PKR protein kinase is activated by hepatitis C virus and inhibits viral replication through translational control.
Hepatitis C virus (HCV) infection is currently treated with IFNalpha-based therapy but little is known how IFNalpha inhibits HCV replication. We show here that HCV JFH1 infection of human hepatoma Huh-7 cells leads to the activation of IFN-inducible protein kinase PKR and phosphorylation of the translation initiation factor eIF2alpha. Compared to a control cell HCV replication was significantly elevated in a PKR-knockdown cell, giving rise to a 10-fold higher viral titer, and was less sensitive to IFNalpha treatment. Conversely, transient expression of PKR inhibited HCV replication in a kinase-dependent manner with concomitant increase of eIF2alpha phosphorylation. Further, expression of a phospho-mimetic eIF2alpha mutant moderately inhibited HCV replication. Together, these results demonstrate that PKR is activated by HCV infection and plays a critical antiviral role through inhibition of viral protein translation.
Kang
Ju-Il
JI
School of Life Sciences & Biotechnology, Korea University, 5-1 Anamdong, Seoul 136-701, Republic of Korea.
Kwon
Shi-Nae
SN
Park
Se-Hoon
SH
Kim
Yun Ki
YK
Choi
Sang-Yun
SY
Kim
Jungsuh P
JP
Ahn
Byung-Yoon
BY
D002460:Cell Line; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D006801:Humans; D010766:Phosphorylation; D014176:Protein Biosynthesis; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000235:genetics* / Q000378:metabolism
D015852:Eukaryotic Initiation Factor-2; D014764:Viral Proteins; D019892:eIF-2 Kinase