Hepatitis C Virus Nonstructural Protein 5A Inhibits Thapsigargin-Induced Apoptosis

Jiang, Xia; Wu, Shuang; Nakamoto, Shingo; Wakita, Takaji; Shirasawa, Hiroshi; Yokosuka, Osamu

doi:10.1371/journal.pone.0113499

Cited by 14 publications

(19 citation statements)

References 49 publications

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“…Plasmid pCXN2 was generously provided by Prof. J. Miyazaki (Osaka University) [ 23 ]. pCXN2-HCV NS5A vectors were described previously [ 14 ]. pCXN2-NS5A plasmids with the HCV genotype 1b NS5A, including 2 wide-type, 2 intermediate-type, and 1 mutant-type interferon sensitivity determining region (ISDR, aa2209-aa2248) were named pCXN2-NS5A-W1 and pCXN2-NS5A-W2, pCXN2-NS5A-I1 and pCXN2-NS5A-I2, and pCXN2-NS5A-M1, respectively [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…pCXN2-HCV NS5A vectors were described previously [ 14 ]. pCXN2-NS5A plasmids with the HCV genotype 1b NS5A, including 2 wide-type, 2 intermediate-type, and 1 mutant-type interferon sensitivity determining region (ISDR, aa2209-aa2248) were named pCXN2-NS5A-W1 and pCXN2-NS5A-W2, pCXN2-NS5A-I1 and pCXN2-NS5A-I2, and pCXN2-NS5A-M1, respectively [ 14 ]. The human hepatoma cell HepG2 was cultured in Dulbecco’s modified Eagle’s medium (Invitrogen, Carlsbad, CA, USA) containing 10% heat-inactivated fetal bovine serum, 100 units/ml penicillin and 100 μg/ml streptomycin (Sigma, St. Louis, MO, USA) under 5% CO2 at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…The human hepatoma cell HepG2 was cultured in Dulbecco’s modified Eagle’s medium (Invitrogen, Carlsbad, CA, USA) containing 10% heat-inactivated fetal bovine serum, 100 units/ml penicillin and 100 μg/ml streptomycin (Sigma, St. Louis, MO, USA) under 5% CO2 at 37°C. Stable HepG2 cell lines as control cells, which expressed pCXN2 [ 14 ], and HepG2-NS5A cells, which expressed various HCV genotype 1b NS5A proteins, have been described previously [ 13 , 14 ]. Huh7 cells were infected with JFH1 genotype 2a as described elsewhere [ 24 , 25 ].…”

Section: Methodsmentioning

confidence: 99%

“…The caspase-Glo 3/7 assay (Promega, Madison, WI, USA) was used to detect caspase-3 and caspase-7 activities according to the manufacturer’s instructions [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…HCV NS5A is important for HCV replication [ 8 ] and is involved in multiple cellular processes [ 9 , 10 ]. HCV NS5A has been shown to block hepatic apoptosis mediated by tumor necrosis factor (TNF) [ 11 , 12 ], lipopolysaccharide (LPS) [ 13 ] or thapsigargin [ 14 ], suggesting that the disruption of this apoptosis may play a role in the pathogenesis of HCV infection.…”

Section: Introductionmentioning

confidence: 99%

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

Jiang

Nakamoto

et al. 2015

PLoS ONE

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BackgroundHepatitis 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.MethodsApoptotic 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.ResultsHCV 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.ConclusionsHCV 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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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The caspase-Glo 3/7 assay (Promega, Madison, WI, USA) was used to detect caspase-3 and caspase-7 activities according to the manufacturer’s instructions [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Jiang

Nakamoto

et al. 2015

PLoS ONE

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Diversity in heat shock protein families: functional implications in virus infection with a comprehensive insight of their role in the HIV-1 life cycle

Iyer

Chand

Mitra

et al. 2021

Cell Stress and Chaperones

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Heat shock proteins (HSPs) are a group of cellular proteins that are induced during stress conditions such as heat stress, cold shock, UV irradiation and even pathogenic insult. They are classified into families based on molecular size like HSP27, 40, 70 and 90 etc, and many of them act as cellular chaperones that regulate protein folding and determine the fate of mis-folded or unfolded proteins. Studies have also shown multiple other functions of these proteins such as in cell signalling, transcription and immune response. Deregulation of these proteins leads to devastating consequences, such as cancer, Alzheimer’s disease and other life threatening diseases suggesting their potential importance in life processes. HSPs exist in multiple isoforms, and their biochemical and functional characterization still remains a subject of active investigation. In case of viral infections, several HSP isoforms have been documented to play important roles with few showing pro-viral activity whereas others seem to have an anti-viral role. Earlier studies have demonstrated that HSP40 plays a pro-viral role whereas HSP70 inhibits HIV-1 replication; however, clear isoform-specific functional roles remain to be established. A detailed functional characterization of all the HSP isoforms will uncover their role in cellular homeostasis and also may highlight some of them as potential targets for therapeutic strategies against various viral infections. In this review, we have tried to comprehend the details about cellular HSPs and their isoforms, their role in cellular physiology and their isoform-specific functions in case of virus infection with a specific focus on HIV-1 biology.

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Bromodomain containing protein represses the Ras/Raf/MEK/ERK pathway to attenuate human hepatoma cell proliferation during HCV infection

et al. 2016

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Hepatitis C virus (HCV) infection facilitates the development of hepatocellular carcinoma (HCC). Activation of Ras/Raf/MEK/ERK pathway is found in more than 30% human cancers. Here, we revealed a novel mechanism underlying the regulation of hepatoma cell proliferation mediated by HCV. On one hand, hepatoma cell proliferation is facilitated by HCV infection through a positive feedback regulatory cycle. HCV promotes hepatoma cell proliferation by activating the Ras/Raf/MEK/ERK pathway, which in turn facilitates HCV replication to further enhance hepatoma cell proliferation. On the other hand, hepatoma cell proliferation is attenuated by the bromodomain containing 7 (BRD7), a tumor suppressor, through a negative feedback regulatory mechanism. After activation, the Ras/Raf/MEK/ERK pathway stimulates BRD7 production, which in turn represses the Ras/Raf/MEK/ERK pathway, leading to the attenuation of hepatoma cell proliferation. However, HCV persistent infection attenuates BRD7 gene expression and facilitates the protein degradation to release the Ras/Raf/MEK/ERK signaling, which results in the facilitation of hepatoma cell proliferation. Therefore, we proposed that the balance between BRD7 function and Ras/Raf/MEK/ERK activity is important for determining the outcomes of HCV infection and HCC development.

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Hepatitis C Virus Nonstructural Protein 5A Inhibits Thapsigargin-Induced Apoptosis

Cited by 14 publications

References 49 publications

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

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

Diversity in heat shock protein families: functional implications in virus infection with a comprehensive insight of their role in the HIV-1 life cycle

Bromodomain containing protein represses the Ras/Raf/MEK/ERK pathway to attenuate human hepatoma cell proliferation during HCV infection

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