Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In several vertebrate species, Borna disease virus (BDV), the prototype of a new group of animal viruses, causes central nervous system disease accompanied by diverse behavioral abnormalities. Seroepidemiological data indicate that BDV may contribute to the pathophysiology of certain human mental disorders. This hypothesis is further supported by the detection of both BDV antigens and BDV RNA in peripheral blood mononuclear cells (PBMCs) of patients with psychiatric disorders and the isolation of BDV from such PBMCs. Here we describe serological and molecular epidemiological studies on psychiatric patients and healthy individuals from the area of Homburg, Germany. Using a novel Western blot (immunoblot) assay, we found a BDV seroprevalence of 9.6% among 416 neuropsychiatric patients, which is significantly higher than the 1.4% found among 203 healthy control individuals. Human sera displayed a prominent immunoreactivity against the virus nucleoprotein, the p40 antigen. Reverse transcriptase-mediated PCR analysis of RNA extracted from PBMCs of a subset of 26 of the neuropsychiatric patients revealed that 50% were BDV RNA positive. Three of the 13 BDV RNA-positive patients also had BDV-positive serology, whereas one patient with serum antibodies to BDV p40 antigen did not harbor detectable BDV RNA in PBMCs. BDV p40 and p24 sequences derived from human PBMCs exhibited both a high degree of inter- and intrapatient conservation and a close genetic relationship to animal-derived BDV sequences.
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PMID:Detection of Borna disease virus (BDV) antibodies and BDV RNA in psychiatric patients: evidence for high sequence conservation of human blood-derived BDV RNA. 889 92

The Borna disease virus antigenome includes five major open reading frames (ORFs) which encode, from 5' to 3', the putative nucleoprotein (N), the phosphoprotein (P), the putative matrix protein (M), the major glycoprotein (G), and the RNA-dependent RNA polymerase (pol). Whereas the N and P ORFs are translated from monocistronic transcripts, the M, G, and pol ORFs are translated from polycistronic transcripts. Expression of the M, G, and pol ORFs is dependent upon differential splicing of two introns (intron 1, 94 nucleotides [nt]; intron 2, 1,294 nt). In vitro transcription-translation assays of wild-type and mutant sequences indicated that the G ORF is translated from an unspliced 2.8-kb RNA by leaky ribosomal scanning. Splicing of intron 1 enhances the translation of the G ORF by converting the M ORF into a 13-amino-acid minicistron, a structure that facilitates ribosomal reinitiation.
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PMID:Evidence for translation of the Borna disease virus G protein by leaky ribosomal scanning and ribosomal reinitiation. 918 36

Borna disease virus (BDV) is a neurotropic enveloped virus with a nonsegmented, single-, negative-stranded RNA genome. This virus induced encephalitis in experimentally infected adult rats, but in newborn rats BDV established a persistent, tolerant infection with no apparent clinical signs. Here, we report evidence that newborn Mongolian gerbils (Meriones unguiculatus) are more susceptible to experimental intracranial inoculation of horse-derived BDV in persistently infected MDCK cells, compared with similar inoculation in newborn rats. All inoculated newborn gerbils, but not rats, died 30 days after infection. Reverse transcriptase-polymerase chain reaction amplified BDV-specific sequences in several regions including the brain. Histopathological analysis revealed apparent inflammatory reactions in the brains of inoculated gerbils but not rats, although similar levels of BDV RNA were detected in both gerbil and rat brains. BDV-specific antigen and RNA were identified predominantly in neurons in the brains by immunohistochemistry with antibodies to BDV and in situ hybridization with BDV-specific riboprobes, respectively. BDV in the gerbil brain was easily rescued by co-cultivation of the brain homogenate with human oligodendroglioma cells. Thus, gerbils seem to be a useful animal model for studying BDV-induced pathogenesis in the brain.
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PMID:High susceptibility of Mongolian gerbil (Meriones unguiculatus) to Borna disease virus. 1007 27

Borna disease virus (BDV) has been suggested to play a role in the etiology of schizophrenia. We tested the hypothesis that markers of BDV infection are more frequent in Surinamese immigrants to the Netherlands, diagnosed with schizophrenia, than in Dutch-born healthy subjects. For reasons that are poorly understood there is an increased incidence of schizophrenia in this immigrant group. Blood was obtained from 29 male schizophrenic patients (DSM-IV criteria) and from 26 healthy males. For detection of anti-BDV antibodies an indirect immunofluorescence assay (IFA) was performed. A nested, reverse-transcriptase-PCR, using primers specific for the p24 and p40 BDV genes, was used to determine BDV-RNA in peripheral blood mononuclear cells. Contrary to our expectations, the frequencies of BDV markers in the group of healthy subjects, as determined by IFA and both PCRs, exceeded that in the group of patients. The results do not support an association between markers of BDV infection in blood and schizophrenia. It is unlikely that the high incidence of schizophrenia in Surinamese immigrants is caused by BDV, but the small number of subjects examined do not warrant definitive conclusions.
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PMID:Borna disease virus and schizophrenia in Surinamese immigrants to the Netherlands. 1113 37

Borna disease virus (BDV) is a nonsegmented negative-strand RNA virus that replicates and transcribes its genome in the nucleus of infected cells. BDV proteins involved in replication and transcription must pass through the nuclear envelope to associate with the genomic viral RNA. The RNA-dependent RNA polymerase (L) of BDV is postulated to be the catalytic enzyme of replication and transcription. We demonstrated previously that BDV L localizes to the nucleus of BDV-infected cells and L-transfected cells. Nuclear localization of the protein presupposes the presence of a nuclear localization signal (NLS) within its primary amino acid sequence or cotransport to the nucleus with another karyophilic protein. Because L localized to the nucleus in the absence of other viral proteins, we investigated the possibility that L contains an NLS. The minimal sequence required for nuclear localization of L was identified by analyzing the subcellular distribution of deletion mutants of L fused to a flag epitope tag or beta-galactosidase. Although the majority of the L fusion proteins localized to the cytoplasm of transfected BSR-T7 cells, a strong NLS (844RVVKLRIAP852) with basic and proline residues was identified. Mutation of this sequence resulted in cytoplasmic distribution of L, confirming that this sequence was necessary and sufficient to drive the nuclear localization of L.
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PMID:Characterization of the nuclear localization signal of the borna disease virus polymerase. 1213 49

Genome and antigenome synthesis of negative-strand RNA viruses is initiated at promoters located in inverted terminal repeats (ITR). The ITR of Borna disease virus (BDV), a persisting neurotropic virus with a nuclear replication phase, are exceptional in that they appear to be noncomplete. Our analysis showed that the vast majority of genomic and antigenomic RNA molecules of BDV lack four 5'-terminal nucleotides required for perfect complementarity with the 3' ITR. By using a previously undescribed reverse genetics system, we investigated whether the structure of the ITR would affect virus propagation. BDV rescued from cDNA encoding complete ITR (rBDVc) showed wild-type virulence, whereas virus rescued from cDNA encoding a viral genome with noncomplete ITR (rBDVnc) was strongly attenuated. Both recombinant viruses expressed similar RNA and protein levels in persistently infected cells. However, rBDVnc particles were less infectious, indicating that complete ITR are required for high viral replicase but not transcriptase activity. Interestingly, genomic RNA from purified rBDVc particles lacked 5'-terminal nucleotides like authentic BDV, strongly suggesting programmed genome truncation. By specifically trimming its genome at the 5' terminus, BDV seems to limit viral genome amplification, which may favor noncytolytic viral persistence.
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PMID:Genome trimming: a unique strategy for replication control employed by Borna disease virus. 1572 64

The phosphoprotein P of Borna disease virus (BDV) is an essential cofactor of the viral RNA-dependent RNA polymerase. It is preferentially phosphorylated at serine residues 26 and 28 by protein kinase C epsilon (PKCepsilon) and, to a lesser extent, at serine residues 70 and 86 by casein kinase II (CKII). To determine whether P phosphorylation is required for viral polymerase activity, we generated P mutants lacking either the PKCepsilon or the CKII phosphate acceptor sites by replacing the corresponding serine residues with alanine (A). Alternatively, these sites were replaced by aspartic acid (D) to mimic phosphorylation. Functional characterization of the various mutants in the BDV minireplicon assay revealed that D substitutions at the CKII sites inhibited the polymerase-supporting activity of P, while A substitutions maintained wild-type activity. Likewise, D substitutions at the PKC sites did not impair the cofactor function of BDV-P, whereas A substitutions at these sites led to increased activity. Interestingly, recombinant viruses could be rescued only when P mutants with modified PKCepsilon sites were used but not when both CKII sites were altered. PKCepsilon mutant viruses showed a reduced capacity to spread in cell culture, while viral RNA and protein expression levels in persistently infected cells were almost normal. Further mutational analyses revealed that substitutions at individual CKII sites were, with the exception of a substitution of A for S86, detrimental for viral rescue. These data demonstrate that, in contrast to other viral P proteins, the cofactor activity of BDV-P is negatively regulated by phosphorylation.
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PMID:Functional characterization of the major and minor phosphorylation sites of the P protein of Borna disease virus. 1737 20

