Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival

PLoS Pathog. 2019 Sep 13;15(9):e1008030. doi: 10.1371/journal.ppat.1008030. eCollection 2019 Sep.


Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with multiple human malignancies. EBV drives B-cell proliferation, which contributes to the pathogenesis of multiple lymphomas. Yet, knowledge of how EBV subverts host biosynthetic pathways to transform resting lymphocytes into activated lymphoblasts remains incomplete. Using a temporal proteomic dataset of EBV primary human B-cell infection, we identified that cholesterol and fatty acid biosynthetic pathways were amongst the most highly EBV induced. Epstein-Barr nuclear antigen 2 (EBNA2), sterol response element binding protein (SREBP) and MYC each had important roles in cholesterol and fatty acid pathway induction. Unexpectedly, HMG-CoA reductase inhibitor chemical epistasis experiments revealed that mevalonate pathway production of geranylgeranyl pyrophosphate (GGPP), rather than cholesterol, was necessary for EBV-driven B-cell outgrowth, perhaps because EBV upregulated the low-density lipoprotein receptor in newly infected cells for cholesterol uptake. Chemical and CRISPR genetic analyses highlighted downstream GGPP roles in EBV-infected cell small G protein Rab activation. Rab13 was highly EBV-induced in an EBNA3-dependent manner and served as a chaperone critical for latent membrane protein (LMP) 1 and 2A trafficking and target gene activation in newly infected and in lymphoblastoid B-cells. Collectively, these studies identify highlight multiple potential therapeutic targets for prevention of EBV-transformed B-cell growth and survival.

Publication types

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

MeSH terms

  • Alkyl and Aryl Transferases / metabolism
  • B-Lymphocytes / pathology
  • B-Lymphocytes / virology*
  • Cell Proliferation
  • Cell Survival
  • Cholesterol / biosynthesis
  • Epstein-Barr Virus Infections / metabolism
  • Epstein-Barr Virus Infections / pathology
  • Epstein-Barr Virus Infections / virology
  • Epstein-Barr Virus Nuclear Antigens / metabolism
  • Fatty Acids / biosynthesis*
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / pathogenicity*
  • Herpesvirus 4, Human / physiology
  • Host Microbial Interactions / genetics
  • Host Microbial Interactions / physiology
  • Humans
  • Metabolic Networks and Pathways
  • Mevalonic Acid / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism
  • Viral Proteins / metabolism
  • rab GTP-Binding Proteins / metabolism


  • EBNA-2 protein, Human herpesvirus 4
  • EBNA-3C, epstein-barr virus
  • Epstein-Barr Virus Nuclear Antigens
  • Fatty Acids
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • SREBF2 protein, human
  • Sterol Regulatory Element Binding Protein 2
  • Viral Proteins
  • Cholesterol
  • Alkyl and Aryl Transferases
  • Rab geranylgeranyltransferase
  • RAB13 protein, human
  • rab GTP-Binding Proteins
  • Mevalonic Acid