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)

Human hepatitis B virus (HBV) envelopes contain three distinct glycoproteins called L, M, and S HBsAg. Each is posttranslationally modified to contain N-linked oligosaccharides. N-linked oligosaccharides, after attachment to a polypeptide backbone, are processed by enzymes within the endoplasmic reticulum (ER). There is uncertainty about what role, if any, these N glycans and their modification in the ER play in the function of the HBV envelope proteins. By treating hepatoblastoma cultures which secrete HBV (HepG 2.2.15 cells) with inhibitors of different steps of the glycosylation and glycan modifying pathway, we provide evidence that glycosylation and the first step in the processing pathway are necessary for virion, but not subviral particle, secretion. That is, using a highly sensitive immunoprecipitation/polymerase chain reaction system, enveloped HBV could not be detected in the medium of HepG2.2.15 cells incubated with tunicamycin. However, HBV subviral particle secretion was not prevented by tunicamycin. Moreover, inhibitors of alpha-glucosidase I (the first step in the glycan processing pathway) also prevented virion secretion. Inhibitors of mannose trimming (a later step) and glycolipid synthesis, did not prevent virion secretion, defining the limits of the glycosylation requirements in secretion. These results demonstrate a requirement for N-glycosylation and glucosidase processing in the secretion of virions and further distinguish between the requirements for virion and subviral particle secretion.
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PMID:Evidence that N-linked glycosylation is necessary for hepatitis B virus secretion. 749 90

The small (S), middle (M) and large (L) envelope proteins of the hepatitis B virus (HBV) are initially synthesized as multispanning membrane proteins of the endoplasmic reticulum membrane. We now demonstrate that all envelope proteins synthesized in transfected cells or in a cell-free system adopt more than one transmembrane orientation. The L protein disposes its N-terminal preS domain both to the cytoplasmic and the luminal side of the membrane. This unusual topology does not depend on interaction with the viral nucleocapsid, but is preserved in secreted empty envelope particles. Pulse-chase analysis suggests a novel process of post-translational translocation leading to the non-uniform topology. Analysis of L deletion mutants indicates that the block to co-translational translocation can be attributed to a specific sequence within preS, suggesting that translocation of L may be regulated. Additional topological heterogeneity is displayed in the S region of the envelope proteins and in the S protein itself, as assayed in a cell-free system. S proteins integrated into microsomal membranes exhibit both a luminal and a cytoplasmic orientation of the internal hydrophilic region carrying the major antigenic determinants. This may explain the unusual partial glycosylation of the HBV envelope proteins.
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PMID:Novel transmembrane topology of the hepatitis B virus envelope proteins. 783 36

Hepatocyte turnover rates were studied in two lineages of transgenic mice that overproduce the hepatitis B virus (HBV) large envelope protein and retain filamentous hepatitis B surface antigen (HBsAg) particles in the endoplasmic reticulum, resulting in the formation of ground glass hepatocytes. The high producer lineage (50-4) develops a necroinflammatory liver disease that progresses to hepatocellular carcinoma (HCC), whereas the low producer lineage (107-5) displays no histopathologic changes other than ground glass hepatocytes. Bromodeoxyuridine (BrdU)-labeling studies of S-phase hepatocytes provide quantitative evidence for a strong, sustained proliferative response in the hepatocytes in lineage 50-4 that occurs after the onset of hepatocellular injury but long before the development of liver cell tumors. In contrast, the level of hepatocellular proliferation in lineage 107-5 is the same as nontransgenic controls. The findings support the concept that sustained hepatocellular proliferation plays an important role in the development of hepatocellular carcinoma (HCC).
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PMID:Strong, sustained hepatocellular proliferation precedes hepatocarcinogenesis in hepatitis B surface antigen transgenic mice. 787 58