Rabies virus is a negative-strand RNA virus. Its RNA genome is condensed by the viral nucleoprotein (N), and it is this N-RNA complex that is the template for transcription and replication by the viral RNA-dependent RNA polymerase complex. Here we discuss structural and functional aspects of viral transcription and replication based on the atomic structure of a recombinant rabies virus N-RNA complex. We situate available biochemical data on N-RNA interactions with viral and cellular factors in the structural framework with regard to their implications for transcription and replication. Finally, we compare the structure of the rabies virus nucleoprotein with the structures of the nucleoproteins of vesicular stomatitis virus, Borna disease virus and influenza virus, highlighting potential similarities between these virus families.
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PMID:Structural aspects of rabies virus replication. 1793 61

Borna disease virus (BDV) is one of the infectious agents that causes diseases of the central nervous system in a wide range of vertebrate species and, perhaps, in humans. The phosphoprotein (P) of BDV, an essential cofactor of virus RNA-dependent RNA polymerase, is required for virus replication. In this study, we identified the gamma-aminobutyric acid receptor-associated protein (GABARAP) with functions in neurobiology as one of the viral P protein-interacting cellular factors by using an approach of phage display-based protein-protein interaction analysis. Direct binding between GABARAP and P protein was confirmed by coimmunoprecipitation, protein pull-down, and mammalian two-hybrid analyses. GABARAP originally was identified as a linker between the gamma-aminobutyric acid receptor (GABAR) and the microtubule to regulate receptor trafficking and plays important roles in the regulation of the inhibitory neural transmitter gamma-aminobutyric acid (GABA). We showed that GABARAP colocalizes with P protein in the cells infected with BDV or transfected with the P gene, which resulted in shifting the localization of GABARAP from the cytosol to the nucleus. We further demonstrated that P protein blocks the trafficking of GABAR, a principal GABA-gated ion channel that plays important roles in neural transmission, to the surface of cells infected with BDV or transfected with the P gene. We proposed that during BDV infection, P protein binds to GABARAP, shifts the distribution of GABARAP from the cytoplasm to the nucleus, and disrupts the trafficking of GABARs to the cell membranes, which may result in the inhibition of GABA-induced currents and in the enhancement of hyperactivity and anxiety.
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PMID:Borna disease virus P protein affects neural transmission through interactions with gamma-aminobutyric acid receptor-associated protein. 1881 98

The RNA-dependent RNA polymerase L protein of vesicular stomatitis virus, a prototype of nonsegmented negative-strand (NNS) RNA viruses, forms a covalent complex with a 5'-phosphorylated viral mRNA-start sequence (L-pRNA), a putative intermediate in the unconventional mRNA capping reaction catalyzed by the RNA:GDP polyribonucleotidyltransferase (PRNTase) activity. Here, we directly demonstrate that the purified L-pRNA complex transfers pRNA to GDP to produce the capped RNA (Gpp-pRNA), indicating that the complex is a bona fide intermediate in the RNA transfer reaction. To locate the active site of the PRNTase domain in the L protein, the covalent RNA attachment site was mapped. We found that the 5'-monophosphate end of the RNA is linked to the histidine residue at position 1,227 (H1227) of the L protein through a phosphoamide bond. Interestingly, H1227 is part of the histidine-arginine (HR) motif, which is conserved within the L proteins of the NNS RNA viruses including rabies, measles, Ebola, and Borna disease viruses. Mutagenesis analyses revealed that the HR motif is required for the PRNTase activity at the step of the enzyme-pRNA intermediate formation. Thus, our findings suggest that an ancient NNS RNA viral polymerase has acquired the PRNTase domain independently of the eukaryotic mRNA capping enzyme during evolution and PRNTase becomes a rational target for designing antiviral agents.
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PMID:Histidine-mediated RNA transfer to GDP for unique mRNA capping by vesicular stomatitis virus RNA polymerase. 2016 4


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