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Activation of the Ras/Raf/MEK Pathway Facilitates Hepatitis C Virus Replication via Attenuation of the Interferon-JAK-STAT Pathway
- Source :
- Journal of Virology. 86:1544-1554
- Publication Year :
- 2012
- Publisher :
- American Society for Microbiology, 2012.
-
Abstract
- Hepatitis C virus (HCV) is a major cause of chronic liver diseases worldwide, often leading to the development of hepatocellular carcinoma (HCC). Constitutive activation of the Ras/Raf/MEK pathway is responsible for approximately 30% of cancers. Here we attempted to address the correlation between activation of this pathway and HCV replication. We showed that knockdown of Raf1 inhibits HCV replication, while activation of the Ras/Raf/MEK pathway by V12, a constitutively active form of Ras, stimulates HCV replication. We further demonstrated that this effect is regulated through attenuation of the interferon (IFN)-JAK-STAT pathway. Activation of the Ras/Raf/MEK pathway downregulates the expression of IFN-stimulated genes (ISGs), attenuates the phosphorylation of STAT1/2, and inhibits the expression of interferon (alpha, beta, and omega) receptors 1 and 2 (IFNAR1/2). Furthermore, we observed that HCV infection activates the Ras/Raf/MEK pathway. Thus, we propose that during HCV infection, the Ras/Raf/MEK pathway is activated, which in turn attenuates the IFN-JAK-STAT pathway, resulting in stimulation of HCV replication.
- Subjects :
- MAPK/ERK pathway
Hepatitis C virus
Immunology
Cellular Response to Infection
Hepacivirus
Biology
Real-Time Polymerase Chain Reaction
Virus Replication
medicine.disease_cause
Microbiology
Cell Line
Interferon
Virology
medicine
Humans
STAT1
Phosphorylation
Receptor
DNA Primers
Janus Kinases
Base Sequence
virus diseases
JAK-STAT signaling pathway
Molecular biology
digestive system diseases
Enzyme Activation
STAT Transcription Factors
Viral replication
Gene Knockdown Techniques
Insect Science
biology.protein
Interferons
Protein Kinases
medicine.drug
Subjects
Details
- ISSN :
- 10985514 and 0022538X
- Volume :
- 86
- Database :
- OpenAIRE
- Journal :
- Journal of Virology
- Accession number :
- edsair.doi.dedup.....f595e48b97a2b08f1d05db7ad0eafdab