Hepatitis C virus core inhibits the Fas-mediated p38 mitogen activated kinase signaling pathway in hepatocytes.
The p38 mitogen activated kinase (MAPK) signaling pathway plays an essential role in regulating many cellular processes, including inflammation, cell differentiation, and cell death. Here, we report that the hepatitis C virus (HCV) core inhibits the Fas-mediated p38 signaling pathway. The Fas-mediated p38 activation is suppressed in core-expressing HepG2 cell lines, as well as in the hepatocytes of transgenic mice. In addition, core protein blocked the Fas-mediated activation of apoptosis signal-regulating kinase 1 (ASK1), a major upstream MAPKKK of p38. Treatment of a specific p38 inhibitor (SB203580) or overexpression of a kinase-defective mutant, ASK1 (K709R), promoted Fas-mediated cell death in HepG2 cells. This suggests that the p38 and ASK1 activation is required for cell survival against Fas-mediated cell death. In addition, we observed that the HCV core protein enhances Fas-mediated liver injury and lethality in transgenic mice. Collectively, our findings suggest that the HCV core inhibits the Fas-mediated p38 signaling pathway, which results in accelerated Fas-mediated cell death.
Department of Life Science, Pohang University of Science and Technology, Korea.
Se-Hwan
SH
Yang
Chang Geun
CG
Lee
Chang Woo
CW
Lee
Eui-Ju
EJ
Choi
Seung Kew
SK
Yoon
Kwang Seog
KS
Ahn
Young Chul
YC
Sung
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003593:Cytoplasm / Q000821:virology; D004195:Disease Models, Animal; D016174:Hepacivirus; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology*; D006801:Humans; D008099:Liver / Q000821:virology; D017093:Liver Failure / Q000821:virology; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014758:Viral Core Proteins / Q000494:pharmacology*; D019014:fas Receptor / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D014758:Viral Core Proteins; D019014:fas Receptor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse