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)

In two recently reported cases, integrated hepatitis B virus (HBV) DNAs cloned from hepatocellular carcinoma were found to express a transcriptional transactivator from 3'-terminally truncated HBV surface (preS/S) genes. In this study, we characterized the transactivator at the protein level. Expression of a 3'-truncated preS2/S gene in Spodoptera frugiperda (Sf9) insect cells resulted in a C-terminally truncated middle surface protein of 76 amino acids (MHBst76), which was found to be associated with membranes of the endoplasmic reticulum and retained from Golgi processing and secretion. Accordingly, the microsome fraction of MHBst76-expressing Sf9 cells displayed transactivator activity after electric field-mediated transfer into Chang liver cells. In contrast to full-length MHBs, MHBst76 is unglycosylated, and glycosylation is not required for transactivation as shown by mutation of the glycosylation site at asparagine-4. Since highly purified MHBst76 derived from an E. coli expression system also showed transactivator activity, it is concluded that unglycosylated MHBst76 protein is the authentic transactivating factor. As the transactivator protein derives from inactive MHbs by rearrangements of integrated HBV DNA, it may be important for HBV-associated liver carcinogenesis.
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PMID:ER-localization and functional expression of the HBV transactivator MHBst. 824 38

Hepatitis B virus surface protein variants are described, capable of translocating to the lumenal side of the endoplasmic reticulum membrane their myristylated N-termini, as revealed by the contestual modification of N-terminal, N-linked glycosylation sites. To our knowledge, this is the first example of transmembrane translocation of a preformed protein acyl adduct. The possible significance of this event for hepatitis B virus biology is discussed.
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PMID:Trans-membrane translocation of a myristylated protein amino terminus. 837 3

A positive association between the incidence of hepatocellular carcinoma and the consumption of alcoholic beverages has been reported from some countries. The possible mechanistic nature of the association remains unclear, however. The effects of alcohol, as ethanol and as ethanol in various complex mixtures in the many different alcoholic beverages, were compared with the effects of well-known genotoxic and nongenotoxic or epigenetic carcinogens in carcinogenesis. There is no convincing evidence that alcohol can initiate the long multistep process of development of hepatocellular carcinoma. Thus, it appears that alcohol cannot be considered as a complete carcinogen. The effects of alcohol were also compared with known promoting agents for liver cancer. Although the available data are less clear, nevertheless it appears that alcohol cannot be considered as a bona fide promoting agent for liver cancer development. The most likely roles of alcohol in the genesis of liver cancer are: (1) to induce a well-known precancerous liver lesion, cirrhosis, and (2) to modulate, in an as yet ill-defined manner, the process of cancer development with known human carcinogenic influences such as hepatitis due to hepatitis B and hepatitis C viruses. Alcohol is well known to induce several enzymes in the liver and, thus, could theoretically modulate one or more steps in the carcinogenic process. Because alcohol has been found to alter cell membranes in well-defined ways and cell membrane changes, especially in the liver endoplastic reticulum, appear to be common in the later steps in liver cancer development, it is suggested that one site of alcohol action might be in the modulation of the biophysical composition of the liver endoplasmic reticulum and plasma membrane, favoring the cellular evolution to neoplasia.
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PMID:Alcohol and other chemicals in the development of hepatocellular carcinoma. 879 78

The three envelope proteins of the hepatitis B virus (HBV) are encoded by a single open reading frame in the genome containing three separate in-phase AUG codons. This organization defines three protein domains (pre-S1, pre-S2, S) which form the small (S), middle (M, pre-S2/S), and large (L, pre-S1 /pre-S2/S) proteins. Mature virions are generated by the budding of preformed nucleocapsids through endoplasmic reticulum (ER) membranes containing S and L proteins, whereas the M protein is not necessary. This suggests an important function for the pre-S1 domain. To investigate the protein-protein interactions involved during the maturation process of the HBV virion, we studied in vitro the binding affinity to purified HBV core particles of various synthetic peptides identical to regions of the envelope proteins. Data previously obtained with deletion mutants were confirmed and refined. The 13 C-terminal amino acids of pre-S1 bound efficiently to core particles, whereas other pre-S domains did not. Moreover, the amino acid sequence 56-80 in the cytosolic loop of S bound efficiently to the HBV core. This double interaction between the HBV capside and both S and pre-S1 domains may be required for virion morphogenesis.
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PMID:Both pre-S1 and S domains of hepatitis B virus envelope proteins interact with the core particle. 902 17

