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

Liang, Jin‐Hua; Wang, Chong; Yiu, Stephanie Pei Tung; Guo, Rui; Gewurz, Benjamin E.

doi:10.1101/2021.01.08.426018

Cited by 3 publications

(2 citation statements)

References 56 publications

(89 reference statements)

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“…Similarly, the de novo pyrimidine synthesis enzyme dihydroorotate dehydrogenase (DHODH) generates CoQH 2 , which can be used to quench lipid ROS within the mitochondrial inner membrane (54). We recently identified that EBV highly induces DHODH and de novo pyrimidine activity in newly infected B-cells (55). Furthermore, GTP cyclohydrolase 1 (GCH1) can suppress ferroptosis via the generation of the radical-trapping antioxidant tetrahydrobiopterin (BH4) (56).…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr virus latency programs dynamically sensitize B-cells to ferroptosis

Burton

Voyer

Gewurz

2022

Preprint

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Epstein-Barr virus (EBV) causes 200,000 cancers annually. Upon B-cell infection, EBV induces lipid metabolism to support B-cell proliferation. Yet, little is known about how latent EBV infection, or human B-cell stimulation more generally, alter sensitivity to ferroptosis, a non-apoptotic form of programmed cell death driven by iron-dependent lipid peroxidation and membrane damage. To gain insights, we analyzed lipid reactive oxygen species (ROS) levels and ferroptosis vulnerability in primary human CD19+ B-cells infected by EBV or stimulated by key B-cell receptors. Prior to the first mitosis, EBV-infected cells were exquisitely sensitive to blockade of glutathione biosynthesis, a phenomenon not observed with B-cell receptor stimulation. Subsequently, EBV-mediated Burkitt-like hyper-proliferation generated elevated levels of lipid ROS, which necessitated SLC7A11-mediated cystine import and glutathione peroxidase 4 (GPX4) activity to prevent ferroptosis. By comparison, B-cells were sensitized to ferroptosis induction by combinatorial CD40-ligand and interleukin-4 stimulation or anti-B-cell receptor and Toll-like receptor 9 stimulation upon GPX4 inhibition, but not with SLC7A11 blockade. EBV transforming B-cells became progressively resistant to ferroptosis induction upon switching to the latency III program and lymphoblastoid physiology. Similarly, latency I Burkitt cells were particularly vulnerable to blockade of SLC7A11 or GPX4 or cystine withdrawal, while latency III Burkitt and lymphoblastoid cells were comparatively resistant. The selenocysteine biosynthesis kinase PSTK was newly implicated as a cellular target for ferroptosis induction including in Burkitt cells, likely due to roles in GPX4 biosynthesis. These results highlight ferroptosis as an intriguing therapeutic target for the prevention or treatment of particular EBV-driven B-cell malignancies.

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Section: Discussionmentioning

confidence: 99%

Epstein-Barr virus latency programs dynamically sensitize B-cells to ferroptosis

Burton

Voyer

Gewurz

2022

Preprint

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“…Other significant metabolites included the nucleotide cytosine, and related nucleosides cytidine and 2'-deoxy-cytidine, key building blocks in the creation of DNA and RNA. More recently, cytidine metabolism was revealed to be important during EBV virus induced B cell transformation, growth, and survival (51), highlighting its importance in gammaherpesvirus induced oncogenesis. The purine nucleoside 1-methyladenosine showed a significant increase during MHV-68 infection.…”

Section: While Metabolomics Analysis Of Host Cells During Viral Infec...mentioning

confidence: 99%

Rewiring of the host cell metabolome and lipidome during lytic gammaherpesvirus infection is essential for infectious virus production

Clark¹,

Vazquez²,

Furiya³

et al. 2023

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Oncogenic virus infections are estimated to cause ~15% of all cancers. Two prevalent human oncogenic viruses are members of the gammaherpesvirus family: Epstein Barr Virus (EBV) and Kaposis Sarcoma Herpesvirus (KSHV). We use murine herpesvirus 68 (MHV-68), which shares significant homology with KSHV and EBV, as a model system to study gammaherpesvirus lytic replication. Viruses implement distinct metabolic programs to support their life cycle, such as increasing the supply of lipids, amino acids, and nucleotide materials necessary to replicate. Our data define the global changes in the host cell metabolome and lipidome during gammaherpesvirus lytic replication. Our metabolomics analysis found that MHV-68 lytic infection induces glycolysis, glutaminolysis, lipid metabolism, and nucleotide metabolism. We additionally observed an increase in glutamine consumption and glutamine dehydrogenase protein expression. While both glucose and glutamine starvation of host cells decreased viral titers, glutamine starvation led to a greater loss in virion production. Our lipidomics analysis revealed a peak in triacylglycerides early during infection and an increase in free fatty acids and diacylglyceride later in the viral life cycle. Furthermore, we observed an increase in the protein expression of multiple lipogenic enzymes during infection. Interestingly, pharmacological inhibitors of glycolysis or lipogenesis resulted in decreased infectious virus production. Taken together, these results illustrate the global alterations in host cell metabolism during lytic gammaherpesvirus infection, establish essential pathways for viral production, and recommend targeted mechanisms to block viral spread and treat viral induced tumors.

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Differential roles of CTP synthetases CTPS1 and CTPS2 in cell proliferation

Minet

Boschat

Lane³

et al. 2023

Preprint

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The CTP nucleotide is a key precursor of nucleic acids metabolism essential for DNA replication. De novo CTP production relies on CTP synthetases 1 and 2 (CTPS1 and 2) that catalyze the conversion of UTP into CTP. CTP synthetase activity is high in proliferating cells including cancer cells, however, the respective roles of CTPS1 and CTPS2 in cell proliferation are not known. By inactivation of CTPS1 and/or CTPS2 and complementation experiments, we showed that both CTPS1 and CTPS2 are differentially required for cell proliferation. CTPS1 was more efficient in promoting proliferation than CTPS2, in association with a higher intrinsic enzymatic activity that was more resistant to inhibition by 3-Deaza-uridine, an UTP analog. The contribution of CTPS2 to cell proliferation was modest when CTPS1 was expressed, but essential in absence of CTPS1. Public databases analysis of more than 1,000 inactivated cancer cell lines for CTPS1 or CTPS2 confirmed that cell growth is highly dependent of CTPS1 but less of CTPS2. Therefore, our results demonstrate that CTPS1 is the main contributor to cell proliferation.

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

Cited by 3 publications

References 56 publications

Epstein-Barr virus latency programs dynamically sensitize B-cells to ferroptosis

Epstein-Barr virus latency programs dynamically sensitize B-cells to ferroptosis

Rewiring of the host cell metabolome and lipidome during lytic gammaherpesvirus infection is essential for infectious virus production

Differential roles of CTP synthetases CTPS1 and CTPS2 in cell proliferation

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