Hepatitis C virus nonstructural 4B protein modulates sterol regulatory element-binding protein signaling via the AKT pathway.
Hepatitis C virus (HCV) infection is often associated with hepatic steatosis and yet the molecular mechanisms of HCV-associated steatosis are poorly understood. Because sterol regulatory element-binding proteins (SREBPs) are the major transcriptional factors in lipogenic gene expression including fatty acid synthase (FAS), we examined the effects of HCV nonstructural proteins on the signaling pathways of SREBP. In this study, we demonstrated that HCV nonstructural 4B (NS4B) protein increased the transcriptional activities of SREBPs. We also showed that HCV NS4B enhanced the protein expression levels of SREBPs and FAS. This was further confirmed in the context of viral RNA replication and HCV infection. The up-regulation of both SREBP and FAS by NS4B protein required phosphatidylinositol 3-kinase activity. We also demonstrated that NS4B protein induced a lipid accumulation in hepatoma cells. In addition, NS4B protein synergistically elevated the transcriptional activity of HCV core-mediated SREBP-1. These results strongly suggest that NS4B may play an important role in HCV-associated liver pathogenesis by modulating the SREBP signaling pathway.
Park
Chul-Yong
CY
National Research Laboratory of Hepatitis C Virus and Ilsong Institute of Life Science, Hallym University, Anyang 431-060, Korea.
Jun
Hyun-Jeong
HJ
Wakita
Takaji
T
Cheong
Jae Hun
JH
Hwang
Soon B
SB
D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D017361:Viral Nonstructural Proteins; D051057:Proto-Oncogene Proteins c-akt