Global Proteomic Changes Induced by the Epstein-Barr Virus Oncoproteins Latent Membrane Protein 1 and 2A

DeKroon, Robert M.; Gunawardena, Harsha; Edwards, Rachel Hood; Raab‐Traub, Nancy

doi:10.1128/mbio.00959-18

Cited by 14 publications

(9 citation statements)

References 66 publications

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“…Alternatively, other Rab protein(s) may act redundantly with Rab13 to support LMP1 and LMP2A transport in B and epithelial cells with EBV latency II expression. For instance, LMP1 was recently found to upregulate Rab11, which can have major roles in protein trafficking [122].…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…LMP1 mimics signaling by CD40, a key B cell coreceptor activated by T cell CD40-ligand (CD40L) ( 19 – 22 ). 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 ).…”

mentioning

confidence: 99%

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

Burton

Voyer

Gewurz

2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Epstein–Barr virus (EBV) contributes to Burkitt lymphoma and post-transplant lymphoproliferative disease (PTLD). EBV-transforming programs activate lipid metabolism to convert B cells into immortalized lymphoblastoid cell lines (LCL), a PTLD model. We found that stages of EBV transformation generate lipid reactive oxygen species (ROS) byproducts to varying degrees, and that a Burkitt-like phase of B cell outgrowth requires lipid ROS detoxification by glutathione peroxidase 4 and its cofactor glutathione. Perturbation of this redox defense in early stages of transformation or in Burkitt cells triggered ferroptosis, a programmed cell death pathway. LCLs were less dependent on this defense, a distinction tied to EBV latency programs. This highlights ferroptosis induction as a potential therapeutic approach for prevention or treatment of certain EBV+ lymphomas.

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“…Therefore, LMP2A may have a dual effect on the EBVaGC. LMP2A plays an important role in the carcinogenesis and progression of EBV‐associated tumors by regulating various pathways . As Smad2 is a key gene in the TGF‐β signaling pathway, this study focused on the correlation between LMP2A and TGF‐β signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Latent membrane protein 2A inhibits expression level of Smad2 through regulating miR‐155‐5p in EBV‐associated gastric cancer cell lines

Shi

Zhang

et al. 2019

Journal of Medical Virology

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Epstein-Barr virus (EBV) infection is one of the causes of gastric cancer (GC). Besides,previous studies have demonstrated that EBV-encoded latent membrane protein 2A (LMP2A) influences the pathogenesis of EBV-associated gastric cancer (EBVaGC) through regulating several key pathways. In this study, the expression level of Smad2 was observed, which was reduced in EBVaGC cell lines, especially in the presence of LMP2A. Meanwhile, we found that LMP2A promoted the expression of miR-155-5p by activated nuclear factor-κB (NF-κB) signaling. After being treated with NF-κB inhibitor (BAY 11-7082), miR-155-5p sharply decreased. Western blot analysis proved that the overexpression of miR-155-5p could inhibit Smad2. Functional studies showed that the role of miR-155-5p might lead to good prognosis in EBVpositive GC through promoting cell apoptosis and cell cycle arrest, as well as inhibiting tumor proliferation. In addition, p-Smad2 protein was also reduced or induced by overexpression or knockdown, respectively, of miR-155-5p. Immunofluorescence analysis further indicated that LMP2A prevented p-Smad2 from transferring to the nucleus, which played a crucial role in transforming growth factor-β (TGF-β) signaling. In summary, our findings confirmed the relationship between LMP2A and Smad2 and provided a potential regulation of the TGF-β pathway in EBVaGC. K E Y W O R D S LMP2A, miR-155-5p, NF-κB, Smad2, TGF-β signaling pathway 1 | INTRODUCTION Gastric cancer (GC), originating from the gastric mucosa, is a malignant tumor. 1 Evidence shows that GC is caused by multiple factors such as sanitation, food preservation, Helicobacter pylori infection, and Epstein-Barr virus (EBV) infection. 2 EBV was first discovered as an oncogenic virus in humans over 50 years ago. 3 EBV, which adopts both latent and lytic forms of infection, has a high prevalence all over the world, and it is thought that roughly 95% of the world's population presents an asymptomatic life-long infection. 4 EBV is best known as the cause of infectious mononucleosis, a variety of lymphomas, nasopharyngeal carcinoma (NPC), and GC. 4,5 EBV-associated gastric cancer (EBVaGC), detected in approximately 10% of GC cases worldwide, is the monoclonal growth of EBV-infected epithelial cells. 6 EBVaGC belongs to latency type I or II, in which only EBV-encoded RNA, EBV nuclear antigen 1, EBVencoded latent membrane protein 2A (LMP2A) and BART micro-RNAs (miRNAs) are expressed. 7 Plenty of studies have demonstrated that LMP2A might influence genomic features of host DNA, messenger RNA (mRNA), miRNA, and CpG methylation profiles

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Global Proteomic Changes Induced by the Epstein-Barr Virus Oncoproteins Latent Membrane Protein 1 and 2A

Cited by 14 publications

References 66 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

Latent membrane protein 2A inhibits expression level of Smad2 through regulating miR‐155‐5p in EBV‐associated gastric cancer cell lines

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