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.

中文翻译：

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爱泼斯坦-巴尔病毒诱导的胞嘧啶核苷代谢在转化的B细胞生长和存活中的作用。

爱泼斯坦巴尔病毒（EBV）每年与20万种癌症相关，包括免疫抑制宿主中的B细胞淋巴瘤。从头嘧啶合成途径酶胞苷5'三磷酸合酶1（CTPS1）的亚型突变抑制细胞介导的免疫，导致暴发性EBV感染和EBV +中枢神经系统（CNS）淋巴瘤。由于CTP是DNA，RNA和磷脂合成的关键前体，因此这一发现提出了同工酶CTPS2或胞苷拯救途径是否有助于满足EBV感染B细胞对CTP的需求的问题。在这里，我们发现EBV在新感染的B细胞中以不同的动力学上调了CTPS1和CTPS2。CRISPR CTPS1敲除导致淋巴母细胞样细胞系（LCL）发生DNA损伤和增殖缺陷，表达在CNS淋巴瘤中观察到的EBV潜伏期III程序，两次CTPS1 / 2敲除引起更强的表型。EBNA2，MYC和非典型NF-κB阳性调节CTPS1表达。CTPS1耗竭会削弱EBV裂解DNA的合成，这表明潜在的EBV可能会导致CTPS1缺乏的发病机理。胞苷可挽救EBV转化的LCL和Burkitt B细胞中的CTPS1 / 2缺乏表型，突显出CTPS1 / 2作为EBV驱动的淋巴增生性疾病的潜在治疗靶点。总的来说，我们的结果表明CTPS1和CTPS2在EBV转化的B细胞中具有部分冗余的作用，并为CTPS1缺乏的EBV发病机理提供了见识。提示潜在的EBV可能导致CTPS1缺乏症的发病机理。胞苷可挽救EBV转化的LCL和Burkitt B细胞中的CTPS1 / 2缺乏表型，突显出CTPS1 / 2作为EBV驱动的淋巴增生性疾病的潜在治疗靶点。总的来说，我们的结果表明CTPS1和CTPS2在EBV转化的B细胞中具有部分冗余的作用，并为CTPS1缺乏的EBV发病机理提供了见识。提示潜在的EBV可能导致CTPS1缺乏症的发病机理。胞苷可挽救EBV转化的LCL和Burkitt B细胞中的CTPS1 / 2缺乏表型，突显出CTPS1 / 2作为EBV驱动的淋巴增生性疾病的潜在治疗靶点。总的来说，我们的结果表明CTPS1和CTPS2在EBV转化的B细胞中具有部分冗余的作用，并为CTPS1缺乏的EBV发病机理提供了见识。