Up-regulation of hepatitis C virus replication and production by inhibition of MEK/ERK signaling.
BACKGROUND
Viruses interact with and exploit the host cellular machinery for their multiplication and propagation. The MEK/ERK signaling pathway positively regulates replication of many RNA viruses. However, whether and how this signaling pathway affects hepatitis C virus (HCV) replication and production is not well understood.


RESULTS
In this study, we took advantage of two well-characterized MEK/ERK inhibitors and MEK/ERK dominant negative mutants and investigated the roles of the MEK/ERK signaling pathway in HCV gene expression and replication. We showed that inhibition of MEK/ERK signaling enhanced HCV gene expression, plus- and minus-strand RNA synthesis, and virus production. In addition, we showed that this enhancement was independent of interferon-alpha (IFN-alpha) antiviral activity and did not require prior activation of the MEK/ERK signaling pathway. Furthermore, we showed that only MEK and ERK-2 but not ERK-1 was involved in HCV replication, likely through regulation of HCV RNA translation.


CONCLUSIONS
Taken together, these results demonstrate a negative regulatory role of the MEK/ERK signaling pathway in HCV replication and suggest a potential risk in targeting this signaling pathway to treat and prevent neoplastic transformation of HCV-infected liver cells.
Ndjomou
Jean
J
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Park
In-woo
IW
Liu
Ying
Y
Mayo
Lindsey D
LD
He
Johnny J
JJ
D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D014176:Protein Biosynthesis; D012367:RNA, Viral / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D014779:Virus Replication
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D012367:RNA, Viral; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases