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

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. 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.

B Cell Receptor Activation and Chemical Induction Trigger Caspase-Mediated Cleavage of PIAS1 to Facilitate Epstein-Barr Virus Reactivation

“…Our demonstration of caspase-dependent cleavage of the cellular repressor PIAS1 (Figures 4–6) provides an explanation for the role of apoptotic caspases in the replication of EBV, and possibly other viruses. This is consistent with recent studies showing that apoptotic induction triggers the lytic replication of a variety of herpesviruses (De Leo et al, 2017; Du et al, 2012; Gastaldello et al, 2013; Harold et al, 2016; Kim et al, 2015; Lin et al, 2015; Prasad et al, 2012; Prasad et al, 2013). …”

The oncogenic role of Epstein–Barr virus‐encoded microRNAs in Epstein–Barr virus‐associated gastric carcinoma

“…Inhibit apoptosis and suppresses lytic induction in AGS-EBV [92,93] Maintain latency in EBVaGC [69] miR-BARTs BIM (BCL2L11) Inhibit cell death [50].…”

Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes

“…39,40 An association between miRNAs and non-lytic herpesvirus and hepatitis C virus infection has been reported. 41,42 Recent reports support the role of miRNAs in enterovirus pathogenesis. 43 An improved understanding of the impact of viral persistence on the host cell and the virus could provide new insights into the enteroviral pathogenesis of T1D.…”