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)

At least two proteolytic events are involved in the biogenesis of hepatitis B virus e antigen. The first proteolytic event removes the signal peptide and results in the translocation of the precursor protein, P22, into the lumen of the endoplasmic reticulum (ER). The second proteolytic event removes the carboxy-terminal arginine-rich sequence of P22 and converts it to the 16-kDa hepatitis B virus e antigen end product. In contrast to the first proteolytic event, the second proteolytic event is suppressed by brefeldin A, a chemical that inhibits the transport of protein from the ER to the Golgi apparatus. In subcellular fractionation experiments, P22 was detected in both the ER and the Golgi fractions, but P16 was detected only in the Golgi fraction. On the basis of these results, we conclude that the conversion of P22 to P16 occurs ina post-ER compartment, mostly likely the Golgi apparatus.
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PMID:Proteolytic conversion of hepatitis B virus e antigen precursor to end product occurs in a postendoplasmic reticulum compartment. 187 Feb 12

No duck hepatitis B virus (DHBV) pre-C transcript has been identified so far, and neither the interrelationship of e-antigen (DHBeAg) with the expression of other viral antigens or virus replication nor its function is known. In this study we identified in infected livers a minor transcript from which the precursor protein of DHBeAg could be synthesized. Mutation of the first AUG on this transcript abolished expression of DHBeAg. DHBV genomes containing this mutation were infectious in Pekin ducks, the kinetics of pre-S envelope protein expression and virus secretion were not significantly different from wild-type, and the mutant genomes did not revert to wild-type to a detectable level after several passages. In contrast to pre-S protein, the level of DHBeAg in the serum was independent of the level of viremia, accumulated gradually to a high and constant level after a lag phase, and was also easily detectable in a mixed infection containing less than 0.1% of wild-type in a pre-C mutant virus containing inoculum. These data indicate that precore protein is synthesized from a minor pre-C mRNA with translation initiation at the pre-C AUG codon, and leads to high levels of DHBeAg rather late in infection. High levels of DHBeAg can even be produced efficiently by a very small subpopulation of wild-type virus in a mixed infection with predominantly pre-C mutant virus. Lack of DHBeAg appears to have no effect on DHBV viability and kinetics of virus secretion into the bloodstream when ducklings are infected with the pre-C AUG mutant virus a few days after birth.
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PMID:Mechanism, kinetics, and role of duck hepatitis B virus e-antigen expression in vivo. 202 87

The biosynthesis of the secretory core gene product of the duck hepatitis B virus (DHBe protein) was examined. Recombinant vaccinia viruses were constructed encoding either the full-length or C-terminally truncated forms of the DHBe precursor protein (precore protein) and used to express these proteins in the human hepatoma cell line HepG2. Western immunoblot analysis of core gene products isolated from cells producing the full-length precore protein revealed the presence of DHBe precursor proteins containing the strongly basic C-terminal sequence which is lacking in the mature DHBe protein. These proteins were not secreted, suggesting that C-terminal proteolytic processing of the precore protein represents an obligatory step for DHBe biosynthesis. Pulse-chase experiments showed that this cleavage reaction occurs late during DHBe synthesis. Interestingly, when mutated precore proteins were expressed which lacked the basic C-terminal domain, proteins were produced which were glycosylated but not secreted. This shows that the transient presence of this region is essential for intracellular transport of the precore protein. Cell sorter analyses revealed that production of a cell surface-expressed variant of the secretory core protein is a feature conserved between the duck and the human hepatitis B viruses. Surprisingly, the C terminus of the membrane-expressed DHBe protein was accessible from the outside, showing that the topology of this interesting protein is more complicated than expected.
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PMID:Biosynthesis of the secretory core protein of duck hepatitis B virus: intracellular transport, proteolytic processing, and membrane expression of the precore protein. 204 Oct 77

