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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phosphoprotein (P) of vesicular stomatitis virus (VSV) is a subunit of the viral RNA polymerase. In previous studies, we demonstrated that insertion of 19 amino acids in the hinge region of the protein had no significant effect on P protein function. In the present study, we inserted full-length enhanced green fluorescent protein (eGFP) in frame into the hinge region of P and show that the fusion protein (PeGFP) is functional in viral genome transcription and replication, albeit with reduced activity. A recombinant vesicular stomatitis virus encoding PeGFP in place of the P protein (VSV-PeGFP), which possessed reduced growth kinetics compared to the wild-type VSV, was recovered. Using the recombinant VSV-PeGFP, we show that the viral replication proteins and the de novo-synthesized RNA colocalize to sites throughout the cytoplasm, indicating that replication and transcription are not confined to any particular region of the cytoplasm. Real-time imaging of the cells infected with the eGFP-tagged virus revealed that, following synthesis, the nucleocapsids are transported toward the cell periphery via a microtubule (MT)-mediated process, and the nucleocapsids were seen to be closely associated with mitochondria. Treatment of cells with nocodazole or Colcemid, drugs known to inhibit MT polymerization, resulted in accumulation of the nucleocapsids around the nucleus and also led to inhibition of infectious-virus production. These findings are compatible with a model in which the progeny viral nucleocapsids are transported toward the cell periphery by MT and the transport may be facilitated by mitochondria.
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PMID:Visualization of intracellular transport of vesicular stomatitis virus nucleocapsids in living cells. 1677 25

Our recent observation that hepatitis B virus (HBV) DNA polymerase (P) might initiate minus-strand DNA synthesis without primer [Kim et al., (2004) Virology 322, 22-30], raised a possibility that HBV P protein may have the potential to function as an RNA polymerase. Thus, we mutated Phe 436, a bulky amino acid with aromatic side chain, at the putative dNTP-binding cleft in reverse transcriptase (RT) domain of P protein to smaller amino acids (Gly or Val), and examined RNA polymerase activity. HBV core particles containing RT dNTP-binding cleft mutant P protein were able to incorporate (32)P-ribonucleotides, but not HBV core particles containing wild type (wt), priming-deficient mutant, or RT-deficient mutant P proteins. Since all the experiments were conducted with core particles isolated from transfected cells, our results indicate that the HBV RT mutant core particles containing RT dNTP-binding cleft mutant P protein could incorporate both deoxyribonucleotides and ribonucleotides in replicating systems.
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PMID:Incorporation of deoxyribonucleotides and ribonucleotides by a dNTP-binding cleft mutated reverse transcriptase in hepatitis B virus core particles. 1790 Jun 49

The order Mononegavirales (comprised of nonsegmented negative-stranded RNA viruses or NNSVs) contains many important pathogens. Parainfluenza virus 5 (PIV5), formerly known as simian virus 5, is a prototypical paramyxovirus and encodes a V protein, which has a cysteine-rich C terminus that is conserved among all paramyxoviruses. The V protein of PIV5, like that of many other paramyxoviruses, plays an important role in regulating viral RNA synthesis. In this work, we show that V interacts with Akt, a serine/threonine kinase, also known as protein kinase B. Both pharmacological inhibitors and small interfering RNA against Akt1 reduced PIV5 replication, indicating that Akt plays a critical role in PIV5 replication. Furthermore, treatment with Akt inhibitors also reduced the replication of several other paramyxoviruses, as well as vesicular stomatitis virus, the prototypical rhabdovirus, indicating that Akt may play a more universal role in NNSV replication. The phosphoproteins (P proteins) of NNSVs are essential cofactors for the viral RNA polymerase complex and require heavy phosphorylation for their activity. Inhibition of Akt activity reduced the level of P phosphorylation, suggesting that Akt is involved in regulating viral RNA synthesis. In addition, Akt1 phosphorylated a recombinant P protein of PIV5 purified from bacteria. The finding that Akt plays a critical role in replication of NNSV will lead to a better understanding of how these viruses replicate, as well as novel strategies to treat infectious diseases caused by NNSVs.
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PMID:Akt plays a critical role in replication of nonsegmented negative-stranded RNA viruses. 1795 76