The role of N-glycan trimming in glycoprotein fate and function is unclear. We have recently shown that hepatitis B virus (HBV) DNA is not efficiently secreted from cells in which alpha-glucosidase mediated N-glycan trimming is inhibited. Here it is shown that, in cells in glucosidase-inhibited cells, viral DNA, accompanied by envelope and core proteins, most likely accumulate within lysosomal compartments. Pulse-chase experiments show that although the viral glycoproteins (L, M, and S) are dysfunctional, in the sense that they do not mediate virion egress and are not efficiently secreted from the cell, they all still leave the endoplasmic reticulum (ER). Surprisingly, however, the glycoproteins retained within the cell were not rapidly degraded, appearing as aggregates, enriched for L and M, with intracellular half-lives exceeding 20 h. Moreover, by 24 h after synthesis, a substantial fraction of the detained glycoproteins appeared to return to the ER, although a considerable amount was also found in the lysosomes. To our knowledge, this is the first report that shows, as a consequence of inhibiting glycosylation processing, certain glycoproteins (i) become dysfunctional and aggregate, yet still depart from the ER, and (ii) have extended rather than shortened half-lives. Taken together, these data suggest that proper intracellular routing of HBV glycoproteins requires ER glucosidase function. It is hypothesized that failure to process N-glycan causes HBV glycoproteins to aggregate and that impaired protein-protein interactions and trafficking are the result of misfolding.
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PMID:Aberrant trafficking of hepatitis B virus glycoproteins in cells in which N-glycan processing is inhibited. 912 3

Naturally occurring deletions in the hepatitis B virus pre-S1 domain have been frequently found during persistent viral infection. In this study we have investigated the functional properties of a mutant viral genome that carries an in-frame deletion of 183 nucleotides in the pre-S1 region. This deletion removes the promoter of the small envelope gene. Transfection into human hepatocellular carcinoma cells of a replication-competent construct containing this deletion resulted in an increase of intermediate DNA replicative forms compared to those produced by wild-type hepatitis B virus. Northern blot analysis revealed that such cells lack the 2.1-kb transcripts encoding the small envelope protein and that hepatitis B surface antigen was absent as well. Furthermore, nucleocapsids containing the genome with pre-S1 deleted were not secreted, and the deleted large envelope protein was retained with the cytoplasm and exhibited a perinuclear pattern of distribution. However, coexpression with the small envelope protein was sufficient to restore virion secretion and to change the cellular distribution of the deleted large envelope protein. In addition, the creation of point mutations that prevent the synthesis of large or small envelope proteins also inhibited viral secretion and led to increased levels of hepatitis B virus intermediate replicative forms within the cell. These studies suggest that naturally occurring viral mutants with pre-S1 deletions involving the promoter region of the small envelope gene will generate a deleted large envelope protein that is retained in the endoplasmic reticulum, resulting in the accumulation of nucleocapsids containing viral DNA; transcomplementation with the wild-type small envelope protein will allow mutant virion secretion to occur.
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PMID:The small envelope protein is required for secretion of a naturally occurring hepatitis B virus mutant with pre-S1 deleted. 918 17

Hepatitis B virus small surface protein is synthesized as a transmembrane protein of the rough endoplasmic reticulum (RER) and then buds into the lumen in the form of subviral particles that are secreted. The closely related large surface protein is also targeted to the RER but is retained in a pre-Golgi compartment and cannot be secreted. It has been assumed that the large surface protein remains as a transmembrane RER protein and hence cannot form particles, possibly because of binding to a host factor on the cytosolic face of the RER membranes. We have reexamined this question and found the following results. (i) The retained large surface protein is associated not with RER but, rather, with a more distal compartment. (ii) Electron microscopy reveals intravesicular 20-nm particles, similar to those formed by the small surface protein. (iii) The large surface protein colocalizes with and binds to calnexin, an ER chaperone protein. Therefore, our results indicate that the large surface protein is capable of budding and forming particles, and hence its intracellular retention cannot be attributed to a cytosolic factor. We interpret the data as evidence that the large surface protein is retained by virtue of interacting with calnexin, a component of what is considered the quality control mechanism of the ER.
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PMID:Formation of intracellular particles by hepatitis B virus large surface protein. 918 22

