Regulation of the latent-lytic switch in Epstein–Barr virus

Kenney, Shannon C.; Mertz, Janet E.

doi:10.1016/j.semcancer.2014.01.002

Cited by 232 publications

(256 citation statements)

References 97 publications

(123 reference statements)

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“…Induction of lytic EBV infection by MTX requires activation of p38, PI3K, and MEK pathways and the EBV immediate early promoters, BZLF1 and BRLF1 (29). BZLF1 is the major switch for lytic reactivation of EBV in B cells, and expression of BZLF1 is regulated by the AP-1 transcription factor (28). Phosphorylation of p38 also plays a key role in reactivation of EBV from latency (27).…”

Section: Resultsmentioning

confidence: 99%

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Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

Liu

Cohen

2016

J Virol

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IMPORTANCE Epstein-Barr virus (EBV) is associated with both B cell and epithelial cell malignancies, and the virus activates multiple signaling pathways important for its persistence in latently infected cells. We identified a viral tegument protein, BGLF2, which activates members of the mitogen-activated protein kinase signaling pathway. Expression of BGLF2 increased expression of EBV BZLF1, which activates a switch from latent to lytic virus infection, and increased production of EBV. Inhibition of BGFL2 expression or inhibition of p38/MAPK, which is activated by BGLF2, reduced virus reactivation from latency. These results indicate that a viral tegument protein which is delivered to cells upon infection activates signaling pathways to enhance virus production and facilitate virus reactivation from latency. E pstein-Barr virus (EBV) is a cause of infectious mononucleosis and is associated with both B lymphocyte and epithelial cell malignancies. EBV encodes a number of proteins that trigger cell signaling pathways, such as AP-1, JAK-STAT, NF-B, and phosphatidylinositol 3-kinase (PI3K)/Akt, which are critical for cell survival, virus latency, and growth transformation (1-6). For example, EBV latent membrane protein 1 (LMP1) mimics CD40 signaling and is important for EBV-induced B cell growth proliferation, inhibition of apoptosis, and EBV transformation. LMP1 interacts with tumor necrosis factor receptor-associated factors (TRAFs), leading to activation of NF-B, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), PI3K/Akt, and STAT3 (7-12). EBV LMP2A mimics B cell receptor signaling and contributes to the long-term survival of B cells (13-16). LMP2A activates extracellular signal-related protein kinase (ERK), PI3K/Akt, and JNK (17) and downregulates NF-B and STAT signaling pathways (18). The EBV immediate early protein BZLF1 activates virus reactivation from latency (19-21). BZLF1 activates p38 and JNK to turn on the ATF2 transcription factor (22). BRLF1, another EBV immediate early protein, activates the AP-1 pathway by increasing the levels of phosphorylated p38, JNK, and ERK (22, 23) and induces phosphorylation of Akt through the PI3K pathway (24). Activation of Akt, ERK, and p38 signaling is required for EBV reactivation from latency (25-28).To identify additional EBV proteins important for regulating cell signaling, we used a proteomic approach to screen viral proteins for AP-1 promoter activity in AP-1-luciferase reporter assays. We found that the EBV tegument protein BGLF2 induced AP-1 reporter activity and activated p38 and JNK. BGLF2 promoted EBV reactivation by enhancing BZLF1 expression and EBV production, and p38 activation by BGLF2 was required for these activities. Citation Liu X, Cohen JI. 2016. Epstein-Barr virus (EBV) tegument protein BGLF2 promotes EBV reactivation through activation of the p38 mitogen-activated protein kinase.

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Section: Resultsmentioning

confidence: 99%

“…BRLF1, another EBV immediate early protein, activates the AP-1 pathway by increasing the levels of phosphorylated p38, JNK, and ERK (22,23) and induces phosphorylation of Akt through the PI3K pathway (24). Activation of Akt, ERK, and p38 signaling is required for EBV reactivation from latency (25)(26)(27)(28).…”

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confidence: 99%

Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

Liu

Cohen

2016

J Virol

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“…1A). Additionally, the constructed CNE1-LMP1 cell line that constitutively expressed LMP1 exhibited markedly increased expression levels of the EBV lytic proteins BZLF1 and BMRF1 (37,38) when compared with the CNE1 control cells (Fig. 1B).…”

Section: Lmp1 Enhances the Expression Levels Of Ebv Lytic Proteins Inmentioning

confidence: 96%

(-)-Epigallocatechin‑3‑gallate inhibition of Epstein‑Barr virus spontaneous lytic infection involves downregulation of latent membrane protein 1

