Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The replication of hepatitis B virus (HBV) in hepatocytes is strongly inhibited in response to IFN-alpha/beta and IFN-gamma. Although it has been previously demonstrated that IFN-alpha/beta eliminates HBV RNA-containing capsids from the cell in a proteasome-dependent manner, the precise cellular pathway that mediates this antiviral effect has not been identified. Because IFN-induced signal transduction involves kinase-mediated activation of gene expression, we used an immortalized hepatocyte cell line that replicates HBV in an IFN-sensitive manner to investigate the role of cellular kinase activity and the cellular transcription and translation machinery in the antiviral effect. Our results indicate that Janus kinase activity is required for the antiviral effect of IFN against HBV, but that phosphatidylinositol 3-kinase, cyclin-dependent kinase, mitogen-activated protein kinase, and NF-kappaB activity are not. Additionally, we found that inhibitors of cellular transcription and translation completely abolish the antiviral effect, which also appears to require cellular kinase activity downstream of signal transduction and gene expression. Collectively, these results identify IFN-regulated pathways that interrupt the HBV replication cycle by eliminating viral RNA-containing capsids from the cell, and they provide direction for discovery of the terminal effector molecules that ultimately mediate this antiviral effect.
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PMID:Signal transduction pathways that inhibit hepatitis B virus replication. 1475 13

The X protein (HBX) of the hepatitis B virus (HBV) is not essential for the HBV life cycle in vitro but is important for productive infection in vivo. Our previous study suggests that interaction of HBX with the proteasome complex may underlie the pleiotropic functions of HBX. With the woodchuck model, we demonstrated that the X-deficient mutants of woodchuck hepatitis virus (WHV) are not completely replication defective, possibly behaving like attenuated viruses. In the present study, we analyzed the effects of the proteasome inhibitors on the replication of wild-type and X-negative HBV and WHV. Recombinant adenoviruses or baculoviruses expressing replicating HBV or WHV genomes have been developed as a robust and convenient system to study viral replication in tissue culture. In cells infected with either the recombinant adenovirus-HBV or baculovirus-WHV, the replication level of the X-negative construct was about 10% of that of the wild-type virus. In the presence of proteasome inhibitors, the replication of the wild-type virus was not affected, while the replication of the X-negative virus of either HBV or WHV was enhanced and restored to the wild-type level. Our data suggest that HBX affects hepadnavirus replication through a proteasome-dependent pathway.
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PMID:Inhibition of cellular proteasome activities enhances hepadnavirus replication in an HBX-dependent manner. 1507 38

Hepatitis B virus X (HBX) is essential for the productive infection of hepatitis B virus (HBV) in vivo and has a pleiotropic effect on host cells. We have previously demonstrated that the proteasome complex is a cellular target of HBX, that HBX alters the proteolytic activity of proteasome in vitro, and that inhibition of proteasome leads to enhanced viral replication, suggesting that HBX and proteasome interaction plays a crucial role in the life cycle and pathogenesis of HBV. In the present study, we tested the effect of HBX on the proteasome activities in vivo in a transgenic mouse model in which HBX expression is developmentally regulated by the mouse major urinary promoter in the liver. In addition, microarray analysis was performed to examine the effect of HBX expression on the global gene expression profile of the liver. The results showed that the peptidase activities of the proteasome were reduced in the HBX transgenic mouse liver, whereas the activity of another cellular protease was elevated, suggesting a compensatory mechanism in protein degradation. In the microarray analysis, diverse genes were altered in the HBX mouse livers and the number of genes with significant changes increased progressively with age. Functional clustering showed that a number of genes involved in transcription and cell growth were significantly affected in the HBX mice, possibly accounting for the observed pleiotropic effect of HBX. In particular, insulin-like growth factor-binding protein 1 was down-regulated in the HBX mouse liver. The down-regulation was similarly observed during acute woodchuck hepatitis virus infection. Other changes including up-regulation of proteolysis-related genes may also contribute to the profound alterations of liver functions in HBV infection.
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PMID:Altered proteolysis and global gene expression in hepatitis B virus X transgenic mouse liver. 1641 18

