A Novel Nuclear Trafficking Module Regulates the Nucleocytoplasmic Localization of the Rabies Virus Interferon Antagonist, P Protein

Oksayan, Sibil; Wiltzer, Linda; Rowe, Caitlin; Blondel, Danielle; Jans, David A.; Moseley, Gregory W.

doi:10.1074/jbc.m112.374694

Cited by 39 publications

(94 citation statements)

References 66 publications

(186 reference statements)

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“…Truncation of the NTR to generate isoforms impacts localization both by inactivating/deleting the N-terminal NES and, in P3, by activating the N-terminal NLS de novo resulting in strong nuclear import (Oksayan et al, 2012b). Trafficking by the NTR also appears to involve an additional CRM1-dependent NES, but this has not been fully characterized (Oksayan et al, 2012b).…”

Section: Genusmentioning

confidence: 99%

“…Notably, several key trafficking sequences show broad conservation in the lyssavirus genus, indicative of important roles in viral biology (Jacob et al, 2000;Pasdeloup et al, 2005;Wiltzer et al, 2012). RABV P protein contains two nuclear trafficking modules/domains, located in the N-terminal region (NTR) (Oksayan et al, 2012b) and globular CTD (Pasdeloup et al, 2005;Rowe et al, 2016), both of which incorporate a CRM1-dependent NES and an IMPbinding NLS in overlapping or closely associated sequences, enabling efficient co-regulation of import and export. Truncation of the NTR to generate isoforms impacts localization both by inactivating/deleting the N-terminal NES and, in P3, by activating the N-terminal NLS de novo resulting in strong nuclear import (Oksayan et al, 2012b).…”

Section: Genusmentioning

confidence: 99%

“…RABV P protein contains two nuclear trafficking modules/domains, located in the N-terminal region (NTR) (Oksayan et al, 2012b) and globular CTD (Pasdeloup et al, 2005;Rowe et al, 2016), both of which incorporate a CRM1-dependent NES and an IMPbinding NLS in overlapping or closely associated sequences, enabling efficient co-regulation of import and export. Truncation of the NTR to generate isoforms impacts localization both by inactivating/deleting the N-terminal NES and, in P3, by activating the N-terminal NLS de novo resulting in strong nuclear import (Oksayan et al, 2012b). Trafficking by the NTR also appears to involve an additional CRM1-dependent NES, but this has not been fully characterized (Oksayan et al, 2012b).…”

Section: Genusmentioning

confidence: 99%

“…Trafficking function of the CTD, which is present in all RABV P isoforms, is proposed to be regulated by a phosphorylation-dependent mechanism that switches between conformations favouring export or import by the NES and non-conventional conformational NLS (Moseley et al, 2007a, b;Oksayan et al, 2012b;Pasdeloup et al, 2005;Rowe et al, 2016). Notably, the CTD can interact directly with IMPa/b heterodimer and IMPb alone, suggesting that the conformational NLS has non-classical function in coupling to multiple transport pathways (Rowe et al, 2016), which parallels the broad IMP-binding specificity of some paramyxovirus M proteins (Pentecost et al, 2015).…”

Section: Genusmentioning

confidence: 99%

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Roles of nuclear trafficking in infection by cytoplasmic negative-strand RNA viruses: paramyxoviruses and beyond

Audsley

Jans

Moseley

2016

Journal of General Virology

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Genome replication and virion production by most negative-sense RNA viruses (NSVs) occurs exclusively in the cytoplasm, but many NSV-expressed proteins undergo active nucleocytoplasmic trafficking via signals that exploit cellular nuclear transport pathways. Nuclear trafficking has been reported both for NSV accessory proteins (including isoforms of the rabies virus phosphoprotein, and V, W and C proteins of paramyxoviruses) and for structural proteins. Trafficking of the former is thought to enable accessory functions in viral modulation of antiviral responses including the type I IFN system, but the intranuclear roles of structural proteins such as nucleocapsid and matrix proteins, which have critical roles in extranuclear replication and viral assembly, are less clear. Nevertheless, nuclear trafficking of matrix protein has been reported to be critical for efficient production of Nipah virus and Respiratory syncytial virus, and nuclear localization of nucleocapsid protein of several morbilliviruses has been linked to mechanisms of immune evasion. Together, these data point to the nucleus as a significant host interface for viral proteins during infection by NSVs with otherwise cytoplasmic life cycles. Importantly, several lines of evidence now suggest that nuclear trafficking of these proteins may be critical to pathogenesis and thus could provide new targets for vaccine development and antiviral therapies.

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Section: Genusmentioning

confidence: 99%

Section: Genusmentioning

confidence: 99%

Section: Genusmentioning

confidence: 99%

Section: Genusmentioning

confidence: 99%

See 2 more Smart Citations

Roles of nuclear trafficking in infection by cytoplasmic negative-strand RNA viruses: paramyxoviruses and beyond

Audsley

Jans

Moseley

2016

Journal of General Virology

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“…L protein functions were mostly predicted from studies on vesicular stomatitis virus. In recent years, reports about RABV were mainly focused on the viral G (5-7), P (8)(9)(10)(11)(12)(13)(14), M (15)(16)(17)(18), and N (9,(19)(20)(21)(22)(23)(24) proteins. However, the work on L protein of RABV has been relatively limited.…”

Section: Introductionmentioning

confidence: 99%

Prokaryotic Expression, Purification, and Polyclonal Antibody Production of a Truncated Recombinant Rabies Virus L Protein

