()-Epigallocatechin-3-Gallate Inhibits EBV Lytic Replication via Targeting LMP1-Mediated MAPK Signal Axes
| Autor: | Zigang Dong, Xinqi Liu, Min Tang, Xiangjian Luo, Ann M. Bode, Yueshuo Li, Jianmin Hu, Hongde Li, Sufang Liu, Ya Cao, Weihua Liao |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
p53
MAPK/ERK pathway Epstein-Barr Virus Infections Herpesvirus 4 Human Cancer Research MAP Kinase Signaling System Mutant Virus Replication medicine.disease_cause Antiviral Agents Catechin Article Viral Matrix Proteins MAPKs hemic and lymphatic diseases Cell Line Tumor medicine Humans Epstein–Barr virus (EBV) lytic replication Phosphorylation Promoter Regions Genetic Latent membrane protein 1 (LMP1) Chemistry General Medicine Viral membrane (−)-Epigallocatechin-3-gallate (EGCG) BZLF1 Cell biology Oncology Membrane protein Lytic cycle Mutation Mitogen-Activated Protein Kinases Tumor Suppressor Protein p53 Carcinogenesis |
| Zdroj: | Oncology Research |
| ISSN: | 0965-0407 |
| DOI: | 10.3727/096504021x16135618512563 |
| Popis: | EpsteinBarr virus (EBV)-encoded latent membrane protein 1 (LMP1) plays an important oncogenic role in the viral latent infection. Recently, increasing evidence indicates that the high expression of LMP1 during EBV lytic cycle is related to the viral lytic replication. However, the mechanism by which LMP1 regulates EBV lytic replication remains unclear. ()-Epigallocatechin-3-gallate (EGCG) prevents carcinogenesis by directly targeting numerous membrane proteins and effectively inhibits EBV lytic cascade. Here, we demonstrated that LMP1 promotes EBV lytic replication through the downstream signal molecules MAPKs, including ERKs, p38, and JNKs. LMP1 induces the phosphorylation of p53 through MAPKs to enhance the ability of wild-type p53 (wt-p53) to activate expression of BZLF1 gene, while the JNKs/c-Jun signal axis appears to be involved in EBV lytic replication induced by LMP1 in p53 mutant manner. We provided the first evidence that EGCG directly targets the viral membrane LMP1 (K d=0.36 M, n=1) using fluorescence quenching, isothermal titration calorimetry (ITC) assay, and CNBR-activated Sepharose 4B pull-down affinity chromatography. Furthermore, we revealed that EGCG inhibits EBV lytic replication via suppressing LMP1 and thus blocking the downstream MAPKs/wt-p53 signal axis in AGS-EBV cells and JNKs/c-Jun signal axis in p53 mutant B95.8 cells. Our study, for the first time, reports the binding and inhibitory efficacy of EGCG to the LMP1, which is a key oncoprotein encoded by EBV. These findings suggest the novel function of LMP1 in the regulation of EBV lytic cycle and reveal the new role of EGCG in EBV-associated malignancies through suppressing viral reactivation. |
| Databáze: | OpenAIRE |
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