The role of PERK and GCN2 in basal and hydrogen peroxide-regulated translation from the hepatitis C virus internal ribosome entry site
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- 作者：Samantha C. Jack (1)
Shiu-Wan Chan (1) shiu-wan.chan@manchester.ac.uk - 关键词：Hepatitis C virus – ; PERK – ; GCN2 – ; IRES – ; Translation – ; Oxidative stress
- 刊名：Virus Genes
- 出版时间：October 2011
- 出版年：2011
- 期刊代码：7_09208569
- 类别：art
- 卷：43
- 期：2
- 页码：208-214
- 数据来源：sp
摘要
We have previously shown that translation from the HCV IRES is up-regulated by patho/physiological doses of H2O2 but is still sensitive to the inhibitory effect of phospho-eIF2α in hepatocytes. In this study using wild type and ‘knockout’ mouse embryonic fibroblasts (MEFs), we showed that two of the eIF2α kinases, PERK and GCN2, were not responsible for translational regulation under physiological and a higher apoptotic doses of H2O2 (100 μM). However, a differential translational response was observed at a lower apoptotic dose of H2O2 (50 μM) between Perk+/+ and Perk−/− MEFs but not that between Gcn2+/+ and Gcn2−/− MEFs, suggesting that PERK may play a role in translational up-regulation under oxidative stress. Our results also suggest that PERK mediates such an effect via an eIF2-independent pathway. This is in contrast to the canonical role of PERK on translational inhibition under stress conditions via phosphorylation of eIF2α. When tested for the role of PERK and GCN2 on basal translation from the HCV IRES under non-stressed condition, we found that basal translation from the HCV IRES was also favoured in the presence of PERK or GCN2 in MEFs over that of cap-dependent translation and was favoured in the presence of GCN2 but not PERK in Huh-7 cells. These results suggest that PERK and GCN2 also have a functional role on regulating translation under non-stressed conditions, apart from their long established roles as stress kinases.