Zhang¹,

Jin²,

Sun³

et al. 2015

Iran J Biotech

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Rabies is an old known disease to mankind in recorded history. Approximately 55,000 individuals die from rabies, caused by rabies virus (RABV), worldwide per annum (1). The ~12 kb genome of RABV is composed of five genes that encode the structural proteins of glycoprotein (G), nucleoprotein (N), phosphoprotein (P), matrix protein (M), and large protein (L) (2). The cDNA of L protein encodes a long polypeptide of 2128 amino acids with a relative molecular weight of 243.09 kDa (silver-haired bat-associated strain (SHBRV)). L protein (named after its large molecular weight) is considered to work with the phosphorylated non-catalytic subunit of viral RNA polymerase, P protein, and as a catalytic subunit of RNA polymerase (3). The polymerase complex of L and P displays all the enzymatic activity of transcription, including co-transcriptional modifications of RNAs, such as capping and polyadenylation, and the initiation and elongation of transcripts (4). L protein functions were mostly predicted from studies on vesicular stomatitis virus. In recent years, reports about RABV were mainly focused on the viral G (5-7), P (8-14), M (15-18), and N (9,19-24) proteins. However, the work on L protein of RABV has been relatively limited. Its potential role in the virus cycle and host factors interacting with L protein remains to be determined.In our previous study (9), we have established 11 mAbs, including three neutralizing antibodies, one anti-nucleoprotein antibody and seven mAbs against phosphoprotein, through a strategy of suckling mouse brain antigen immunization. The large molecular size of L protein and the lack of commercially available antibodies against RABV L protein restricted the progression of RABV L protein research work. Development of an effective antibody is especially Background: Rabies virus (RABV) is a deadly neurotropic virus that causes the disease of rabies in humans and animals. L protein is one of the large structural protein of rabies virus, which displays multiple enzymatic activities, and is required for viral transcription and replication. Objectives: A truncated L protein of Rabies virus is being cloned, expressed and purified to produce relevant polyclonal antibody. Materials and Methods:The gene fragment of L protein of RABV was subcloned into prokaryotic expression vector pET28a and transformed into E. coli Rosetta DE3 host strain. The recombinant L protein of RABV was expressed and characterized by SDS-PAGE and western blot analysis using anti-his tag antibody. Mice were immunized with the purified recombinant L protein, the reaction of the anti-serum was checked by immunofluorescence and dot-blot, respectively. Results:The results of PCR and sequencing confirmed that the fragment of L gene of RABV was successfully cloned into the expression vector. The expression of recombinant L protein fragment induced by IPTG was confirmed by the band of 43 kDa in SDS-PAGE and western blot. The antiserum of purified L protein immunized mice was reacted with RABV infected N2a cells and suckling mouse brai...

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Rabies: Virus and Disease

Nadin-Davis¹

2015

Encyclopedia of Life Sciences

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This article summarises the current literature on rabies and the aetiological agents responsible for this disease, which includes all members of the Lyssavirus genus, of which rabies virus ( RABV ) is the prototype species. Members of the orders Chiroptera and Carnivora serve as maintenance reservoirs for all recognised lyssavirus species and knowledge of the diversity, evolution and geographical range of these viruses is continually improving. Many mammalian species, including humans, are susceptible to spill‐over infections from the maintenance hosts. Despite the availability of efficacious prophylactics, once clinical signs develop, the disease is almost invariably fatal. Effective rabies control requires elimination of the disease from animal reservoirs. In developed countries, parenteral dog vaccination and oral vaccination of wildlife have effectively controlled rabies in many regions but socioeconomic factors limit the application of similar measures in many developing countries where the vast majority of human cases are reported. Better understanding of disease pathogenesis and host immune responses is sought in efforts to develop effective therapeutic interventions. Key Concepts Rabies is a neurological disease that can affect almost all mammals and is almost invariably fatal once clinical signs develop. Rabies is caused by all members of the Lyssavirus genus, bullet‐shaped neurotropic viruses with small RNA genomes, which are normally transmitted in virus‐laden saliva through bites. The vast majority of human rabies cases are the result of exposure to rabid animals. Prevention of human disease is undertaken by a regimen of timely post‐exposure prophylaxis. Distinct Lyssavirus species and variants thereof are maintained in dogs in many developing countries and by several wildlife species including foxes, skunks, raccoons, raccoon dogs, mongooses, jackals and many species of bats throughout much of the world. Through a series of viral–host interactions, rabies virus (RABV) has evolved mechanisms that maintain the neural network required for its propagation and spread within the infected host while avoiding clearance by the host's immune system. Knowledge of the diversity of the Lyssavirus genus is steadily expanding with increased surveillance and development of molecular tools to enable rapid characterisation of new isolates. Current vaccines and biologicals are ineffective against the more diverse members of the genus, thereby indicating that novel reagents with broader efficacy may be required for future disease control. Ultimately, control and eradication of rabies will require elimination of the disease from animal reservoirs through the application of efficacious and cost‐effective methods of animal vaccination.

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A Novel Nuclear Trafficking Module Regulates the Nucleocytoplasmic Localization of the Rabies Virus Interferon Antagonist, P Protein

Cited by 39 publications

References 66 publications

Roles of nuclear trafficking in infection by cytoplasmic negative-strand RNA viruses: paramyxoviruses and beyond

Roles of nuclear trafficking in infection by cytoplasmic negative-strand RNA viruses: paramyxoviruses and beyond

Prokaryotic Expression, Purification, and Polyclonal Antibody Production of a Truncated Recombinant Rabies Virus L Protein

Rabies: Virus and Disease

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