Hepatitis B virus X protein modulates peroxisome proliferator-activated receptor γ through protein-protein interaction

FEBS Letters ◽  
2003 ◽  
Vol 557 (1-3) ◽  
pp. 73-80 ◽  
Author(s):  
Youn-Hee Choi ◽  
Ha-il Kim ◽  
Je Kyung Seong ◽  
Dae-Yeul Yu ◽  
Hyeseong Cho ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Protein Interaction ◽  
Peroxisome Proliferator ◽  
X Protein ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Protein Interaction ◽  
B Virus

scholarly journals Peroxisome Proliferator-Activated Receptor γ Coactivator 1α and Small Heterodimer Partner Differentially Regulate Nuclear Receptor-Dependent Hepatitis B Virus Biosynthesis

2009 ◽  
Vol 83 (23) ◽  
pp. 12535-12544 ◽  
Author(s):  
Caitlin R. Ondracek ◽  
Christel N. Rushing ◽  
Vanessa C. Reese ◽  
Claudia E. Oropeza ◽  
Alan McLachlan
Keyword(s):  
Transcription Factors ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Line ◽  
Nuclear Receptors ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Small Heterodimer Partner ◽  
B Virus ◽  
Transcription And Replication

ABSTRACT Hepatitis B virus (HBV) biosynthesis involves the transcription of the 3.5-kb viral pregenomic RNA, followed by its reverse transcription into viral DNA. Consequently, the modulation of viral transcription influences the level of virus production. Nuclear receptors are the only transcription factors known to support viral pregenomic RNA transcription and replication. The coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and corepressor small heterodimer partner (SHP) have central roles in regulating energy homeostasis in the liver by modulating the transcriptional activities of nuclear receptors. Therefore, the effect of PGC1α and SHP on HBV transcription and replication mediated by nuclear receptors was examined in the context of individual nuclear receptors in nonhepatoma cells and in hepatoma cells. This analysis indicated that viral replication mediated by hepatocyte nuclear factor 4α, retinoid X receptor α (RXRα) plus peroxisome proliferator-activated receptor α (PPARα), and estrogen-related receptor (ERR) displayed differential sensitivity to PGC1α activation and SHP inhibition. The effects of PGC1α and SHP on viral biosynthesis in the human hepatoma cell line Huh7 were similar to those observed in the nonhepatoma cells expressing ERRα and ERRγ. This suggests that these nuclear receptors, potentially in combination with RXRα plus PPARα, may have a major role in governing HBV transcription and replication in this cell line. Additionally, this functional approach may help to distinguish the transcription factors in various liver cells governing viral biosynthesis under a variety of physiologically relevant conditions.

scholarly journals Local stabilization of subunit-subunit contacts causes global destabilization of Hepatitis B virus capsids

2020 ◽  
Author(s):  
Christopher John Schlicksup ◽  
Patrick Laughlin ◽  
Steven Dunkelbarger ◽  
Joseph Che-Yen Wang ◽  
Adam Zlotnick
Keyword(s):  
Electron Microscopy ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Surface Area ◽  
Protein Interaction ◽  
Structural Defects ◽  
Protein Protein Interaction ◽  
Cryo Electron Microscopy ◽  
Virus Capsids ◽  
B Virus

AbstractDevelopment of antiviral molecules that bind virion is a strategy that remains in its infancy and the details of their mechanisms are poorly understood. Here we investigate the behavior of DBT1, a dibenzothiazapine, which specifically interacts with the capsid protein of Hepatitis B Virus (HBV). We found that DBT1 stabilizes protein-protein interaction, accelerates capsid assembly, and can induce formation of aberrant particles. Paradoxically, DBT1 can cause pre-formed capsids to dissociate. These activities may lead to (i) assembly of empty and defective capsids, inhibiting formation of new virus and (ii) disruption of mature viruses, which are metastable, to inhibit new infection. Using cryo-electron microscopy we observed that DBT1 led to asymmetric capsids where well-defined DBT1 density was bound at all inter-subunit contacts. These results suggest that DBT1 can support assembly by increasing buried surface area but induce disassembly of metastable capsids by favoring asymmetry to induce structural defects.

scholarly journals PGC1α Transcriptional Adaptor Function Governs Hepatitis B Virus Replication by Controlling HBcAg/p21 Protein-Mediated Capsid Formation

