c-Myc Represses Transcription of the Epstein-Barr Virus Latent Membrane Protein 1 Early After Primary B Cell Infection

Price, Alexander M.; Messinger, Joshua E.; Luftig, Micah A.

doi:10.1101/168484

Cited by 6 publications

(7 citation statements)

References 53 publications

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“…EBV-driven increases in amino acid uptake may also activate the nutrient sensing mammalian target of rapamycin (mTOR) pathway [27, 28] in this phase of B-cell transformation. By day 7 post-infection, infected cells begin to demonstrate lymphoblastoid-like cell physiology as LMP1 and 2A signaling increases and cell division slows to once daily [14, 25, 29, 30]. LMP1 and LMP2A mimic CD40 and B-cell receptor signaling to activate NF-κB and PI3K/AKT/mTOR pathways, respectively [31–34].…”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival

Wang

Ersing

et al. 2019

PLoS Pathog

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Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with multiple human malignancies. EBV drives B-cell proliferation, which contributes to the pathogenesis of multiple lymphomas. Yet, knowledge of how EBV subverts host biosynthetic pathways to transform resting lymphocytes into activated lymphoblasts remains incomplete. Using a temporal proteomic dataset of EBV primary human B-cell infection, we identified that cholesterol and fatty acid biosynthetic pathways were amongst the most highly EBV induced. Epstein-Barr nuclear antigen 2 (EBNA2), sterol response element binding protein (SREBP) and MYC each had important roles in cholesterol and fatty acid pathway induction. Unexpectedly, HMG-CoA reductase inhibitor chemical epistasis experiments revealed that mevalonate pathway production of geranylgeranyl pyrophosphate (GGPP), rather than cholesterol, was necessary for EBV-driven B-cell outgrowth, perhaps because EBV upregulated the low-density lipoprotein receptor in newly infected cells for cholesterol uptake. Chemical and CRISPR genetic analyses highlighted downstream GGPP roles in EBV-infected cell small G protein Rab activation. Rab13 was highly EBV-induced in an EBNA3-dependent manner and served as a chaperone critical for latent membrane protein (LMP) 1 and 2A trafficking and target gene activation in newly infected and in lymphoblastoid B-cells. Collectively, these studies identify highlight multiple potential therapeutic targets for prevention of EBV-transformed B-cell growth and survival.

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Section: Introductionmentioning

confidence: 99%

Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival

Wang

Ersing

et al. 2019

PLoS Pathog

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“…Erastin sensitivity progressively diminished as EBV-infected cells converted to lymphoblastoid physiology (Fig. 2B and S1F) and express increasing levels of LMP1 (25). By contrast, stimulation by the panel of B-cell agonists, including combinatorial CD40+IL-4 and αIgM+CpG stimuli, failed to sensitize B-cells to erastin, despite increasing lipid ROS levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…LMP2A mimics aspects of B-cell receptor signaling (23, 24). Decreasing MYC levels and likely also feedback regulation enable steadily increasing LMP1 levels over the first weeks of the lymphoblastoid phase (25). Infected cells can then be grown as immortalized lymphoblastoid cell lines (LCL), which model PTLD and CNS lymphomas, which express the EBV latency III program.…”

Section: Introductionmentioning

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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“…However, neither EBNA2 nor EBNA3C are expressed in BL. Moreover, MYC represses the EBV transforming LMP1 gene [64] and inhibits the reactivation of the viral lytic cycle [65].…”

Section: Discussionmentioning

confidence: 99%

MYC directly transactivates CR2/CD21, the receptor of the Epstein-Barr virus, and enhances the viral infection of Burkitt lymphoma cells

Molina

García-Gutiérrez

Junco

et al. 2022

Preprint

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The molecular hallmark of Burkitt lymphoma (BL) is a chromosomal translocation that results in deregulated expression of MYC oncogene. This translocation is present in virtually all BL. MYC is an oncogenic transcription factor deregulated in about half of total human tumors, by translocation or other mechanisms. Transcriptomic studies reveal more than 1000 genes regulated by MYC but a much smaller fraction of these genes is directly activated by MYC. All the endemic BL and many sporadic BL cells are associated to the Epstein-Barr virus (EBV) infection. The currently accepted mechanism for the MYC and BL association is that EBV is the causing agent inducing MYC translocation. Complement receptor 2 or CR2 (also called CD21) is a membrane protein that serves as EBV receptor in lymphoid cells. Here we show that CR2 is a direct MYC target gene. This conclusion is based on several evidences. First, MYC downregulation is linked to CR2 downregulation both in proliferating and in arrested cells. Second, MYC binds human CR2 promoter and this binding depends on E-box elements. Third, MYC activates CR2 promoter in an E-box dependent manner. Four, MYC activates CR2 transcription in the absence of protein synthesis. Importantly, MYC also induces CR2 expression in mouse primary B cells. Thus, CR2 is a bona fide MYC direct target gene. Moreover, higher MYC expression levels in Burkitt lymphoma-derived cells result in a more efficient EBV infection. We propose an alternative mechanism compatible with the correlation between EBV infection and MYC translocation observed in endemic BL, i.e., that deregulated MYC in BL cells occurs first and favors the EBV infection.

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c-Myc Represses Transcription of the Epstein-Barr Virus Latent Membrane Protein 1 Early After Primary B Cell Infection

Cited by 6 publications

References 53 publications

Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival

Epstein-Barr virus subverts mevalonate and fatty acid pathways to promote infected B-cell proliferation and survival

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

MYC directly transactivates CR2/CD21, the receptor of the Epstein-Barr virus, and enhances the viral infection of Burkitt lymphoma cells

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