In the serum of hepatitis B virus (HBV)-infected patients, two different types of particles, a 42 nm virion and a 22 nm subviral particle, were identified. The envelope of both particles is composed of three proteins, the large (L), middle (M), and major/small (S) surface proteins but the ratio between these components varies in each. The M protein appears in a lesser amount than the S protein in both virion and subviral particles, although it is translated from the same subgenomic RNA, and this is due to its poor initiation context of translation. In addition, only the glycosylated form of M protein is secreted in contrast to both glycosylated and unglycosylated forms of L and S proteins that are secreted. To investigate the biogenesis of M protein, human hepatoma cells transfected with plasmids containing a mutated HBV DNA were used to produce a high amount of M protein. Electron microscopic observation revealed that despite a higher proportion of the M protein being found in the transfected cells, the secreted surface antigen particles possess similar size and density to 22 nm subviral particles. Detailed biochemical analyses showed the following. (1) The unglycosylated M protein was predominantly present in the microsomal fraction but not present in any other subcellular fractions. (2) The M protein formed 22-nm-like particles in the endoplasmic reticulum (ER) and was retained in the post-ER or pre-Golgi regions. (3) In addition to the complex glycosylated form of M protein, a high-mannose form of M protein could be secreted. (4) Normally, no unglycosylated M protein was secreted. However, glycosylation was not essential for M protein secretion since M protein deprived of glycosylation by tunicamycin treatment was detected in the medium. These findings suggest that (i) the M protein was probably translated and co-translocated into the ER and at least one site was glycosylated before leaving the ER resulting in no secretion of unglycosylated M protein, and (ii) the M protein had two secretion pathways, one through the conventional pathway and the other probably directly through the ER.
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PMID:Biogenesis of the hepatitis B viral middle (M) surface protein in a human hepatoma cell line: demonstration of an alternative secretion pathway. 796 12

The large envelope glycoprotein (L protein) of Hepatitis B virus (HBV) contains the preS1 domain, which is responsible for retention of the protein in the endoplasmic reticulum. To identify sequences of the preS1 domain involved in this phenomenon we constructed vaccinia virus-HBV recombinants containing the gene for L protein in which the preS1 coding sequence had been partially deleted. The retention of L protein in the endoplasmic reticulum was found to be mediated by a sequence contained within a region of 35 amino acids of the preS1 C-terminus, and not exclusively by amino acid sequences of the N-terminus of the preS1 domain as proposed by Kuroki et al. (Mol. Cell. Biol. 9, 4459-4466, 1989). Our finding could be explained by a specifically VV promoter sequence leading to exclusive synthesis of L or deleted (delta)L proteins, respectively. The ability of the coexpressed HBV S protein to facilitate export of the delta L proteins was demonstrated by coinfection experiments.
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PMID:A carboxy-terminal portion of the preS1 domain of hepatitis B virus (HBV) occasioned retention in endoplasmic reticulum of HBV envelope proteins expressed by recombinant vaccinia viruses. 803 Feb 3

The biosynthesis of the secretory core gene product of the woodchuck hepatitis virus (WHV) was studied in human cells. We have shown that the WHV e antigen was a N-glycosylated (most likely a diglycosylated) protein, with an apparent M(r) of 24K. To demonstrate that the WHV precore protein was correctly processed in human cells, we engineered chimeric proteins in which signal peptides or arginine-rich domains of WHV and hepatitis B virus (HBV) precore proteins were exchanged. Our results showed that both the signal peptide and the arginine-rich region of WHV precore protein were cleaved off during the secretion pathway, as previously reported for precore protein of human HBV and duck HBV. These observations demonstrate that the maturation process of the e antigen is conserved in hepadnaviruses. In addition, on the basis of inhibition experiments, we suggest that the cleavage of the carboxy terminus of the WHV precore protein occurred in a post-endoplasmic reticulum compartment, most likely beyond the medial Golgi, and that this cleavage was catalysed by an aspartyl protease.
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PMID:Characterization and biosynthesis of the woodchuck hepatitis virus e antigen. 811 24

