1887

Abstract

Chronic hepatitis C is often associated with oxidative stress. (HCV) utilizes an internal ribosome entry site (IRES) element for translation, in contrast to cap-dependent translation of the majority of cellular proteins. To understand how virus translation is modulated under oxidative stress, HCV IRES-mediated translation was compared with cap-dependent translation using a bicistronic reporter construct and hydrogen peroxide (HO) as a stress inducer. In HO-sensitive HeLa cells, HO repressed translation in a time- and dose-dependent manner, concomitant with the kinetics of eIF2 phosphorylation. A phosphomimetic of eIF2, which mimics the structure of the phosphorylated eIF2, was sufficient to repress translation in the absence of HO. In HO-resistant HepG2 cells, HO activated both HCV IRES-mediated and cap-dependent translation, associated with an increased level of phospho-eIF2. It was postulated that HO might stimulate translation in HepG2 cells via an eIF2-independent mechanism, whereas the simultaneous phosphorylation of eIF2 repressed part of the translational activities. Indeed, the translational repression was released in the presence of a non-phosphorylatable mutant, eIF2-SA, resulting in further enhancement of both translational activities after exposure to HO. In HuH7 cells, which exhibited an intermediate level of sensitivity towards HO, both HCV IRES-mediated and cap-dependent translational activities were upregulated after treatment with various doses of HO, but the highest level of induction was achieved with a low level of HO, which may represent the physiological level of HO. At this level, the HCV IRES-mediated translation was preferentially upregulated compared with cap-dependent translation.

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2006-11-01
2021-08-02
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