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Hepatitis C Virus Nonstructural Protein 5A Inhibits MG132-Induced Apoptosis of Hepatocytes in Line with NF-κB-Nuclear Translocation

BACKGROUND: Hepatitis C virus (HCV) infection is one of the major causes of cirrhosis and hepatocellular carcinoma. HCV nonstructural protein 5A (NS5A) is an attractive antiviral target and plays an important role in HCV replication as well as hepatocarcinogenesis. The aim of this study was to asses...

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Autores principales: Jiang, Xia, Kanda, Tatsuo, Wu, Shuang, Nakamoto, Shingo, Nakamura, Masato, Sasaki, Reina, Haga, Yuki, Wakita, Takaji, Shirasawa, Hiroshi, Yokosuka, Osamu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489642/
https://www.ncbi.nlm.nih.gov/pubmed/26133378
http://dx.doi.org/10.1371/journal.pone.0131973
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author Jiang, Xia
Kanda, Tatsuo
Wu, Shuang
Nakamoto, Shingo
Nakamura, Masato
Sasaki, Reina
Haga, Yuki
Wakita, Takaji
Shirasawa, Hiroshi
Yokosuka, Osamu
author_facet Jiang, Xia
Kanda, Tatsuo
Wu, Shuang
Nakamoto, Shingo
Nakamura, Masato
Sasaki, Reina
Haga, Yuki
Wakita, Takaji
Shirasawa, Hiroshi
Yokosuka, Osamu
author_sort Jiang, Xia
collection PubMed
description BACKGROUND: Hepatitis C virus (HCV) infection is one of the major causes of cirrhosis and hepatocellular carcinoma. HCV nonstructural protein 5A (NS5A) is an attractive antiviral target and plays an important role in HCV replication as well as hepatocarcinogenesis. The aim of this study was to assess the effect of HCV NS5A protein in the abrogation of apoptotic cell death induced by the proteasome inhibitor MG132. METHODS: Apoptotic responses to MG132 and the expression of molecules involved in NF-κB signaling pathways in human hepatocytes were investigated with or without the expression of HCV NS5A. RESULTS: HCV NS5A protected HepG2 cells against MG132-induced apoptosis, in line with NF-κB-nuclear translocation. A similar NF-κB-nuclear translocation was observed in Huh7 cells infected with HCV JFH1. In agreement with this, after treatment with MG132, HCV NS5A could elevate the transcription of several NF-κB target genes such as BCL2 and BCLXL to inhibit MG132-induced apoptosis in hepatocytes. HCV HCV NS5A also enhanced phosphorylation of IκBα. Consistent with a conferred prosurvival advantage, HCV NS5A reduced MG132-induced poly(adenosine diphosphate-ribose) polymerase cleavage. CONCLUSIONS: HCV NS5A expression enhances phosphorylation of IκBα, liberates NF-κB for nuclear translocation and downregulates MG132-induced apoptotic pathways in human hepatocytes. It is possible that the disruption of proteasome-associated apoptosis plays a role in the pathogenesis of HCV infection.
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spelling pubmed-44896422015-07-15 Hepatitis C Virus Nonstructural Protein 5A Inhibits MG132-Induced Apoptosis of Hepatocytes in Line with NF-κB-Nuclear Translocation Jiang, Xia Kanda, Tatsuo Wu, Shuang Nakamoto, Shingo Nakamura, Masato Sasaki, Reina Haga, Yuki Wakita, Takaji Shirasawa, Hiroshi Yokosuka, Osamu PLoS One Research Article BACKGROUND: Hepatitis C virus (HCV) infection is one of the major causes of cirrhosis and hepatocellular carcinoma. HCV nonstructural protein 5A (NS5A) is an attractive antiviral target and plays an important role in HCV replication as well as hepatocarcinogenesis. The aim of this study was to assess the effect of HCV NS5A protein in the abrogation of apoptotic cell death induced by the proteasome inhibitor MG132. METHODS: Apoptotic responses to MG132 and the expression of molecules involved in NF-κB signaling pathways in human hepatocytes were investigated with or without the expression of HCV NS5A. RESULTS: HCV NS5A protected HepG2 cells against MG132-induced apoptosis, in line with NF-κB-nuclear translocation. A similar NF-κB-nuclear translocation was observed in Huh7 cells infected with HCV JFH1. In agreement with this, after treatment with MG132, HCV NS5A could elevate the transcription of several NF-κB target genes such as BCL2 and BCLXL to inhibit MG132-induced apoptosis in hepatocytes. HCV HCV NS5A also enhanced phosphorylation of IκBα. Consistent with a conferred prosurvival advantage, HCV NS5A reduced MG132-induced poly(adenosine diphosphate-ribose) polymerase cleavage. CONCLUSIONS: HCV NS5A expression enhances phosphorylation of IκBα, liberates NF-κB for nuclear translocation and downregulates MG132-induced apoptotic pathways in human hepatocytes. It is possible that the disruption of proteasome-associated apoptosis plays a role in the pathogenesis of HCV infection. Public Library of Science 2015-07-02 /pmc/articles/PMC4489642/ /pubmed/26133378 http://dx.doi.org/10.1371/journal.pone.0131973 Text en © 2015 Jiang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Jiang, Xia
Kanda, Tatsuo
Wu, Shuang
Nakamoto, Shingo
Nakamura, Masato
Sasaki, Reina
Haga, Yuki
Wakita, Takaji
Shirasawa, Hiroshi
Yokosuka, Osamu
Hepatitis C Virus Nonstructural Protein 5A Inhibits MG132-Induced Apoptosis of Hepatocytes in Line with NF-κB-Nuclear Translocation
title Hepatitis C Virus Nonstructural Protein 5A Inhibits MG132-Induced Apoptosis of Hepatocytes in Line with NF-κB-Nuclear Translocation
title_full Hepatitis C Virus Nonstructural Protein 5A Inhibits MG132-Induced Apoptosis of Hepatocytes in Line with NF-κB-Nuclear Translocation
title_fullStr Hepatitis C Virus Nonstructural Protein 5A Inhibits MG132-Induced Apoptosis of Hepatocytes in Line with NF-κB-Nuclear Translocation
title_full_unstemmed Hepatitis C Virus Nonstructural Protein 5A Inhibits MG132-Induced Apoptosis of Hepatocytes in Line with NF-κB-Nuclear Translocation
title_short Hepatitis C Virus Nonstructural Protein 5A Inhibits MG132-Induced Apoptosis of Hepatocytes in Line with NF-κB-Nuclear Translocation
title_sort hepatitis c virus nonstructural protein 5a inhibits mg132-induced apoptosis of hepatocytes in line with nf-κb-nuclear translocation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489642/
https://www.ncbi.nlm.nih.gov/pubmed/26133378
http://dx.doi.org/10.1371/journal.pone.0131973
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