Epstein-Barr viral microRNAs target caspase 3

Abstract

The Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that transforms B cells and causes several malignancies including Burkitt’s lymphoma. EBV differentially expresses at least 49 mature microRNAs (miRNAs) during latency in various infected epithelial and B cells. Recent high-throughput studies and functional assays have begun to reveal the function of the EBV miRNAs suggesting roles in latency, cell cycle control, and apoptosis. In particular, the central executioner of apoptosis, Caspase 3 (CASP3), was proposed as a target of select EBV miRNAs. However, whether CASP3 is truly a target of EBV miRNAs, and if so, which specific miRNAs target CASP3 is still under debate. Based on previously published high-throughput biochemical data and a bioinformatic analysis of the entire CASP3 3′-UTR, we identified 12 EBV miRNAs that have one or more seed binding sites in the CASP3 3′-UTR. We individually tested all 12 miRNAs for repression of CASP3 in luciferase reporter assays, and nine showed statistically significant (P < 0.001) repression of a full-length CASP3 reporter. Further, three EBV miRNAs, including BART22, exhibited repression of endogenous CASP3 protein. These data confirm that CASP3 is a direct target of specific EBV BART miRNAs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-016-0602-7) contains supplementary material, which is available to authorized users.

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). …”

Implication of viral microRNAs in the genesis and diagnosis of Epstein‑Barr virus‑associated tumors (Review)

“…A total of 12 EBV miRs were found to have one or more seed binding sites in the 3'-UTR of the caspase 3 (CASP3) mRNA, while nine induced significant repression of a full-length CASP3 reporter. Furthermore, three EBV miRs, including BART22, repressed the endogenous CASP3 protein (74). With regards to the crucial role of CASP3 in executing apoptosis, the data supports the notion that EBV-encoded miRs exert apoptosis inhibition to facilitate viral replication.…”

“…The cells with EBV lacking the BHRF1 miRs progressed through the cell cycle less efficiently and died due to apoptosis more frequently than cells infected with the parental EBV. According to phenotypic characterizations, EBV-encoded BHRF1 miRs supported B-cell activation mediated by EBV, but were not involved in maintaining viral latency (74,76) The role of EBV-encoded miRs on the transformation of B cells and growth of LCLs was examined using a mutant BHRF1 miR cluster. Deficient BHRF1 miRs still increased the number of B-cell-derived lymphoblastoid cell lines (LCLs) in the S phase, and this finding prompted a screening of the expression of cell cycle regulators.…”

Epstein–Barr virus-associated lymphomas

“…There is now strong evidence that these viral miRNAs are not only critical for optimal EBV-induced B cell growth transformation [ 40 ], but also play a key role in maintaining the BL phenotype [ 41 – 43 ]. However, with the notable exception of caspase-3 [ 41 , 44 ], few direct targets of EBV BART-miRNAs relevant to BL survival have been identified to date.…”