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 (LCL), which express the EBV latency III program observed in CNS lymphomas, double CTPS1/2 knockout caused stronger phenotypes. EBNA2, MYC and non-canonical NF-?B 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 LCL 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.
%0 Journal Article
%1 Liang2021.01.08.426018
%A Liang, Jin-Hua
%A Wang, Chong
%A Tung Yiu, Stephanie Pei
%A Zhao, Bo
%A Guo, Rui
%A Gewurz, Benjamin
%D 2021
%I Cold Spring Harbor Laboratory
%J bioRxiv
%K b-cell epstein-barr lytic myown virus
%R 10.1101/2021.01.08.426018
%T Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival
%U https://www.biorxiv.org/content/early/2021/01/09/2021.01.08.426018
%X 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 (LCL), which express the EBV latency III program observed in CNS lymphomas, double CTPS1/2 knockout caused stronger phenotypes. EBNA2, MYC and non-canonical NF-?B 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 LCL 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.
@article{Liang2021.01.08.426018,
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{\textquoteright} 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 (LCL), which express the EBV latency III program observed in CNS lymphomas, double CTPS1/2 knockout caused stronger phenotypes. EBNA2, MYC and non-canonical NF-?B 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 LCL 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.},
added-at = {2021-01-09T15:15:35.000+0100},
author = {Liang, Jin-Hua and Wang, Chong and Tung Yiu, Stephanie Pei and Zhao, Bo and Guo, Rui and Gewurz, Benjamin},
biburl = {https://www.bibsonomy.org/bibtex/2681c6779995cad99350ad1e2bae44ac5/bgewurz},
doi = {10.1101/2021.01.08.426018},
elocation-id = {2021.01.08.426018},
eprint = {https://www.biorxiv.org/content/early/2021/01/09/2021.01.08.426018.full.pdf},
interhash = {92ae28aae8e43ac5fe54423a73dad7a2},
intrahash = {681c6779995cad99350ad1e2bae44ac5},
journal = {bioRxiv},
keywords = {b-cell epstein-barr lytic myown virus},
publisher = {Cold Spring Harbor Laboratory},
timestamp = {2021-01-09T15:15:35.000+0100},
title = {Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival},
url = {https://www.biorxiv.org/content/early/2021/01/09/2021.01.08.426018},
year = 2021
}