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Hepatitis C virus NS4B induces unfolded protein response and endoplasmic reticulum overload response-dependent NF-kappaB activation.
- Source :
-
Virology [Virology] 2009 Sep 01; Vol. 391 (2), pp. 257-64. Date of Electronic Publication: 2009 Jul 22. - Publication Year :
- 2009
-
Abstract
- 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 Ca(2+) homeostasis. Luciferase assay showed that HCV NS4B also activates the multifunctional transcription factor, NF-kappaB, in a dose-dependent manner through Ca(2+) signaling and ROS. Further immunoblot analysis showed that HCV NS4B promotes NF-kappaB translocation into the nucleus via protein-tyrosine kinase (PTK) mediated phosphorylation and subsequent degradation of IkappaBalpha. 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.
- Subjects :
- Activating Transcription Factor 6 metabolism
Calcium metabolism
Cell Line
Cell Nucleus chemistry
Cytoplasm chemistry
DNA-Binding Proteins metabolism
Humans
I-kappa B Proteins metabolism
NF-KappaB Inhibitor alpha
Reactive Oxygen Species metabolism
Regulatory Factor X Transcription Factors
Transcription Factors metabolism
X-Box Binding Protein 1
Endoplasmic Reticulum metabolism
Hepacivirus physiology
Hepatocytes virology
NF-kappa B biosynthesis
Viral Nonstructural Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0341
- Volume :
- 391
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Virology
- Publication Type :
- Academic Journal
- Accession number :
- 19628242
- Full Text :
- https://doi.org/10.1016/j.virol.2009.06.039