The envelope of hepatitis B virus contains three related glycoproteins (termed L, M and S) produced by alternative translation initiation in a single coding region. The smallest of these, the S protein, is a 24 kDa glycoprotein with multiple transmembrane domains. The M and L proteins contain the entire S domain at their C-termini, but harbor at their N-terminal additional (preS) domains of 55 or 174 amino acids, respectively. Most of these preS residues are displayed on the surface of mature virions and hence would be expected to be translocated into the endoplasmic reticulum (ER) lumen during biosynthesis. Using a coupled, in vitro translation/translocation system we now demonstrate that, contrary to expectation, virtually all preS residues of the L protein are cytoplasmically disposed in the initial translocation product. This includes some preS sequences which in the M protein are indeed translocated into the ER lumen. Since preS sequences are found on the external surface of the virion envelope, our results indicate that during or following budding a dramatic reorganization of either the envelope proteins or the lipid bilayer (or both components) must occur to allow surface display of these sequences. These findings imply that some membrane budding events can have remarkable and previously unsuspected topological consequences.
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PMID:A dramatic shift in the transmembrane topology of a viral envelope glycoprotein accompanies hepatitis B viral morphogenesis. 813 39

Liver tissue samples from four chimpanzees submitted to viral challenge in order to test a recombinant anti-hepatitis B virus vaccine, were studied by electron microscopy. The vaccinated monkeys showed no evidences of acute viral hepatitis (AVH), demonstrating the protection against an infective viral dose; on the contrary, the non-vaccinated chimps developed signs of AVH in hepatocytes such as: different size and shape, slight dilatation of the rough endoplasmic reticulum, disappearance of the mitochondrial crests, broadening of the normal space between the membranes of the nuclear coating and presence of laminar bodies and cytoplasmic vacuoles. Furthermore, the presence of the hepatitis B virus surface (HBV) antigen was confirmed in non-vaccinated monkeys using immunocytochemical techniques. Transmission electron microscopy and immunocytochemical analysis corroborated the protective effect of the recombinant vaccine against the HBV in the vaccinated animals.
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PMID:Ultrastructural and immunocytochemical characteristics of hepatocytes from hepatitis B virus infected chimpanzees. 814 May 81

The preS domain at the N-terminus of the large envelope protein (LHBs) of the hepatitis B virus is involved in (i) envelopment of viral nucleocapsids and (ii) binding to the host cell. While the first function suggests a cytosolic location of the preS domain during virion assembly, the function as an attachment site requires its translocation across the lipid bilayer and final exposure on the virion surface. We compared the transmembrane topology of newly synthesized LHBs in the endoplasmic reticulum (ER) membrane with its topology in the envelope of secreted virions. Protease sensitivity and the absence of glycosylation suggest that the entire preS domain of newly synthesized LHBs remains at the cytosolic side of ER vesicles. However, virions secreted from transfected cell cultures or isolated from the blood of persistent virus carriers expose antibody binding sites and proteolytic cleavage sites of the preS domain at their surface in approximately half of the LHBs molecules. Thus, preS domains appear to be transported across the viral lipid barrier by a novel post-translational translocation mechanism to fulfil a dual function in virion assembly and attachment to the host cell.
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PMID:Post-translational alterations in transmembrane topology of the hepatitis B virus large envelope protein. 819 18

During chronic infection by hepatitis B virus, the viral genome frequently integrates into the host chromosome, causing gross disruption and rearrangement of the viral DNA. We have obtained data showing that viral genomic disruptions which delete the enhancers from the transcribed region of the viral surface gene can lead to dysregulation of surface gene expression at the transcriptional level. Specifically, in cells transfected with such disrupted genomes, there is a decreased amount of transcripts coding for the major form of the surface protein but little change in the amount of transcripts coding for the large surface protein. In these cells, secretion of the surface proteins is blocked in the endoplasmic reticulum-Golgi intermediate compartment, consistent with previous work from other groups showing that relative overexpression of the large surface protein can block secretion of all forms of the surface protein. Our findings suggest that viral genomic rearrangements during integration may be a contributing factor in the pathogenesis of ground-glass hepatocytes, which contain large amounts of intracellular surface proteins as a result of a block in secretion and are frequently seen in the livers of patients with chronic hepatitis B.
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PMID:Dysregulated surface gene expression from disrupted hepatitis B virus genomes. 823 Apr 28


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