Journal
JOURNAL OF VIROLOGY
Volume 86, Issue 3, Pages 1544-1554Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00688-11
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Funding
- National Mega Project on Major Infectious Diseases Prevention [2012ZX10002006-003]
- Major State Basic Research Development Program (973 Program) [2012CB518900, 2009CB52, 2011CB522903]
- National Natural Science Foundation of China [81171525, 30730001]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT0745]
- Chinese Ministry of Education [204114208]
- Department of Science Technology of Hubei Province [2005ABC003]
- Science and Technology Programs of Wuhan [200760323102]
- Fundamental Research Funds for the Central Universities [1102001]
- specialized research fund for a doctoral program [20090141110033]
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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.
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