Epstein–Barr virus oncoprotein–driven B cell metabolism remodeling

Burton, Eric; Gewurz, Benjamin E.

doi:10.1371/journal.ppat.1010254

Cited by 20 publications

(21 citation statements)

References 44 publications

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“…LMP1) and cellular (viz. cMyc) genes supports B-cell metabolic remodelling and sustained proliferation [6,8,30,72]. In agreement to this, our study also demonstrated that EBNA2 is responsible for CA9 transcriptional activation.…”

Section: Discussionsupporting

confidence: 89%

Differential Carbonic Anhydrase Activities Control EBV-Induced B-Cell Transformation and Lytic Cycle Reactivation

Malik,

Biswas,

Sarkar

et al. 2023

Preprint

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Epstein-Barr virus (EBV) contributes to ∼1% of all human cancers including several B-cell neoplasms. A characteristic feature of EBV life cycle is its ability to transform metabolically quiescent B-lymphocytes into hyperproliferating B-cell blasts with the establishment of viral latency, while intermittent lytic cycle induction is necessary for the production of progeny virus. Our RNA-Seq analyses of both latently infected naïve B-lymphocytes and transformed B-lymphocytes upon lytic cycle replication indicate a contrasting expression pattern of a membrane-associated carbonic anhydrase isoform CA9, an essential component for maintaining cell acid-base homeostasis. We show that while CA9 expression is transcriptionally activated during latent infection model, lytic cycle replication restrains its expression. Pharmacological inhibition of CA-activity using specific inhibitors retards EBV induced B-cell transformation, inhibits B-cells outgrowth and colony formation ability of transformed B-lymphocytes through lowering the intracellular pH, induction of cell apoptosis and facilitating degradation of CA9 transcripts. Reanalyses of ChIP-Seq data along with utilization of EBNA2 knockout virus and sh-RNA mediated knockdown of CA9 expression we further demonstrate that EBNA2 mediated CA9 transcriptional activation is essential for EBV latently infected B-cell survival. In contrast, during lytic cycle reactivation CA9 expression is transcriptionally suppressed by the key EBV lytic cycle transactivator, BZLF1 through its transactivation domain. Overall, our study highlights the dynamic alterations of CA9 expression and its activity in regulating pH homeostasis act as one of the major drivers for EBV induced B-cell transformation and subsequent B-cell lymphomagenesis.

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Section: Discussionsupporting

confidence: 89%

Differential Carbonic Anhydrase Activities Control EBV-Induced B-Cell Transformation and Lytic Cycle Reactivation

Malik,

Biswas,

Sarkar

et al. 2023

Preprint

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“…As no licensed prophylactic or therapeutic EBV vaccines exist [21], understanding the mechanistic roles that EBV-encoded proteins and miRNAs play in EBVaGC remains a research area of high importance. While a variety of cell line and animal models exist to help understand how EBV manipulates human cells [22,23], many animal models are not robust, and the applicability of these models to humans is unclear [24,25]. These in vitro and in vivo studies benefit from being validated by observations within primary human cancer tissues.…”

Section: Introductionmentioning

confidence: 99%

The EBV Gastric Cancer Resource (EBV-GCR): A Suite of Tools for Investigating EBV-Associated Human Gastric Carcinogenesis

Salnikov

Wang

Christensen

et al. 2023

Viruses

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Epstein-Barr virus (EBV) causes lifelong infection in over 90% of the world’s population. EBV infection leads to several types of B cell and epithelial cancers due to the viral reprogramming of host-cell growth and gene expression. EBV is associated with 10% of stomach/gastric adenocarcinomas (EBVaGCs), which have distinct molecular, pathological, and immunological characteristics compared to EBV-negative gastric adenocarcinomas (EBVnGCs). Publicly available datasets, such as The Cancer Genome Atlas (TCGA), contain comprehensive transcriptomic, genomic, and epigenomic data for thousands of primary human cancer samples, including EBVaGCs. Additionally, single-cell RNA-sequencing data are becoming available for EBVaGCs. These resources provide a unique opportunity to explore the role of EBV in human carcinogenesis, as well as differences between EBVaGCs and their EBVnGC counterparts. We have constructed a suite of web-based tools called the EBV Gastric Cancer Resource (EBV-GCR), which utilizes TCGA and single-cell RNA-seq data and can be used for research related to EBVaGCs. These web-based tools allow investigators to gain in-depth biological and clinical insights by exploring the effects of EBV on cellular gene expression, associations with patient outcomes, immune landscape features, and differential gene methylation, featuring both whole-tissue and single-cell analyses.

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“…An additional difference between the LCL and iPSC-derived neuronal models might be based on their preferential reliance upon the glycolysis and oxidative phosphorylation pathways for energy production. Although EBV strongly induces oxidative phosphorylation upon B-cell infection and transformation into LCLs 77 , these cells might rely more on glycolysis 78 , and defects in the glycolysis pathway, providing pyruvate for the tricarboxylic acid cycle, might force a shift from glycolysis to mitochondrial respiration in the heterozygous PRKN variant carrier group. Overall, we consider this study as a proof of concept for detecting molecular phenotypes in cellular models derived from heterozygous PRKN variant carriers.…”

Section: Discussionmentioning

confidence: 99%

Molecular phenotypes of mitochondrial dysfunction in clinically non-manifesting heterozygous PRKN variant carriers

Rueda

Zanon

Gilmozzi

et al. 2023

npj Parkinsons Dis.

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Homozygous or compound heterozygous (biallelic) variants in PRKN are causal for PD with highly penetrant symptom expression, while the much more common heterozygous variants may predispose to PD with highly reduced penetrance, through altered mitochondrial function. In the presence of pathogenic heterozygous variants, it is therefore important to test for mitochondrial alteration in cells derived from variant carriers to establish potential presymptomatic molecular markers. We generated lymphoblasts (LCLs) and human induced pluripotent stem cell (hiPSC)-derived neurons from non-manifesting heterozygous PRKN variant carriers and tested them for mitochondrial functionality. In LCLs, we detected hyperactive mitochondrial respiration, and, although milder compared to a biallelic PRKN-PD patient, hiPSC-derived neurons of non-manifesting heterozygous variant carriers also displayed several phenotypes of altered mitochondrial function. Overall, we identified molecular phenotypes that might be used to monitor heterozygous PRKN variant carriers during the prodromal phase. Such markers might also be useful to identify individuals at greater risk of eventual disease development and for testing potential mitochondrial function-based neuroprotective therapies before neurodegeneration advances.

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Epstein–Barr virus oncoprotein–driven B cell metabolism remodeling

Cited by 20 publications

References 44 publications

Differential Carbonic Anhydrase Activities Control EBV-Induced B-Cell Transformation and Lytic Cycle Reactivation

Differential Carbonic Anhydrase Activities Control EBV-Induced B-Cell Transformation and Lytic Cycle Reactivation

The EBV Gastric Cancer Resource (EBV-GCR): A Suite of Tools for Investigating EBV-Associated Human Gastric Carcinogenesis

Molecular phenotypes of mitochondrial dysfunction in clinically non-manifesting heterozygous PRKN variant carriers

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