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Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD-Mediated caspase-3-Dependent Apoptosis.
J Virol. 2016 02 01; 90(3):1359-68.JV

Abstract

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.

IMPORTANCE

EBV 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.

Authors+Show Affiliations

Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea sukklee@catholic.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26581978

Citation

Kim, Hyoji, et al. "Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction By Inhibiting BAD-Mediated caspase-3-Dependent Apoptosis." Journal of Virology, vol. 90, no. 3, 2016, pp. 1359-68.
Kim H, Choi H, Lee SK. Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD-Mediated caspase-3-Dependent Apoptosis. J Virol. 2016;90(3):1359-68.
Kim, H., Choi, H., & Lee, S. K. (2016). Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD-Mediated caspase-3-Dependent Apoptosis. Journal of Virology, 90(3), 1359-68. https://doi.org/10.1128/JVI.02794-15
Kim H, Choi H, Lee SK. Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction By Inhibiting BAD-Mediated caspase-3-Dependent Apoptosis. J Virol. 2016 02 1;90(3):1359-68. PubMed PMID: 26581978.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD-Mediated caspase-3-Dependent Apoptosis. AU - Kim,Hyoji, AU - Choi,Hoyun, AU - Lee,Suk Kyeong, Y1 - 2015/11/18/ PY - 2015/10/31/received PY - 2015/11/08/accepted PY - 2015/11/20/entrez PY - 2015/11/20/pubmed PY - 2016/5/24/medline SP - 1359 EP - 68 JF - Journal of virology JO - J Virol VL - 90 IS - 3 N2 - UNLABELLED: 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. IMPORTANCE: EBV 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. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/26581978/Epstein_Barr_Virus_MicroRNA_miR_BART20_5p_Suppresses_Lytic_Induction_by_Inhibiting_BAD_Mediated_caspase_3_Dependent_Apoptosis_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=26581978 DB - PRIME DP - Unbound Medicine ER -