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

Cell Metab. 2019 Sep 3;30(3):539-555.e11. doi: 10.1016/j.cmet.2019.06.003. Epub 2019 Jun 27.


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.

Keywords: B-cell activation; de novo serine synthesis; folate; isotope tracing; metabolic remodeling; mitochondrial one-carbon metabolism; quantitative proteomics; tandem mass tag; tumor virus; virus oncoprotein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminohydrolases / metabolism*
  • B-Lymphocytes / metabolism*
  • B-Lymphocytes / virology*
  • Cell Transformation, Viral*
  • Epstein-Barr Virus Infections / metabolism*
  • Epstein-Barr Virus Infections / virology
  • Epstein-Barr Virus Nuclear Antigens / metabolism
  • Female
  • Folic Acid / metabolism*
  • Glycolysis
  • HEK293 Cells
  • Herpesvirus 4, Human / metabolism*
  • Humans
  • Lymphocyte Activation
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / metabolism*
  • Mitochondria / metabolism
  • Multifunctional Enzymes / metabolism*
  • NADP / biosynthesis
  • Oxidation-Reduction
  • Proteome / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Serine / biosynthesis


  • Epstein-Barr Virus Nuclear Antigens
  • MTHFD2 protein, human
  • MYC protein, human
  • Multifunctional Enzymes
  • Proteome
  • Proto-Oncogene Proteins c-myc
  • Serine
  • NADP
  • Folic Acid
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • Aminohydrolases