title: Activation of the Ras/Raf/MEK pathway facilitates hepatitis C virus replication via attenuation of the interferon-JAK-STAT pathway.
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.
authors: State Key Laboratory of Virology, College of Life Sciences, and Chinese-French Liver Disease Research Institute at Zhongnan Hospital, Wuhan University, Wuhan, People's Republic of China.
authors: Qi
authors: Q
authors: Zhang
authors: Rui
authors: R
authors: Gong
authors: Jing
authors: J
authors: Qu
authors: Yijing
authors: Y
authors: Zhou
authors: Weiyong
authors: W
authors: Liu
authors: Mingzhou
authors: M
authors: Chen
authors: Yingle
authors: Y
authors: Liu
authors: Ying
authors: Y
authors: Zhu
authors: Jianguo
authors: J
authors: Wu
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D017931:DNA Primers; D050791:STAT Transcription Factors; D007372:Interferons; D011494:Protein Kinases; D053612:Janus Kinases