Liu

Tang

et al. 2017

Exp Ther Med

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Abstract. The Epstein-Barr virus (EBV) lytic cycle contributes to the development of EBV-associated diseases. EBV-encoded latent membrane protein 1 (LMP1) is key to EBV lytic replication, and our previous work indicated that epigallocatechin-3-gallate (EGCG) inhibited constitutive EBV lytic infection through the suppression of LMP1-activated phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase kinase/extracellular signal-related protein kinase 1/2 signaling. The present study demonstrated that LMP1 in CNE-LMP1 constructed cells significantly induced the expression of the EBV lytic proteins BZLF1 (P<0.001) and BMRF1 (P<0.05) compared with CNE1 cells. Following treatment with a specific DNAzyme that targets LMP1, significantly reduced protein expression levels of BZLF1 and BMRF1 in EBV-associated epithelial carcinoma CNE1-LMP1 cells (P<0.001 and P<0.01, respectively) and lymphoma B95.8 cells (both P<0.01) were observed. Furthermore, EGCG significantly inhibited the mRNA and protein expression levels of LMP1 (P<0.05) in an apparent dose-dependent manner in CNE1-LMP1 and B95.8 cells. Thus, the present findings indicated that the molecular mechanism underlying EGCG inhibition of EBV lytic infection involves downregulation of LMP1. IntroductionEpstein-Barr virus (EBV) is a human herpes virus that infects over 90% of the human population worldwide (1). EBV is suggested to be an environmental factor associated with the development of several human malignancies, including nasopharyngeal carcinoma (NPC), Burkitt's lymphoma, Hodgkin's disease (HD), gastric cancer, natural killer/T-cell lymphoma, acquired immune deficiency syndrome-and transplantation-associated lymphoma (2,3), breast carcinoma, and hepatocellular carcinoma (4,5). EBV, as all other herpes viruses, may establish a latent or lytic infection in host cells (6). Notably, studies suggest that EBV reactivation into a lytic cycle may contribute to the pathogenesis of malignancies (7,8). EBV lytic infection in vivo has been identified by elevated antibody titers against EBV lytic antigens and by increased viral DNA load in the serum/plasma, and these observations correspond with advanced cancer stages, poor prognosis or tumor recurrence following therapy (9,10). Additionally, serological studies have indicated that EBV lytic infection may occur months or years prior to a clinical diagnosis of NPC, HD or Burkitt's lymphoma, which suggests EBV lytic infection may be a risk factor for cancer development (11-13).Green tea contains (-)-epigallocatechin-3-gallate (EGCG), which is reported to have antioxidant, antibacterial and antitumor effects (14,15). EGCG has been indicated to modulate multiple signaling pathways, including the phosphoinositide 3-kinase (PI3-K)/Akt and mitogen-activated protein kinase (MAPK) signaling pathways, which may enable it to exert its cancer chemopreventive and therapeutic effects (16,17).EBV encoded latent membrane protein 1 (LMP1), which is considered to have oncogenic properties, has been identified in 90% of patients with NPC...

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“…hile Epstein-Barr virus (EBV) can either establish latent infection or undergo a lytic cycle in host cells (1), EBV usually remains latent by expressing a limited number of viral genes, including noncoding RNAs (2). The conversion from latency to a lytic cycle is heralded by the expression of two immediate early genes, BZLF1 and BRLF1, which encode the transcription factors Zta and Rta, respectively (3)(4)(5).…”

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confidence: 99%

Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD -Mediated caspase-3 -Dependent Apoptosis

Kim

Choi

Lee

2016

J Virol

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Epstein-Barr virus (EBV) is a human gammaherpesvirus associated with a variety of tumor types. EBV can establish latency or undergo lytic replication in host cells. In general, EBV remains latent in tumors and expresses a limited repertoire of latent proteins to avoid host immune surveillance. When the lytic cycle is triggered by some as-yet-unknown form of stimulation, lytic gene expression and progeny virus production commence. Thus far, the exact mechanism of EBV latency maintenance and the in vivo triggering signal for lytic induction have yet to be elucidated. Previously, we have shown that the EBV microRNA miR-BART20-5p directly targets the immediate early genes BRLF1 and BZLF1 as well as Bcl-2-associated death promoter (BAD) in EBV-associated gastric carcinoma. In this study, we found that both mRNA and protein levels of BRLF1 and BZLF1 were suppressed in cells following BAD knockdown and increased after BAD overexpression. Progeny virus production was also downregulated by specific knockdown of BAD. Our results demonstrated that caspase-3-dependent apoptosis is a prerequisite for BAD-mediated EBV lytic cycle induction. Therefore, our data suggest that miR-BART20-5p plays an important role in latency maintenance and tumor persistence of EBV-associated gastric carcinoma by inhibiting BAD-mediated caspase-3-dependent apoptosis, which would trigger immediate early gene expression. IMPORTANCEEBV has an ability to remain latent in host cells, including EBV-associated tumor cells hiding from immune surveillance. However, the exact molecular mechanisms of EBV latency maintenance remain poorly understood. Here, we demonstrated that miR-BART20-5p inhibited the expression of EBV immediate early genes indirectly, by suppressing BAD-induced caspase-3-dependent apoptosis, in addition to directly, as we previously reported. Our study suggests that EBV-associated tumor cells might endure apoptotic stress to some extent and remain latent with the aid of miR-BART20-5p. Blocking the expression or function of BART20-5p may expedite EBV-associated tumor cell death via immune attack and apoptosis.

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Regulation of the latent-lytic switch in Epstein–Barr virus

Cited by 232 publications

References 97 publications

Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

(-)-Epigallocatechin‑3‑gallate inhibition of Epstein‑Barr virus spontaneous lytic infection involves downregulation of latent membrane protein 1

Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD -Mediated caspase-3 -Dependent Apoptosis

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