Calcium signaling in hepatitis B virus infection and its potential as a therapeutic target.
TL;DR: In this paper, the authors summarized the molecular mechanisms related to the elevation of Ca2+ signaling induced by hepatitis B virus (HBV) to modulate viral propagation and the recent advances in Ca2 + signaling as a potential therapeutic target for HBV infection.
Abstract: As a ubiquitous second messenger, calcium (Ca2+) can interact with numerous cellular proteins to regulate multiple physiological processes and participate in a variety of diseases, including hepatitis B virus (HBV) infection, which is a major cause of hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. In recent years, several studies have demonstrated that depends on the distinct Ca2+ channels on the plasma membrane, endoplasmic reticulum, as well as mitochondria, HBV can elevate cytosolic Ca2+ levels. Moreover, within HBV-infected cells, the activation of intracellular Ca2+ signaling contributes to viral replication via multiple molecular mechanisms. Besides, the available evidence indicates that targeting Ca2+ signaling by suitable pharmaceuticals is a potent approach for the treatment of HBV infection. In the present review, we summarized the molecular mechanisms related to the elevation of Ca2+ signaling induced by HBV to modulate viral propagation and the recent advances in Ca2+ signaling as a potential therapeutic target for HBV infection. Video Abstract.
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TL;DR: In this article, the authors focus on the crosstalk between Ca2+ signaling and pattern recognition receptors (PRRs) to regulate the innate immune system response to pathogen invasion and endogenous stresses.
22 citations
TL;DR: In this paper , the role and mechanisms of mitochondria dysfunction in chronic liver disease were discussed, focusing on and discussing some of the latest studies on mitochondria and chronic liver diseases, including hepatocellular carcinoma (HCC), viral hepatitis, drug-induced liver injury (DILI), alcoholic fatty liver (AFL), and non-alcoholic fatty liver(NAFL).
Abstract: Mitochondria are generally considered the powerhouse of the cell, a small subcellular organelle that produces most of the cellular energy in the form of adenosine triphosphate (ATP). In addition, mitochondria are involved in various biological functions, such as biosynthesis, lipid metabolism, oxidative phosphorylation, cell signal transduction, and apoptosis. Mitochondrial dysfunction is manifested in different aspects, like increased mitochondrial reactive oxygen species (ROS), mitochondrial DNA (mtDNA) damage, adenosine triphosphate (ATP) synthesis disorder, abnormal mitophagy, as well as changes in mitochondrial morphology and structure. Mitochondrial dysfunction is related to the occurrence and development of various chronic liver diseases, including hepatocellular carcinoma (HCC), viral hepatitis, drug-induced liver injury (DILI), alcoholic fatty liver (AFL), and non-alcoholic fatty liver (NAFL). In this review, we summarize and discuss the role and mechanisms of mitochondrial dysfunction in chronic liver disease, focusing on and discussing some of the latest studies on mitochondria and chronic liver disease.
8 citations
TL;DR: An overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis is provided.
Abstract: As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.
6 citations
TL;DR: In this article , the roles of free radicals in virus pathology are discussed and a review of methods that facilitate the detection of free radical in vivo or in vitro in viral infections is presented.
2 citations
TL;DR: Based on the cellular distribution of hepatitis B virus (HBV) regulatory protein, a review encompasses the current knowledge and previous investigations of HBx in context of cellular signaling pathways and HBV-associated pathogenesis as discussed by the authors .
Abstract: The hepatitis B virus (HBV) counts as a major global health problem, as it presents a significant causative factor for liver-related morbidity and mortality. The development of hepatocellular carcinomas (HCC) as a characteristic of a persistent, chronic infection could be caused, among others, by the pleiotropic function of the viral regulatory protein HBx. The latter is known to modulate an onset of cellular and viral signaling processes with emerging influence in liver pathogenesis. However, the flexible and multifunctional nature of HBx impedes the fundamental understanding of related mechanisms and the development of associated diseases, and has even led to partial controversial results in the past. Based on the cellular distribution of HBx—nuclear-, cytoplasmic- or mitochondria-associated—this review encompasses the current knowledge and previous investigations of HBx in context of cellular signaling pathways and HBV-associated pathogenesis. In addition, particular focus is set on the clinical relevance and potential novel therapeutic applications in the context of HBx.
2 citations
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TL;DR: The capacity of physiological stimuli and inducers of endoplasmic reticulum (ER) stress to releaseCa2+ from ER stores, induce mitochondrial Ca2+ accumulation, and trigger cell death in human cervix and colon carcinoma cell lines is characterized.
