: 03 September 2019
                Publication date (Print): 03 September 2019
                Volume: 30
                Issue: 3
                Pages: 539-555.e11
                Affiliations
                [1 ]Graduate Program in Virology, Division of Medical Sciences, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
                [2 ]Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA
                [3 ]Department of Molecular Biology and Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA
                [4 ]Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
                [5 ]Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
                [6 ]Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK
                [7 ]Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
                [8 ]Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China
                [9 ]Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA
                Author notes
                [∗ ]Corresponding author bgewurz@ 123456bwh.harvard.edu
                [∗∗ ]Corresponding author mpw1001@ 123456cam.ac.uk
                [10]

                These authors contributed equally

                [11]

                Senior author

                [12]

                Lead Contact

                Article
                Publisher ID: S1550-4131(19)30306-7
                DOI: 10.1016/j.cmet.2019.06.003
                PMC ID: 6720460
                PubMed ID: 31257153
                SO-VID: eda5aefd-d884-4662-9e37-650786259aa6
                Copyright © © 2019 The Author(s)
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 8 October 2018
                Date revision received : 14 March 2019
                Date accepted : 5 June 2019
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
                Keywords: tumor virus,b-cell activation,virus oncoprotein,quantitative proteomics,tandem mass tag,isotope tracing,mitochondrial one-carbon metabolism,de novo serine synthesis,metabolic remodeling,folate
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: tumor virus, b-cell activation, virus oncoprotein, quantitative proteomics, tandem mass tag, isotope tracing, mitochondrial one-carbon metabolism, de novo serine synthesis, metabolic remodeling, folate

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