Recent studies suggest that hepatitis B virus (HBV), despite being a DNA virus, replicates via an RNA intermediate (R. H. Miller, P. L. Marion, and S. W. Robinson, Virology 139:64-72, 1984; J. Summers and W. S. Mason, Cell 29:403-415, 1982). The HBV life cycle is therefore a permuted version of the RNA retroviral life cycle. Sequence homology between retroviral reverse transcriptase and the putative HBV polymerase gene product suggests the presence of an HBV reverse transcriptase (H. Toh, H. Hajashida, and T. Miyata, Nature (London) 305:827-829, 1983). As yet, there has been no direct evidence that reverse transcriptase activity is present in the viral particle. We used activity gel analysis to detect the in situ catalytic activities of DNA polymerases after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Our studies demonstrated that HBV-like particles secreted by a differentiated human hepatoma cell line transfected with genomic HBV DNA contain two major polymerase activities which migrate as approximately 90- and approximately 70-kilodalton (kDa) proteins. This demonstrated, for the first time, that HBV-like particles contain a novel DNA polymerase-reverse transcriptase activity. Furthermore, we propose that the 70-kDa reverse transcriptase may be produced by proteolytic self-cleavage of the 90-kDa precursor protein.
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PMID:Two proteins with reverse transcriptase activities associated with hepatitis B virus-like particles. 244 93

The core gene of hepatitis B virus contains two in-phase AUG codons which may both be used in the viral life cycle. By in vitro translation of transcripts produced in vitro, we investigated the corresponding core gene products and their counterparts in vivo. Depending on the location of the 5' end of the transcripts, two major core gene-derived proteins were obtained. In transcripts with both in-phase AUGs, only the first one was efficiently used and resulted in synthesis of a 25-kilodalton protein (precore). This protein contains a leader sequence and could be cotranslationally processed to a protein of 22.3 kilodaltons. Translation of transcripts lacking the first AUG of the core gene produced a core protein of 21.5 kilodaltons which comigrated with the core antigen expressed in infected livers. These data suggest that the major nucleocapsid protein expressed in vivo is initiated at the second ATG of the C gene and that a precore protein is probably synthesized as a precursor protein which is cotranslationally processed. Proteins consistent in size with processed and unprocessed precore proteins detected in woodchuck hepatitis virus-infected livers support this conclusion.
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PMID:Expression of the hepatitis B virus core gene in vitro and in vivo. 362 40

A significant proportion (20 to 40%) of highly purified 22-nm hepatitis B surface antigen (HBsAg) particles contain human serum albumin (HSA) as demonstrated by specific precipitation of radioiodinated particles by anti-HSA. Preparations of the isolated major HBsAg polypeptides (P-1, P-2, and P-6) were iodinated and analyzed by radiommunoprecipitation for reactivity with rabbit antisera to human plasma proteins. Only the P-6 fraction (molecular weight, 68,000) was precipitated and only by anti-HSA; specific precipitation was observed with guinea pig antisera to P-6 and native HBsAg and goat or rabbit antisera to HSA. Coprecipitation of P-6 with antiserum to HBsAg and with anti-HSA, compared to precipitation with each antiserum alone, indicated that the HBsAg and HSA determinants were on separate molecules. The P-6 polypeptide may represent a precursor protein of the hepatitis B virion.
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PMID:Relationship of large hepatitis B surface antigen polypeptide to human serum albumin. 739 72

Hepadnaviruses encode two core-related open reading frames. One directs the synthesis of the p21 core protein, which subsequently becomes a structural component of the viral nucleocapsid. The other produces a p25 precore protein that is targeted by a signal peptide to a cell secretory pathway where N-terminal processing will create a p22 species. This molecule will be further modified at the C-terminal region to generate p17, and the truncated protein is secreted from the cell as hepatitis B e antigen (HBeAg). The function of the precore gene in the biology of hepadnaviruses is unknown. We found that ablation of the precore gene resulted in the generation of a hepatitis B virus (HBV) species with a high-replication-level phenotype. More important, expression in trans of physiologic levels of p25 restored viral replication to wild-type levels. Moreover, transient or stable overexpression of the precore gene resulted in striking inhibition of HBV replication. The molecular species responsible for this viral inhibitory effect was identified as the p22 nonsecreted HBeAg precursor protein. By sucrose gradient sedimentation analysis, we determined that expression of p22 leads to the formation of nucleocapsids similar to those made with wild-type p21 core protein. Immunoprecipitation experiments revealed that the p21 and p22 physically interact and form hybrid nucleocapsid structures devoid of pregenomic viral RNA. These experiments suggest that expression of the precore gene may be important in the regulation of HBV replication and describe a possible molecular mechanism(s) for this effect.
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PMID:Posttranscriptional regulation of hepatitis B virus replication by the precore protein. 898 56

