Abstract
Following our observation that clofoctol led to Epstein–Barr virus (EBV) lytic gene expression upon activation of the integrated stress response (ISR), we decided to investigate the impact of As2O3 on viral lytic gene expression. As2O3 has also been reported to activate the ISR pathway by its activation of the heme-regulated inhibitor (HRI). Our investigations show that As2O3 treatment leads to eIF2α phosphorylation, upregulation of ATF4 and TRB3 expression, and an increase of EBV Zta gene expression in lymphoid tumor cell lines as well as in naturally infected epithelial cancer cell lines. However, late lytic gene expression and virion production were blocked after arsenic treatment. In comparison, a small molecule HRI activator also led to increased Zta expression but did not block late lytic gene expression, suggesting that As2O3 effects on EBV gene expression are also mediated through other pathways.
Highlights
Following our observation that clofoctol led to Epstein–Barr virus (EBV) lytic gene expression upon activation of the integrated stress response (ISR), we decided to investigate the impact of
We reported that eIF2α phosphorylation, by the protein kinase R (PKR)like endoplasmic reticulum (ER) kinase (PERK), activated EBV lytic viral transcription [12]
Induction of lytic replication as judged by green fluorescent protein (GFP) expression was blocked (Figure 3B). These results are consistent with the interpretation that the effects of arsenicals on Trib3 and Zta expression are mediated by heme-regulated inhibitor (HRI) activation of the ISR
Summary
The Epstein–Barr virus (EBV), a human gammaherpesvirus, is associated with a variety of malignancies including some lymphomas of B, T, and NK cell origin, and carcinomas including nasopharyngeal and gastric carcinomas [1,2]. This pathway is known as the integrated stress response (ISR) Four kinases phosphorylate this eIF2α serine: PERK, heme-regulated inhibitor kinase (HRI), general control nonderepressible 2 (GCN2), and double-stranded RNA-dependent protein kinase (PKR). Homologous in their catalytic domains, the regulatory domains of these kinases respond to different stresses. HRI is expressed at the highest levels expression in erythroid cells where is activated by a deficiency in heme It regulates globinmight mRNA translation as a function of the availability in the possibility that the other arms of the ISR mediate activation of lytic of gene heme. The cell lysate proteins on the blot were incubated with actin antibodies
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