Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum

Xu, Zhichang; Jensen, Gitte S.; Yen, T. S. Benedict

doi:10.1128/jvi.71.10.7387-7392.1997

Cited by 139 publications

(74 citation statements)

References 32 publications

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“…The up-regulation of GRP78 upon HBV replication may be explained by the activation of UPR that enhanced the synthesis and translation of ER chaperones in ER stress (29) and the direct activation of GRP78 promoter by HBV proteins (30). To test this hypothesis, we checked whether the UPR signaling pathways, including the inositol-requiring enzyme 1-, the protein kinase R-like ER kinase-, and the activating transcription factor 6-mediated signal transduction, were activated by HBV replication.…”

Section: Differentially Expressed Proteins Identified By 2-de and Ms mentioning

confidence: 99%

Glucose-regulated Protein 78 Is an Intracellular Antiviral Factor against Hepatitis B Virus

Chan

et al. 2009

Molecular & Cellular Proteomics

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Hepatitis B virus (HBV) infection isHepatitis B virus infection is a global public health problem. An estimated 2 billion (one-third of the world's population) people are infected with HBV 1 worldwide, and more than 400 million are chronic hepatitis B (CHB) carriers (1). Epidemiological studies have shown that HBV infection is one of the major risk factors for chronic hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). Every year, over 1 million people die of HBV-related liver diseases, 30 -50% of which are attributed to HCC (2). In China, more than 130 million (10% of the national population) people are suffering from CHB (3), and HCC has been ranked as the second major cause of cancer-related death since 1990 (4). However, the limited efficacy of antiviral therapies, high rates of post-treatment HBV relapse, and the emergence of drug-resistant viral mutants have greatly hindered the effective management of CHB infection. Therefore, it is of prime importance to understand the mechanisms of HBV-host interactions during malignant transformation in CHB infection to identify novel therapeutic anti-HBV targets.Because human HBV is incapable of infecting hepatocytes in vitro efficiently and the availability of reliable in vitro culture systems that favor HBV replication is limited, the pathogenetic studies of HBV and the development of anti-HBV drugs have long been hampered. HepAD38 and HepG2.2.15, both of From the ‡Stanley

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Section: Differentially Expressed Proteins Identified By 2-de and Ms mentioning

confidence: 99%

Glucose-regulated Protein 78 Is an Intracellular Antiviral Factor against Hepatitis B Virus

Chan

et al. 2009

Molecular & Cellular Proteomics

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“…Viruses have developed various strategies to modulate the UPR [11][12][13][14]. The hepatitis C virus (HCV) causes increased transcription from the glucose regulated protein 78 (GRP78) and GRP94 promoters through the activation of PERK and ATF6 pathways [15,16,17], with simultaneous suppression of the IRE1-X box binding protein (XBP1) pathway [18].…”

Section: Introductionmentioning

confidence: 99%

The SARS Coronavirus 3a Protein Causes Endoplasmic Reticulum Stress and Induces Ligand-Independent Downregulation of the Type 1 Interferon Receptor

et al. 2009

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The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) is reported to cause apoptosis of infected cells and several of its proteins including the 3a accessory protein, are pro-apoptotic. Since the 3a protein localizes to the endoplasmic reticulum (ER)-Golgi compartment, its role in causing ER stress was investigated in transiently transfected cells. Cells expressing the 3a proteins showed ER stress based on activation of genes for the ER chaperones GRP78 and GRP94. Since ER stress can cause differential modulation of the unfolded protein response (UPR), which includes the inositol-requiring enzyme 1 (IRE-1), activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) pathways, these were individually tested in 3a-expressing cells. Only the PERK pathway was found to be activated in 3a-expressing cells based on (1) increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) and inhibitory effects of a dominant-negative form of eIF2α on GRP78 promoter activity, (2) increased translation of activating transcription factor 4 (ATF4) mRNA, and (3) ATF4-dependent activation of the C/EBP homologous protein (CHOP) gene promoter. Activation of PERK affects innate immunity by suppression of type 1 interferon (IFN) signaling. The 3a protein was found to induce serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1) degradation motif and to increase IFNAR1 ubiquitination. Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells. These results provide further mechanistic details of the pro-apoptotic effects of the SARS-CoV 3a protein, and suggest a potential role for it in attenuating interferon responses and innate immunity.

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“…Unfolded protein response has been documented in viral infections (Xu et al, 1997;Su et al, 2002;Tardif et al, 2002;. For example, hepatitis C virus (HCV) infection upregulates the ATF6 and IRE1-XBP1 pathways (Tardif et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress is induced and modulated by enterovirus 71

Jheng¹,

Lau²,

Tang³

et al. 2010

Cellular Microbiology

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SummaryPicornavirus infection alters the endoplasmic reticulum (ER) membrane but it is unclear whether this induces ER stress. Infection of rhabdomyosarcoma cells with enterovirus 71 (EV71), a picornavirus, caused overexpression of the ER-resident chaperone proteins, BiP and calreticulin, and phosphorylation of eIF2a, but infection with UV-inactivated virus did not, indicating that ER stress was induced by viral replication and not by viral attachment or entry. Silencing (si)RNA knockdown demonstrated that phosphorylation of eIF2a was dependent on PKR: eIF2a phosphorylation was reduced by siPKR but not by siPERK. We provided evidence showing that PERK is upstream of PKR and is thus able to negatively regulate the PKR-eIF2a pathway. Pulse-chase experiments revealed that EV71 infection inhibited translation and activation of ATF6. Expression of BiP at the protein level was activated by a virus-dependent, ATF6-independent mechanism. EV71 upregulated XBP1 mRNA level, but neither IRE1-mediated XBP1 splicing nor its active spliced protein was detected, and its downstream gene, EDEM, was not activated. Epigenetic BiP overexpression alleviated EV71-induced ER stress and reduced viral protein expression and replication. Our results suggest that EV71 infection induces ER stress but modifies the outcome to assist viral replication.

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Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum

Cited by 139 publications

References 32 publications

Glucose-regulated Protein 78 Is an Intracellular Antiviral Factor against Hepatitis B Virus

Glucose-regulated Protein 78 Is an Intracellular Antiviral Factor against Hepatitis B Virus

The SARS Coronavirus 3a Protein Causes Endoplasmic Reticulum Stress and Induces Ligand-Independent Downregulation of the Type 1 Interferon Receptor

Endoplasmic reticulum stress is induced and modulated by enterovirus 71

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