2017 ◽  
Vol 91 (20) ◽  
Author(s):  
Rasha E. Shalaby ◽  
Saira Iram ◽  
Bülent Çakal ◽  
Claudia E. Oropeza ◽  
Alan McLachlan
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Line ◽  
Viral Capsid ◽  
Peroxisome Proliferator ◽  
Capsid Assembly ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hbv Replication ◽  
Adaptor Molecule ◽  
B Virus

ABSTRACT In the human hepatoma cell line Huh7, the coexpression of the coactivators peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), cyclic AMP-responsive element binding protein binding protein (CBP), steroid receptor coactivator 1 (SRC1), and protein arginine methyltransferase 1 (PRMT1) only modestly increase hepatitis B virus (HBV) biosynthesis. However, by utilizing the human embryonic kidney cell line HEK293T, it was possible to demonstrate that PGC1α alone can support viral biosynthesis independently of the expression of additional coactivators or transcription factors. In contrast, additional coactivators failed to support robust HBV replication in the absence of PGC1α. These observations indicate that PGC1α represents a novel adaptor molecule capable of recruiting the necessary transcriptional machinery to the HBV nucleocapsid promoter to modestly enhance viral pregenomic 3.5-kb RNA synthesis. Although this change in transcription is associated with a similar modest change in hepatitis B virus core antigen polypeptide (HBcAg/p21) synthesis, it mediates a dramatic increase in viral capsid production and robust viral replication. Therefore, it is apparent that the synthesis of cytoplasmic HBcAg/p21 above a critical threshold level is required for the efficient assembly of HBV replication-competent viral capsids. IMPORTANCE Hepatitis B virus (HBV) is a major human pathogen, and novel targets for the development of additional therapeutic agents are urgently needed. Here we demonstrate that the coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) serves as a unique adaptor molecule for the recruitment of additional coactivator proteins, which can finely regulate HBV transcription. The consequence of this precise regulation of viral RNA levels by PGC1α is a subtle increase in cytoplasmic HBcAg/p21 polypeptide translation, which shifts the equilibrium from dimer formation dramatically in favor of viral capsid assembly. These findings suggest that both PGC1α and capsid assembly may represent attractive targets for the development of antiviral agents against chronic HBV infection.

scholarly journals Enhancer I Predominance in Hepatitis B Virus Gene Expression

2004 ◽  
Vol 24 (4) ◽  
pp. 1799-1808 ◽  
Author(s):  
Gilad Doitsh ◽  
Yosef Shaul
Keyword(s):  
Gene Expression ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Time Course ◽  
Leucine Zipper ◽  
Peroxisome Proliferator ◽  
Basic Leucine Zipper ◽  
Peroxisome Proliferator Activated Receptor ◽  
B Virus ◽  
Hepatocyte Nuclear Factor 4Α

ABSTRACT Previous studies of human hepatitis B virus (HBV) transcription revealed the requirement of two enhancer elements. Enhancer I (EnhI) is located upstream of the X promoter and is targeted by multiple activators, including basic leucine zipper proteins, and enhancer II (EnhII) is located upstream to the PreCore promoter and is targeted mainly by nuclear receptors (NRs). The mode of interplay between these enhancers and their unique contributions in regulating HBV transcription remained obscure. By using time course analysis we revealed that the HBV transcripts are categorized into early and late groups. Chang (CCL-13) cells are impaired in expression of the late transcripts. This could be corrected by overexpressing EnhII activators, such as hepatocyte nuclear factor 4α, the retinoid X receptor α, and the peroxisome proliferator-activated receptor α, suggesting that in Chang cells EnhI but not EnhII is active. Replacing the 5′-end EnhI sequence with a synthetic Gal4 response (UAS) DNA fragment ceased the production of the early transcripts. Under this condition NR overexpression poorly activated EnhII. However, activation of the UAS by Gal4-p53 restored both the expression of the early transcripts and the EnhII response to NRs. Thus, a functional EnhI is required for activation of EnhII. We found a major difference between Gal4-p53 and Gal4-VP16 behavior. Gal4-p53 activated the early transcripts, while Gal4-VP16 inhibited the early transcripts but activated the late transcripts. These findings indicate that the composition of the EnhI binding proteins may play a role in early to late switching. Our data provides strong evidence for the role of EnhI in regulating global and temporal HBV gene expression.

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