Abstract: The accumulation of Ca2+ in the mitochondrial matrix can stimulate oxidative phosphorylation, but can also, at high Ca2+ concentrations, transmit and amplify an apoptotic signal. Here, we characterized the capacity of physiological stimuli (for example, histamine and inositol-1,4,5-triphosphate) and inducers of endoplasmic reticulum (ER) stress (for example, A23187, thapsigargin and tunicamycin) to release Ca2+ from ER stores, induce mitochondrial Ca2+ accumulation, and trigger cell death in human cervix and colon carcinoma cell lines. Sustained Ca2+ accumulation in the mitochondrial matrix induced by ER stress triggered signs of proapoptotic mitochondrial alteration, namely permeability transition, dissipation of the electrochemical potential, matrix swelling, relocalization of Bax to mitochondria and the release of cytochrome c and apoptosis-inducing factor from mitochondria. In contrast, rapid and transient accumulation of Ca2+ induced by physiological stimuli failed to promote mitochondrial permeability transition and to affect cell viability. The specificity of this apoptosis pathway was validated in cells using a panel of pharmacological agents that chelate Ca2+ (BAPTA-AM) or inhibit inositol-1,4,5-trisphosphate receptor (IP3R; 2-aminoethoxydiphenyl borate), voltage-dependent anion channel (VDAC) (4,4′-diisothiocyanatostilbene-2,2′-disulfonate, NADH), the permeability transition pore (cyclosporin A and bongkrekic acid), caspases (z-VAD-fmk) and protein synthesis (cycloheximide). Finally, we designed an original cell-free system in which we confronted purified mitochondria and ER vesicles, and identified IP3R, VDAC and the permeability transition pore as key proteins in the ER-triggered proapoptotic mitochondrial membrane permeabilization process.
537 citations
TL;DR: HBx activation of HBV DNA replication was blocked by inhibiting Pyk2 or calcium signaling mediated by mitochondrial calcium channels, which suggests that HBx targets mitochondrial calcium regulation.
Abstract: Hepatitis B virus (HBV) infects more than 300 million people and is a leading cause of liver cancer and disease The HBV HBx protein is essential for infection; HBx activation of Src is important for HBV DNA replication In our study, HBx activated cytosolic calcium-dependent proline-rich tyrosine kinase-2 (Pyk2), a Src kinase activator HBx activation of HBV DNA replication was blocked by inhibiting Pyk2 or calcium signaling mediated by mitochondrial calcium channels, which suggests that HBx targets mitochondrial calcium regulation Reagents that increased cytosolic calcium substituted for HBx protein in HBV DNA replication Thus, alteration of cytosolic calcium was a fundamental requirement for HBV replication and was mediated by HBx protein
376 citations
TL;DR: It is shown that HBx expression in cultured human hepatoma cells leads to alteration of mitochondrial transmembrane potential, which implies a functional role of HBx in functions associated with mitochondria.
Abstract: Understanding the mechanism(s) of action of the hepatitis B virus (HBV)-encoded protein HBx is fundamental to elucidating the underlying mechanisms of chronic liver disease and hepatocellular carcinoma caused by HBV infection. In our continued attempts to identify cellular targets of HBx, we have previously reported the identification of a novel cellular protein with the aid of a yeast two-hybrid assay. This cellular gene was identified as a third member of the family of human genes that encode the voltage-dependent anion channel (HVDAC3). In the present study, physical interaction between HBx and HVDAC3 was established by standard in vitro and in vivo methods. Confocal laser microscopy of transfected cells with respective expression vectors colocalized HVDAC3 and HBx to mitochondria. This novel, heretofore unreported subcellular distribution of HBx in mitochondria implies a functional role of HBx in functions associated with mitochondria. Using a stable cationic fluorophore dye, CMXRos, we show that HBx expression in cultured human hepatoma cells leads to alteration of mitochondrial transmembrane potential. Such functional roles of HBx in affecting mitochondrial physiology have implications for HBV-induced liver injury and the development of hepatocellular carcinoma.
295 citations
TL;DR: It is reported that cyclosporin A (CsA) can inhibit HBV entry into cultured hepatocytes and provides a proof of concept for the novel strategy to identify anti‐HBV agents by targeting the candidate HBV receptor, NTCP, using CsA as a structural platform.
222 citations
TL;DR: How the composition of transcription factors determines HBV gene expression and replication and how this may be influenced by antivirally active substances is discussed, e.g. the cytokine IL‐6 or helioxanthin analogues, or by the differentiation state of the hepatocyte.
Abstract: Hepatitis B virus (HBV) is tightly controlled by a number of noncytotoxic mechanisms. This control occurs within the host hepatocyte at different steps of the HBV replication cycle. HBV persists by establishing a nuclear minichromosome, HBV cccDNA, serving as a transcription template for the viral pregenome and viral mRNAs. Nucleoside/nucleotide analogues widely used for antiviral therapy as well as most antiviral cytokines act at steps after transcription of HBV RNAs and thus can control virus replication but do not directly affect its gene expression. Control of HBV at the level of transcription in contrast is able to restrict both, HBV replication and gene expression. In the review, we focus on how HBV is controlled at the level of transcription. We discuss how the composition of transcription factors determines HBV gene expression and replication and how this may be influenced by antivirally active substances, e.g. the cytokine IL-6 or helioxanthin analogues, or by the differentiation state of the hepatocyte.
183 citations