期刊
VIROLOGY
卷 391, 期 2, 页码 257-264出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2009.06.039
关键词
Hepatitis C virus; NS4B; UPR; EOR; ROS; Ca2+; NF-kappa B; I kappa B alpha; Liver pathogenesis; Signal transduction pathways
类别
资金
- Jiangxi Agricultural University [2727]
- Department of Science Technology of Jiangxi Province [GJJ09171, GJN0016]
- National Nature Science Foundation of China [30070175]
Hepatitis C virus nonstructural Protein 4B (NS4B) is an endoplasmic reticulum (ER) membrane associated protein and a potent causative factor of ER stress. Here we reported that unfolded protein response (UPR) can be activated by HCV NS4B through inducing both XBP1 mRNA splicing and ATF6 cleavage in human hepatic cells. Flow cytometric analysis revealed that HCV NS4B stimulates the production of reactive oxygen species (ROS) by perturbing intracellular Ca2+ homeostasis. Luciferase assay showed that HCV NS4B also activates the multifunctional transcription factor, NF-kappa B, in a dose-dependent manner through Ca2+ signaling and ROS. Further immunoblot analysis showed that HCV NS4B promotes NF-kappa B translocation into the nucleus Via protein-tyrosine kinase (PTK) mediated phosphorylation and subsequent degradation of I kappa B alpha. These studies provide an important insight into the implication of NS4B in HCV life cycle and HCV-associated liver disease by affecting host intracellular signal transduction pathways. (C) 2009 Elsevier Inc. All rights reserved.
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