Hepatitis B virus (HBV) infections play an important role in the development of cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of HBV-related HCC, however, has not been fully described. Evidence suggests that the HBV X protein (HBx) plays a crucial role in the pathogenesis of HCC. The high occurrence of anti-HBx antibody in the serum of HCC patients indicates that it could be a prognostic marker of HBV infection and HCC. HBx stimulates and influences signal transduction pathways within cells. HBx also binds to such protein targets as p53, proteasome subunits, and UV-damaged DNA binding proteins. It also interacts with the cyclic AMP-responsive element binding protein, ATF-2, NFkappaB, and basal transcription factors. HBx is primarily localized to the cytoplasm, where it interacts with and stimulates protein kinases, including protein kinase C, Janus kinase/STAT, IKK, PI-3-K, stress-activated protein kinase/Jun N-terminal kinase, and protein kinase B/Akt. It is also found in the mitochondrion, where it influences the Bcl-2 family. This review examines the role of HBx in the life cycle of HBV as well as the various signal transduction pathways involved in the pathogenesis of HBV-induced hepatocarcinogenesis.
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PMID:Effects of hepatitis B virus X protein on the development of liver cancer. 1645 63

Hepatitis B virus X (HBX) protein is required for the productive infection of hepatitis B virus (HBV) in vivo and implicated in the development of hepatocellular carcinoma. We have previously shown that hTid-1 and Hdj1, the human Hsp40/DnaJ chaperone proteins, bind the HBV core protein and inhibit viral replication in cell culture system. Here, we report evidences to suggest that HBX is the major target of Hdj1 in the inhibition of HBV replication. Expression of Hdj1 in cultured human hepatoma HepG2 cells facilitated degradation of HBX by the proteasome pathway, and thereby inhibited replication of the wild-type HBV as well as that of the HBX-deficient mutant virus rescued by HBX supplied in trans. Mutational analyses indicated that J domain of Hdj1 is required for the process. These results might provide a molecular basis for the antiviral effect of cellular chaperones.
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PMID:Turnover of hepatitis B virus X protein is facilitated by Hdj1, a human Hsp40/DnaJ protein. 1684 47

Inhibition of hepatitis B virus (HBV) replication and viral clearance from an infected host requires both the innate and adaptive immune responses. Expression of interferon (IFN)-inducible proteasome catalytic and regulatory subunits correlates with the IFN-alpha/beta- and IFN-gamma-mediated noncytopathic inhibition of HBV in transgenic mice and hepatocytes, as well as with clearance of the virus in acutely infected chimpanzees. The immunoproteasome catalytic subunits LMP2 and LMP7 alter proteasome specificity and influence the pool of peptides available for presentation by major histocompatibility complex class I molecules. We found that these subunits influenced both the magnitude and specificity of the CD8 T-cell response to the HBV polymerase and envelope proteins in immunized HLA-A2-transgenic mice. We also examined the role of LMP2 and LMP7 in the IFN-alpha/beta- and IFN-gamma-mediated inhibition of virus replication using HBV transgenic mice and found that they do not play a direct role in this process. These results demonstrate the ability of the IFN-induced proteasome catalytic subunits to shape the HBV-specific CD8 T-cell response and thus potentially influence the progression of infection to acute or chronic disease. In addition, these studies identify a potential key role for IFN in regulating the adaptive immune response to HBV through alterations in viral antigen processing.
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PMID:Role of immunoproteasome catalytic subunits in the immune response to hepatitis B virus. 1707 20

It is known that the hepatitis B virus X protein (HBx) plays a crucial role in the pathogenesis of HCC, but the exact functions and molecular mechanisms of HBx in HCC are not well understood. In the present study, HepG2 cell lines were cultured and transfected with pEGFP-N1 and pEGFP-N1-X. Twenty-four hours after transfection, cells were harvested and total RNA was extracted using TRIzol reagent. The expression of HBx in HepG2 cell line was assayed by real-time polymerase chain reaction and was detected by Western blotting. Moreover, proteomic analysis was performed for the HepG2-pEGFP-X cells and HepG2-pEGFP control cells. The combination of 2DE and MALDI-TOF-MS/MS revealed that SEC13L1 (SEC13-like 1 isoform b), PA28 alpha (proteasome activator REG alpha), serine-threonine kinase receptor-associated protein (STRAP) and nm23/nucleoside diphosphate kinase (NME) were upregulated in HepG2-pEGFP-X cells. STRAP is known to be a WD40 domain-containing protein, which interacts with TbetaR-I and TbetaR-II and negatively regulates TGF-beta signalling, was also found increased in human cancers. NME is known to be involved in the regulation of cancer cell progression and metastasis. These results would help the understanding of how HBx maintains tumorigenicity and progression of HCC.
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PMID:The upregulation of expressed proteins in HepG2 cells transfected by the recombinant plasmid-containing HBx gene. 1730 79

