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)

C-terminal truncation of the middle surface antigen from hepatitis B virus (MHBs) gives rise to a novel transactivating protein, called MHBst. In this study we show that MHBst like the HBx protein of HBV, can cause nuclear appearance of NF-kappa B DNA binding activity and induce various kappa B-controlled reporter genes. While an inhibitor of protein kinase C could not block gene induction by MHBst, the antioxidants N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) could potently suppress transactivation at mM and microM concentrations, respectively. Also, kappa B-dependent gene induction by the transactivator HBx was blocked. The effects were selective because PDTC did not interfere with MHBst and HBx-induced activation of the c-fos promoter/enhancer, nor with the basal activity of several other reporter genes lacking functional NF-kappa B binding motifs. Our data suggest that induction of a prooxidant state is crucial for the activation of NF-kappa B by MHBst and HBx and might be related to the hepatocarcinogenic potential of the viral proteins. MHBst had a subcellular localization unusual for a viral transactivator: it appeared to be an integral membrane protein of the endoplasmic reticulum.
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PMID:Hepatitis B virus transactivator MHBst: activation of NF-kappa B, selective inhibition by antioxidants and integral membrane localization. 163 69

Hepatitis B surface antigen (HBsAg), the major coat protein of hepatitis B virus, is also independently secreted from infected cells as a lipoprotein particle. Secretion proceeds without signal sequence removal or cleavage of other segments of the polypeptide. We have examined the synthesis and transport of HBsAg in cultured cells expressing the cloned surface antigen gene. Our results show that HBsAg is initially synthesized as a integral membrane protein. This transmembrane form is slowly converted to a secreted lipoprotein complex in the lumen of the endoplasmic reticulum via a series of definable intermediates, after which it is secreted from the cell. This unusual export process shares many features with the assembly and budding reactions of conventional enveloped animal viruses. However, it differs importantly in its absence of a requirement for the participation of nucleocapsid or other viral proteins.
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PMID:Secreted hepatitis B surface antigen polypeptides are derived from a transmembrane precursor. 319 83

The primary structure of recombinant hepatitis B surface antigen protein produced in yeast has been confirmed by mass spectrometric peptide mapping. These studies corroborate more than 85% of the amino acid sequence derived by sequencing of the gene and identified the presence of an acetyl moiety on approximately 70% of the NH2-terminal methionine residues. Prior to the present work, direct structural analysis was largely prevented by the insolubility of this integral membrane protein and its primary degradation fragments in aqueous buffers and by partial blockage of the NH2 terminus. These difficulties were overcome by preparative isolation using electroelution of the monomeric 226 amino acid protein from a polyacrylamide electrophoretic gel in the presence of sodium dodecyl sulfate. Chymotryptic digestion of the reduced and carboxymethylated monomer produced a large number of small, predominantly hydrophobic peptides ideally suited for peptide mapping by fast atom bombardment mass spectrometry. The percentage of NH2-terminal methionine blocked by acetyl was determined by a new strategy involving cyanogen bromide cleavage, permethylation, and gas chromatography/mass spectrometry identification and quantitation of the N-methyl-N-acetylhomoserine produced.
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PMID:Structural characterization of recombinant hepatitis B surface antigen protein by mass spectrometry. 334 59

