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

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 fulm...

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Autores principales:	Jin Hua Liang, Chong Wang, Stephanie Pei Tung Yiu, Bo Zhao, Rui Guo, Benjamin E. Gewurz
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	tumor virus mononucleosis chronic active EBV gammaherpesvirus nucleotide metabolism pyrimidine metabolism Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3b8ad016c6e6453b88c18d169d66bf18
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spelling	oai:doaj.org-article:3b8ad016c6e6453b88c18d169d66bf182021-11-10T18:37:51ZEpstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival10.1128/mBio.01530-212150-7511https://doaj.org/article/3b8ad016c6e6453b88c18d169d66bf182021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01530-21https://doaj.org/toc/2150-7511ABSTRACT 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.Jin Hua LiangChong WangStephanie Pei Tung YiuBo ZhaoRui GuoBenjamin E. GewurzAmerican Society for Microbiologyarticletumor virusmononucleosischronic active EBVgammaherpesvirusnucleotide metabolismpyrimidine metabolismMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tumor virus mononucleosis chronic active EBV gammaherpesvirus nucleotide metabolism pyrimidine metabolism Microbiology QR1-502
spellingShingle	tumor virus mononucleosis chronic active EBV gammaherpesvirus nucleotide metabolism pyrimidine metabolism Microbiology QR1-502 Jin Hua Liang Chong Wang Stephanie Pei Tung Yiu Bo Zhao Rui Guo Benjamin E. Gewurz Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival
description	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.
format	article
author	Jin Hua Liang Chong Wang Stephanie Pei Tung Yiu Bo Zhao Rui Guo Benjamin E. Gewurz
author_facet	Jin Hua Liang Chong Wang Stephanie Pei Tung Yiu Bo Zhao Rui Guo Benjamin E. Gewurz
author_sort	Jin Hua Liang
title	Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival
title_short	Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival
title_full	Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival
title_fullStr	Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival
title_full_unstemmed	Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival
title_sort	epstein-barr virus induced cytidine metabolism roles in transformed b-cell growth and survival
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/3b8ad016c6e6453b88c18d169d66bf18
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Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival

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