The hepatitis B virus (HBV) e antigen (HBeAg) is a 15 kDa soluble antigen derived from a precursor protein (precore protein) by two processing events, cleavage of the N-terminal signal peptide and cleavage of the C-terminal 34 amino acids. So far, the role of the C-terminal sequences in secretion has not been analysed in full. In this study deletion of the last 60 amino acids was found to abrogate HBeAg secretion whereas deletions of the last 10, 25 or 39 amino acids decreased its secretion rate. These data demonstrate that C-terminal precore protein sequences are crucial for HBe secretion and determine its secretion rate.
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PMID:Importance of the C terminus of the hepatitis B virus precore protein in secretion of HBe antigen. 904 55

Interferon gamma (IFN-gamma), which has been cloned in several mammalian species and recently in birds, plays a critical role in modulating immune system function. IFN-gamma and tumor necrosis factor alpha (TNF-alpha) have been shown to be crucial in the pathogenesis of viral hepatitis and in the transient disappearance of hepatitis B virus (HBV) from the liver after adoptive transfer of HBV-specific cytotoxic T lymphocytes into HBV-transgenic mice. Similar studies in the natural animal hosts of related hepadnaviruses have been limited because the corresponding probes and recombinant cytokines were not available. For this reason, we initiated studies to clone and characterize cytokines from the duck, the natural host of the duck hepatitis B virus (DHBV). We describe here the cDNA cloning and initial characterization of the IFN-gamma homologue of ducks (DuIFN-gamma). The DuIFN-gamma cDNA codes for a predicted mature protein of 145 amino acids with a molecular mass of 16.6 kDa. The precursor protein has 67% identity with the previously cloned chicken IFN-gamma and 21 to 34% identity with mammalian IFN-gamma. Recombinant DuIFN-gamma induces the transcription of several IFN-inducible genes including IFN regulatory factor 1 and guanylate-binding protein, and it exhibits antiviral activity that protects duck cells from vesicular stomatitis virus-mediated lysis. Importantly, treatment of primary duck hepatocytes with recombinant DuIFN-gamma inhibits DHBV replication in a dose-dependent fashion. Time course analysis revealed that IFN-gamma treatment does not affect initial covalently closed circular DNA (cccDNA) conversion but inhibits the synthesis of progeny cccDNA by amplification.
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PMID:Recombinant duck interferon gamma inhibits duck hepatitis B virus replication in primary hepatocytes. 1007 68

Woodchucks (Marmota monax) infected with woodchuck hepatitis virus (WHV) represent a highly valuable laboratory model of hepatitis B virus (HBV) infection, in which molecular, immunological and pathological events occurring in infected humans are adequately reflected. To advance studies on T cell immune responses and propagation of hepadnavirus in T lymphocytes in this animal model, we determined the complete sequence of woodchuck interleukin-2 (wIL-2) cDNA by utilizing RNA ligase-mediated rapid amplification of cDNA ends (RLM-RACE) reaction. The wIL-2 sequence revealed a single open reading frame encoding for the predicted precursor protein comprised of a signal peptide and a 134 amino acid-long mature protein. The mature wIL-2 protein produced in the Escherichia coli expression system, designated as ec-rwIL-2, was found to be immunogenic but not biologically active. In contrast, precursor wIL-2 protein cloned into baculovirus transfer vector and expressed in Sf9 cells, designated as bac-rwIL-2, demonstrated functional competence. Further, bac-rwIL-2 was able to stimulate proliferation and to induce multiple daughter cell generations in woodchuck T cells, as well as facilitated the survival of standard IL-2-dependent mouse CTLL-2 cells in culture. Western blot analysis of bac-rwIL-2 using antibodies generated against ec-rwIL-2 revealed a single protein band of 15.5kDa. The availability of biologically active recombinant wIL-2 should facilitate ex vivo studies on functional competence of woodchuck T lymphocytes derived from different stages of hepadnaviral hepatitis and assist in recognizing their contribution to the pathogenesis of liver injury in the woodchuck model of hepatitis B.
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PMID:Characterization of bioactive recombinant woodchuck interleukin-2 amplified by RLM-RACE and produced in eukaryotic expression system. 1663 32


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