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Cap-dependent and hepatitis C virus internal ribosome entry site-mediated translation are modulated by phosphorylation of eIF2 under oxidative stress

¹ Faculty of Life Sciences, The University of Manchester, Jackson's Mill, PO Box 88, Sackville Street, Manchester M60 1QD, UK
² Centre for Biomolecular Sciences, School of Biology, University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK
³ Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK

Correspondence
Shiu-Wan Chan
shiu-wan.chan{at}manchester.ac.uk

Chronic hepatitis C is often associated with oxidative stress. Hepatitis C virus (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 (H₂O₂) as a stress inducer. In H₂O₂-sensitive HeLa cells, H₂O₂ 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 H₂O₂. In H₂O₂-resistant HepG2 cells, H₂O₂ activated both HCV IRES-mediated and cap-dependent translation, associated with an increased level of phospho-eIF2. It was postulated that H₂O₂ 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 H₂O₂. In HuH7 cells, which exhibited an intermediate level of sensitivity towards H₂O₂, both HCV IRES-mediated and cap-dependent translational activities were upregulated after treatment with various doses of H₂O₂, but the highest level of induction was achieved with a low level of H₂O₂, which may represent the physiological level of H₂O₂. At this level, the HCV IRES-mediated translation was preferentially upregulated compared with cap-dependent translation.

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