The paramyxovirus P protein is an essential component of the transcriptase and replicase complex along with L protein. In this article, we have examined the functional roles of different domains of P proteins of two closely related morbilliviruses, Rinderpest virus (RPV) and Peste des petits ruminants virus (PPRV). The PPRV P protein physically interacts with RPV L as well as RPV N protein when expressed in transfected cells, as shown by co-immunoprecipitation. The heterologous L-P complex is biologically active when tested in a RPV minigenome replication/transcription system, only when used with PPRV N protein but not with RPV N protein. Employing chimeric PPRV/RPV cDNAs having different coding regions of P protein in the minigenome replication/transcription system, we identified a region between 290 and 346 aa in RPV P protein necessary for transcription of the minigenome.
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PMID:Identification of functional domains of phosphoproteins of two morbilliviruses using chimeric proteins. 1842 68

Rinderpest virus belongs to the family of Paramyxoviridae, consisting of non-segmented negative sense RNA viruses. Viral transcription and replication are carried out by the RNA dependent RNA polymerase L protein which functions together with P protein as L-P complex. The exact events triggering the polymerase complex from transcription to replication function is poorly understood. In the present work, an in vitro transcription system has been described with partially purified L-P complex expressed in insect cells and viral genomic RNA. The relative abundance of each species of mRNA synthesized in vitro decreased from the 3' end of the genome to the 5' end similar to their abundance in virus infected cells. Recombinant L-P complex was unable to synthesize leader RNA suggesting the initiation of transcription from gene start site and not at the 3' end of the genome.
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PMID:Recombinant L and P protein complex of Rinderpest virus catalyses mRNA synthesis in vitro. 1843 Apr 84

The human respiratory syncytial virus (HRSV) structural P protein, phosphorylated at serine (S) and threonine (T) residues, is a co-factor of viral RNA polymerase. The phosphorylation of S54 is controlled by the coordinated action of two cellular enzymes: a lithium-sensitive kinase, probably glycogen synthetase kinase (GSK-3) beta and protein phosphatase 2A (PP2A). Inhibition of lithium-sensitive kinase, soon after infection, blocks the viral growth cycle by inhibiting synthesis and/or accumulation of viral RNAs, proteins and extracellular particles. P protein phosphorylation at S54 is required to liberate viral ribonucleoproteins (RNPs) from M protein, during the uncoating process. Kinase inhibition, late in infection, produces a decrease in genomic RNA and infectious viral particles. LiCl, intranasally applied to mice infected with HRSV A2 strain, reduces the number of mice with virus in their lungs and the virus titre. Administration of LiCl to humans via aerosol should prevent HRSV infection, without secondary effects.
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PMID:Phosphorylation of human respiratory syncytial virus P protein at serine 54 regulates viral uncoating. 1870 69

Because viruses are obligate parasites, numerous partnerships between measles virus and cellular molecules can be expected. At the entry level, measles virus uses at least two cellular receptors, CD150 and a yet to be identified epithelial receptor to which the virus H protein binds. This dual receptor strategy illuminates the natural infection and inter-human propagation of this lymphotropic virus. The attenuated vaccine strains use CD46 as an additional receptor, which results in a tropism alteration. Surprisingly, the intracellular viral and cellular protein partnership leading to optimal virus life cycle remains mostly a black box, while the interactions between viral proteins that sustain the RNA-dependant RNA polymerase activity (i.e., transcription and replication), the particle assembly and the polarised virus budding are documented. Hsp72 is the only cellular protein that is known to regulate the virus transcription and replication through its interaction with the viral N protein. The viral P protein is phosphorylated by the casein kinase II with undetermined functional consequences. The cellular partnership that controls the intracellular trafficking of viral components, the assembly and/or the budding of measles virus, remains unknown. The virus to cell innate immunity war is better documented. The 5' triphosphate-ended virus leader transcript is recognised by RIG-I, a cellular helicase, and induces the interferon response. Measles virus V protein binds to the MDAS helicase and prevents the MDA5-mediated activation of interferon. By interacting with STAT1 and Jak1, the viral P and V proteins prevent the type I interferon receptor (IFNAR) signalling. The virus N protein interacts with eIF3-p40 to inhibit the translation of cellular mRNA. The H protein binds to TLR2, which then transduces an activation signal and CD150 expression in monocytes. The P protein activates the expression of the ubiquitin modifier A20, thus blocking the TLR4-mediated signalling. Few other partnerships between measles virus components and cellular proteins have been postulated or demonstrated, and they need further investigations to understand their physiopathological outcome.
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PMID:Measles virus interaction with host cells and impact on innate immunity. 1919 66