The large L envelope protein of the hepatitis B virus has the peculiar capacity to adopt two transmembrane topologies. The N-terminal preS domain of L initially remains in the cytosol while the S domain is cotranslationally inserted into the endoplasmic reticulum membrane. The preS region of about half of the L molecules' is posttranslationally translocated to the lumenal space. We now demonstrate that the repression of cotranslational translocation of preS is conferred by a preS1-specific sequence. By analysis of L deletion mutants, the cytosolic anchorage determinant was mapped to amino acid sequence 70 to 94 of L. The intrinsic potential of this determinant to suppress cotranslational translocation was confirmed by transfer to the HBV middle envelope protein. In searching for cellular factors potentially involved in this novel process, we identified the cytosolic heat shock protein Hsc70 as a specific binding partner of L. The interaction site(s) for the chaperone was mapped to amino acids 63 to 107 of L using coimmunoprecipitation and in vitro binding analyses. Deletion of the cytosolic anchorage determinant almost completely abolished ATP-dependent Hsc70 binding. Therefore, interaction between Hsc70 and L is likely to be responsible for the suppression of cotranslational translocation of the preS domain.
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PMID:Sequence-specific repression of cotranslational translocation of the hepatitis B virus envelope proteins coincides with binding of heat shock protein Hsc70. 930 46

Hepatitis B virus (HBV) codes for three forms of surface protein. The minor, large form is translated from transcripts specified by the preS1 promoter, while the middle and small forms are translated from transcripts specified by the downstream S promoter. When the large surface protein is overexpressed, the secretion of both subviral and virion particles is blocked within the secretory pathway. We show here that overexpression of the large surface protein leads to up to a 10-fold activation of the S promoter but not of an unrelated promoter. Neither the middle nor the small surface protein, nor a secretable form of the large surface protein, activates the S promoter, but agents that induce endoplasmic reticulum (ER) stress have an effect similar to that of the large surface protein. The large surface protein also activates the S promoter in the context of the entire viral genome. Therefore, it appears that HBV has evolved a feedback mechanism, such that ER stress induced by accumulation of the large surface protein increases the synthesis of the middle and small surface proteins, which in combination with the large surface protein can form mixed, secretable particles. In addition, like other agents that induce ER stress, the large surface protein can activate the cellular grp78 and grp94 promoters, raising the possibility that it may alter the physiology of the host cell.
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PMID:Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum. 931 17

Envelopment of the hepatitis B virus (HBV) nucleocapsid depends on the large envelope protein L, which is expressed as a transmembrane polypeptide at the endoplasmic reticulum membrane. Previous studies demonstrated that the cytosolic exposure of the N-terminal pre-S domain (174 amino acids) of L was required for virion formation. N-terminal truncations of L up to Arg 103 were tolerated. To map sites in the remaining C-terminal part of pre-S important for virion morphogenesis, a series of 11 L mutants with linker substitutions between Asn 98 and Pro 171 was generated. The mutants formed stable proteins and were secreted in transfected cell cultures, probably as components of subviral hepatitis B surface antigen particles. All four constructs with mutations between Asn 98 and Thr 125 were unable to complement in trans the block in virion formation of an L-negative HBV genome in cotransfected HuH7 cells. These mutants had a transdominant negative effect on virus yield in cotransfections with the wild-type HBV genome. In contrast, all seven mutants with substitutions downstream of Ser 124 were able to envelop the nucleocapsid and to secrete HBV. The sequence between Arg 103 and Ser 124 is highly conserved among different HBV isolates and also between HBV and the woodchuck hepatitis virus. Point mutations in this region introducing alanine residues at conserved positions blocked virion formation, in contrast to mutations at nonconserved residues. These results demonstrate that the pre-S sequence between Arg 103 and Ser 124 has an important function in HBV morphogenesis.
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PMID:A short linear sequence in the pre-S domain of the large hepatitis B virus envelope protein required for virion formation. 937 94


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