The human asialoglycoprotein receptor (ASGPR), also called hepatic lectin, is an integral membrane protein and is responsible for the clearance of desialylated, galactose-terminal glycoproteins from the circulation by receptor-mediated endocytosis. It can be subdivided into four functional domains: the cytosolic domain, the transmembrane domain, the stalk and the carbohydrate recognition domain (CRD). The galactose-binding domains belong to the superfamily of C-type (calcium-dependent) lectins, in particular to the long-form subfamily with three conserved intramolecular disulphide bonds. It is able to bind terminal non-reducing galactose residues and N-acetyl-galactosamine residues of desialated tri or tetra-antennary N-linked glycans. The ASGPR is a potential liver-specific receptor for hepatitis B virus and Marburg virus and has been used to target exogenous molecules specifically to hepatocytes for diagnostic and therapeutic purposes.Here, we present the X-ray crystal structure of the carbohydrate recognition domain of the major subunit H1 at 2.3 A resolution. While the overall fold of this and other known C-type lectin structures are well conserved, the positions of the bound calcium ions are not, indicating that the fold is stabilised by alternative mechanisms in different branches of the C-type lectin family. It is the first CRD structure where three calcium ions form an intergral part of the structure. In addition, the structure provides direct confirmation for the conversion of the ligand-binding site of the mannose-binding protein to an asialoglycoprotein receptor-like specificity suggested by Drickamer and colleagues. In agreement with the prediction that the coiled-coil domain of the ASGPR is separated from the CRD and its N-terminal disulphide bridge by several residues, these residues are indeed not alpha-helical, while in tetranectin they form an alpha-helical coiled-coil.
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PMID:Crystal structure of the carbohydrate recognition domain of the H1 subunit of the asialoglycoprotein receptor. 1089 Dec 74

IRE1-alpha is an integral membrane protein of the endoplasmic reticulum (ER) that is a key sensor in the cellular transcriptional response to stress in the ER. Upon induction of ER stress, IRE1-alpha is activated, resulting in the synthesis of the active form of the transcription factor XBP1 via IRE1-mediated splicing of its mRNA. In this report, we have examined the role of IRE1-alpha and XBP1 in activation of the hepatitis B virus S promoter by ER stress. Cotransfection experiments revealed that overexpression of either IRE1-alpha or XBP1 activated this promoter. Conversely, cotransfected dominant-negative IRE1-alpha or small interfering RNA directed against XBP1 decreased the activation of the S promoter by ER stress, confirming an important role for the IRE1-alpha/XBP1 signaling pathway in activation of the S promoter. However, XBP1 does not bind directly to the S promoter; rather, a novel S promoter-binding complex that does not contain XBP1 is induced in cells undergoing ER stress in an XBP1-dependent manner. This complex, as well as transcriptional activation of the S promoter, is induced by ER stress in hepatocytes but not in fibroblasts, despite the presence of active XBP1 in the latter. Thus, the hepatitis B virus S promoter responds to a novel, cell type-restricted transcriptional pathway downstream of IRE1-alpha and XBP1.
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PMID:Activation of hepatitis B virus S promoter by a cell type-restricted IRE1-dependent pathway induced by endoplasmic reticulum stress. 1610

M2 is the third integral membrane protein of influenza A. M2e, the extracellular, 23 amino acid residues of M2, has been remarkably conserved in all human influenza A strains. This prompted us to evaluate the use of M2e as a potential broad-spectrum immunogen in a mouse model for influenza infection. Genetic fusion of the M2e and hepatitis B virus core (HBc) coding sequences allowed us to obtain highly immunogenic virus-like particles. This M2e-HBc vaccine induced complete protection in mice against a lethal influenza challenge. Protective immunity was obtained regardless of the position of M2e in the M2e-HBc chimera at the amino-terminus or inserted in the immuno-dominant loop of the HBc protein. Increasing the copy number of M2e inserted at the N-terminus from one to three per monomer (240-720 per particle) significantly enhanced the immune response and reduced the number of vaccinations required for complete protection against a lethal challenge with influenza A virus. A series of M2e-HBc constructs was subsequently combined with CTA1-DD, a recombinant cholera toxin A1 derived mucosal adjuvant, to test its efficacy as an intranasally delivered vaccine. All hybrid VLPs tested with CTA1-DD completely protected mice from a potentially lethal infection and, in addition, significantly reduced morbidity. Overall, increased resistance to influenza challenge in the mice correlated with an enhanced Th1-type M2e-specific antibody response induced by vaccination. These results show that M2e is a valid and versatile vaccine candidate to protect against any strain of human influenza A.
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PMID:Improved design and intranasal delivery of an M2e-based human influenza A vaccine. 1681 30