mBio (Aug 2021)

Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival

  • Jin Hua Liang,
  • Chong Wang,
  • Stephanie Pei Tung Yiu,
  • Bo Zhao,
  • Rui Guo,
  • Benjamin E. Gewurz

DOI
https://doi.org/10.1128/mBio.01530-21
Journal volume & issue
Vol. 12, no. 4

Abstract

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ABSTRACT Epstein-Barr virus (EBV) is associated with 200,000 cancers annually, including B-cell lymphomas in immunosuppressed hosts. Hypomorphic mutations of the de novo pyrimidine synthesis pathway enzyme cytidine 5′ triphosphate synthase 1 (CTPS1) suppress cell-mediated immunity, resulting in fulminant EBV infection and EBV+ central nervous system (CNS) lymphomas. Since CTP is a critical precursor for DNA, RNA, and phospholipid synthesis, this observation raises the question of whether the isozyme CTPS2 or cytidine salvage pathways help meet CTP demand in EBV-infected B cells. Here, we found that EBV upregulated CTPS1 and CTPS2 with distinct kinetics in newly infected B cells. While CRISPR CTPS1 knockout caused DNA damage and proliferation defects in lymphoblastoid cell lines (LCLs), which express the EBV latency III program observed in CNS lymphomas, double CTPS1/2 knockout caused stronger phenotypes. EBNA2, MYC, and noncanonical NF-κB positively regulated CTPS1 expression. CTPS1 depletion impaired EBV lytic DNA synthesis, suggesting that latent EBV may drive pathogenesis with CTPS1 deficiency. Cytidine rescued CTPS1/2 deficiency phenotypes in EBV-transformed LCLs and Burkitt B cells, highlighting CTPS1/2 as a potential therapeutic target for EBV-driven lymphoproliferative disorders. Collectively, our results suggest that CTPS1 and CTPS2 have partially redundant roles in EBV-transformed B cells and provide insights into EBV pathogenesis with CTPS1 deficiency.

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