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Updated: Jan 29, 2026
Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle
Published on: March 5, 2019
Activation of protein kinase R by hepatitis C virus RNA-dependent RNA polymerase
Ryosuke Suzuki1, Mami Matsuda2, Takashi Shimoike3
1Department of Virology II, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-murayama-shi, Tokyo 208-0011, Japan.
Abstract:
Hepatitis C virus (HCV) was shown to activate protein kinase R (PKR), which inhibits expression of interferon (IFN) and IFN-stimulated genes by controlling the translation of newly transcribed mRNAs. However, it is unknown exactly how HCV activates PKR. To address the molecular mechanism(s) of PKR activation mediated by HCV infection, we examined the effects of viral proteins on PKR activation. Here, we show that expression of HCV NS5B strongly induced PKR and eIF2α phosphorylation, and attenuated MHC class I expression. In contrast, expression of Japanese encephalitis virus RNA-dependent RNA polymerase did not induce phosphorylation of PKR. Co-immunoprecipitation analyses showed that HCV NS5B interacted with PKR. Furthermore, expression of NS5B with polymerase activity-deficient mutation failed to phosphorylate PKR, suggesting that RNA polymerase activity is required for PKR activation. These results suggest that HCV activates PKR by association with NS5B, resulting in translational suppression of MHC class I to establish chronic infection.
Insights
Hepatitis C virus (HCV) activates protein kinase R (PKR) through its NS5B protein, inhibiting interferon responses and MHC class I expression. This interaction is crucial for HCV to establish chronic infection.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Hepatitis C virus (HCV) activates protein kinase R (PKR), inhibiting interferon (IFN) and IFN-stimulated gene expression by controlling mRNA translation.
- The precise molecular mechanisms by which HCV activates PKR remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms of PKR activation mediated by HCV infection.
- To investigate the role of viral proteins in PKR activation.
Main Methods:
- Examined the effects of expressing HCV proteins on PKR and eIF2α phosphorylation.
- Utilized co-immunoprecipitation to assess interactions between HCV NS5B and PKR.
- Assessed the impact of NS5B polymerase activity mutations on PKR activation.
Main Results:
- HCV NS5B expression strongly induced PKR and eIF2α phosphorylation, and attenuated MHC class I expression.
- HCV NS5B directly interacted with PKR.
- NS5B polymerase activity was essential for PKR activation, as a polymerase-deficient mutant failed to induce phosphorylation.
Conclusions:
- HCV activates PKR via interaction with the NS5B protein.
- The RNA polymerase activity of NS5B is required for PKR activation.
- This NS5B-mediated PKR activation leads to translational suppression of MHC class I, facilitating chronic HCV infection.
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