Chandipura Virus (CHPV), a member of Rhabdoviridae, is responsible for an explosive outbreak in rural areas of India. It affects mostly children and is characterized by influenza-like illness and neurologic dysfunctions. It is transmitted by vectors such as mosquitoes, ticks and sand flies. An effective real-time one step reverse-transcriptase PCR assay method is adopted for diagnosis of this virus. CHPV has a negative sense RNA genome encoding five different proteins (N, P, M, G, and L). P protein plays a vital role in the virus's life cycle, while M protein is lethal in nature. There is no specific treatment available to date, symptomatic treatment involves use of mannitol to reduce brain edema. A Vero cell based vaccine candidate against CHPV was evaluated efficiently as a preventive agent against it. Prevention is the best method to suppress CHPV infection. Containment of disease transmitting vectors, maintaining good nutrition, health, hygiene and awareness in rural areas will help in curbing the menace of CHPV. Thus, to control virus transmission some immense preventive measures need to be attempted until a good anti-CHPV agent is developed.
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PMID:Chandipura Virus: an emerging tropical pathogen. 2272 25

Measles virus phosphoprotein (P protein) is a cofactor of the viral RNA polymerase (L protein) that associates with the nucleoprotein-RNA complex to support viral transcription and replication. Here, we report a significant inverse correlation between the phosphorylation level of MV-P protein and viral transcriptional activity. Upregulation of P protein phosphorylation resulted in reduction of viral transcription. Additionally, we found that strong phosphorylation at S86 and S151 of P protein, which may be generally prevented by association with nucleoprotein, downregulates the viral transcriptional activity. These findings suggest that P protein is involved in regulation of viral transcription through changes in its phosphorylation status.
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PMID:Phosphorylation of measles virus phosphoprotein at S86 and/or S151 downregulates viral transcriptional activity. 2302 62

The M2-2 protein regulates the balance between human respiratory syncytial virus (HRSV) transcription and replication. Here it is shown that M2-2 mediated transcriptional inhibition is managed through P protein phosphorylation. Transcription inhibition by M2-2 of the HRSV based minigenome pRSVluc, required P protein phosphorylation at serines (S) in positions 116, 117, 119 and increased inhibition is observed if S232 or S237 is also phosphorylated. Phosphorylation of these residues is required for viral particle egression from infected cells. Viral RNA synthesis complementation assays between P protein variants, suggest that two types of P proteins participate in the process as components of RNA dependent RNA polymerase (RdRp). Type I is only functional when, as a homotetramer, it is bound to N and L proteins through residues 203-241. Type II is functionally independent of these interactions and binds to N protein at a region outside residues 232-241. P protein type I phosphorylation at S116, S117 and S119, did not affect the activity of RdRp but this phosphorylation in type II avoids its interaction with N protein and impairs RdRp functionality for transcription and replication. Structural changes in the RdRp, mediated by phosphorylation turnover at the indicated residues, in the two types of P proteins, may result in a fine adjustment, late in the infectious cycle, of transcription, replication and progression in the morphogenetic process that ends in egression of the viral particles from infected cells.
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PMID:Phosphorylation of the human respiratory syncytial virus P protein mediates M2-2 regulation of viral RNA synthesis, a process that involves two P proteins. 2647 24


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