The signal sequences that mediate entry of the hepatitis B virus (HBV) envelope proteins into the endoplasmic reticulum (ER) are located within the S domain at positions 11-32 and at positions 80-98 (from the start of the S domain). In addition, hydrophobic patches at positions 160-184 and 189-210 of the S domain may also be involved in entry into the ER. The role of each of these domains in the entry of the HBV M glycoprotein into the ER was studied by deletion mutations of each of the signal sequences. Glycosylation of proteins was used as a marker of entry into the ER. Our results indicate that association with the ER could not be prevented by the deletion of either individual or combinations of the HBV signal sequences. M protein lacking signal sequence I was able to enter the ER and had limited secretion. In contrast, M protein lacking signal sequence II could not be secreted but still entered the ER. M protein lacking signal sequences I and II, while still associated with the ER, was rapidly degraded by the cytosolic proteasome. The potential use of such a vector as a CTL vaccine was tested through an in vitro antigen presentation assay. In this assay, a DNA vaccine candidate lacking signal sequences I and II lead to a >6-fold increase in CTL activation, as compared to the vector expressing wild type M protein. These results suggest that increased degradation of the HBV envelope proteins can lead to enhanced antigen presentation.
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PMID:The role of the downstream signal sequences in the maturation of the HBV middle surface glycoprotein: development of a novel therapeutic vaccine candidate. 1746 93

The accumulation of complex hepatitis B virus (HBV) variants with internal in-frame deletions in the C gene in immunosuppressed renal transplant recipients is associated with a severe course of the infection leading to end-stage liver disease (ESLD). A set of six HBV C genes with internal in-frame deletions corresponding to the pattern of HBV population in immunosuppressed patients has been expressed in two different eukaryotic cell lines. Synthesis and proteasomal degradation of HBV core (HBc) protein variants were compared with those of the wild-type HBc. In all cases, the steady-state level of internally deleted HBc proteins, predominantly with longer deletions, were considerably lower and turnover was significantly higher in comparison with those of the wild-type HBc, since all deletion variants were degraded rapidly via the proteasome pathway. Involvement and consequences of the proteasomal degradation machinery in the HBc protein turnover during HBV infection with complex HBV variants in the immunosuppressed patients are discussed.
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PMID:Proteasomal degradation of core protein variants from chronic hepatitis B patients. 1760 82

Abnormal accumulation of beta-catenin is considered to be a strong driving force in hepatocellular carcinogenesis; however, the mechanism of beta-catenin accumulation in tumours is unclear. Here, it was demonstrated that hepatitis B virus X protein (HBx) differentially regulates the level of beta-catenin through two ubiquitin-dependent proteasome pathways depending on p53 status. In the presence of p53, HBx downregulated beta-catenin through the activation of a p53-Siah-1 proteasome pathway. For this purpose, HBx upregulated Siah-1 expression at the transcriptional level via activation of p53. In the absence of p53, however, HBx stabilized beta-catenin through the inhibition of a glycogen synthase kinase-3beta-dependent pathway. Interestingly, HBx variants with a Pro-101 to Ser substitution were unable to activate p53 and thus could stabilize beta-catenin irrespective of p53 status. Based on these findings, a model of beta-catenin regulation by HBx is proposed whereby the balance between the two opposite activities of HBx determines the overall expression level of beta-catenin. Differential regulation of beta-catenin by HBx depending on host (p53 status) and viral factors (HBx sequence variation) helps not only to explain the observation that cancers accumulating beta-catenin also exhibit a high frequency of p53 mutations but also to understand the contradictory reports on the roles of HBx during hepatocellular carcinogenesis.
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PMID:Hepatitis B virus X protein differentially affects the ubiquitin-mediated proteasomal degradation of beta-catenin depending on the status of cellular p53. 1762 16


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