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

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 po...

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Autores principales: Wang, Liang Wei, Shen, Hongying, Nobre, Luis, Ersing, Ina, Paulo, Joao A., Trudeau, Stephen, Wang, Zhonghao, Smith, Nicholas A., Ma, Yijie, Reinstadler, Bryn, Nomburg, Jason, Sommermann, Thomas, Cahir-McFarland, Ellen, Gygi, Steven P., Mootha, Vamsi K., Weekes, Michael P., Gewurz, Benjamin E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720460/
https://www.ncbi.nlm.nih.gov/pubmed/31257153
http://dx.doi.org/10.1016/j.cmet.2019.06.003
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author Wang, Liang Wei
Shen, Hongying
Nobre, Luis
Ersing, Ina
Paulo, Joao A.
Trudeau, Stephen
Wang, Zhonghao
Smith, Nicholas A.
Ma, Yijie
Reinstadler, Bryn
Nomburg, Jason
Sommermann, Thomas
Cahir-McFarland, Ellen
Gygi, Steven P.
Mootha, Vamsi K.
Weekes, Michael P.
Gewurz, Benjamin E.
author_facet Wang, Liang Wei
Shen, Hongying
Nobre, Luis
Ersing, Ina
Paulo, Joao A.
Trudeau, Stephen
Wang, Zhonghao
Smith, Nicholas A.
Ma, Yijie
Reinstadler, Bryn
Nomburg, Jason
Sommermann, Thomas
Cahir-McFarland, Ellen
Gygi, Steven P.
Mootha, Vamsi K.
Weekes, Michael P.
Gewurz, Benjamin E.
author_sort Wang, Liang Wei
collection PubMed
description 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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spelling pubmed-67204602019-09-06 Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation Wang, Liang Wei Shen, Hongying Nobre, Luis Ersing, Ina Paulo, Joao A. Trudeau, Stephen Wang, Zhonghao Smith, Nicholas A. Ma, Yijie Reinstadler, Bryn Nomburg, Jason Sommermann, Thomas Cahir-McFarland, Ellen Gygi, Steven P. Mootha, Vamsi K. Weekes, Michael P. Gewurz, Benjamin E. Cell Metab Article 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. Cell Press 2019-09-03 /pmc/articles/PMC6720460/ /pubmed/31257153 http://dx.doi.org/10.1016/j.cmet.2019.06.003 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Liang Wei
Shen, Hongying
Nobre, Luis
Ersing, Ina
Paulo, Joao A.
Trudeau, Stephen
Wang, Zhonghao
Smith, Nicholas A.
Ma, Yijie
Reinstadler, Bryn
Nomburg, Jason
Sommermann, Thomas
Cahir-McFarland, Ellen
Gygi, Steven P.
Mootha, Vamsi K.
Weekes, Michael P.
Gewurz, Benjamin E.
Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation
title Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation
title_full Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation
title_fullStr Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation
title_full_unstemmed Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation
title_short Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation
title_sort epstein-barr-virus-induced one-carbon metabolism drives b cell transformation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720460/
https://www.ncbi.nlm.nih.gov/pubmed/31257153
http://dx.doi.org/10.1016/j.cmet.2019.06.003
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