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Yin, Peng; Keirstead, Natalie D.; Broering, Teresa J.; Arnold, Michelle M.; Parker, John S. L.; Nibert, Max L.; Coombs, Kevin M.

doi:10.1186/1743-422x-1-6

Cited by 44 publications

(37 citation statements)

References 68 publications

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“…However, reovirus is a nonenveloped virus, and 2 does not span cellular membranes, suggesting that it must stimulate Syk by a previously undescribed mechanism. The structure of 2 has not been determined, but the ITAM identified here is located directly adjacent to a 2 sequence predicted to have the greatest likelihood of localization to the protein surface, a finding consistent with a model of direct interaction between the 2 ITAM and the Syk SH2 domain (36).…”

Section: Discussionmentioning

confidence: 49%

“…Notably, both FLAG-2 and FLAG-2-YYFF were tyrosine phosphorylated, providing the first evidence that 2 is a phosphorylated protein. However, 2 contains 30 tyrosines (36), and the significant phos- phorylation of FLAG-2-YYFF suggests that residues outside the ITAM sequence are phosphorylated. This abundant 2 phosphorylation precluded detection of possible decreased phosphorylation in FLAG-2-YYFF relative to FLAG-2, leaving the status of tyrosine phosphorylation in the 2 ITAM sequence unclear.…”

Section: Resultsmentioning

confidence: 99%

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An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB, Induction of Beta Interferon, and Viral Spread

Stebbing

Irvin

Rivera-Serrano

et al. 2014

J Virol

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Immunoreceptor tyrosine-based activation motifs (ITAMs) are signaling domains located within the cytoplasmic tails of many transmembrane receptors and associated adaptor proteins that mediate immune cell activation. ITAMs also have been identified in the cytoplasmic tails of some enveloped virus glycoproteins. Here, we identified ITAM sequences in three mammalian reovirus proteins: 2, 2, and 2. We demonstrate for the first time that 2 is phosphorylated, contains a functional ITAM, and activates NF-B. Specifically, 2 and NS recruit the ITAM-signaling intermediate Syk to cytoplasmic viral factories and this recruitment requires the 2 ITAM. Moreover, both the 2 ITAM and Syk are required for maximal 2 activation of NF-B. A mutant virus lacking the 2 ITAM activates NF-B less efficiently and induces lower levels of the downstream antiviral cytokine beta interferon (IFN-␤) than does wild-type virus despite similar replication. Notably, the consequences of these 2 ITAM effects are cell type specific. In fibroblasts where NF-B is required for reovirus-induced apoptosis, the 2 ITAM is advantageous for viral spread and enhances viral fitness. Conversely, in cardiac myocytes where the IFN response is critical for antiviral protection and NF-B is not required for apoptosis, the 2 ITAM stimulates cellular defense mechanisms and diminishes viral fitness. Together, these results suggest that the cell type-specific effect of the 2 ITAM on viral spread reflects the cell type-specific effects of NF-B and IFN-␤. This first demonstration of a functional ITAM in a nonenveloped virus presents a new mechanism for viral ITAM-mediated signaling with likely organ-specific consequences in the host.

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Section: Discussionmentioning

confidence: 49%

Section: Resultsmentioning

confidence: 99%

An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB, Induction of Beta Interferon, and Viral Spread

Stebbing

Irvin

Rivera-Serrano

et al. 2014

J Virol

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“…The viral r1 protein is unique to each prototype of mammalian reovirus and determines the serotype and is also the major genetic determinant of neurovirulence in infected mice [20]. We determined the full-length sequences of the reovirus S2, S3 and S4 genes by the 3¢ end ligation method [6,14] described in Materials and Methods, but were unable to obtain fulllength sequence of the T2W S1 gene by this method.…”

Section: Resultsmentioning

confidence: 99%

“…Viral genomic RNA was separated on a 1.2% agarose gel and the viral S RNA fragments were collected and purified with Qiagen columns. 3¢ end ligation was performed as previously reported [6,14]. Briefly, the oligonucleotide 3¢L1 (Table 1) was ligated to the 3¢ ends of reovirus S genes with T4 RNA ligase at 37°C overnight according to the manufacturer's directions (Roche).…”

Section: Viral Rna Preparation and 3¢ End Ligationmentioning

confidence: 99%

“…Reovirus strains can be grouped into three serotypes, which are differentiated by the capacity of type-specific antisera to neutralize virus infectivity and inhibit hemagglutination [2,3], represented by three commonly studied prototype isolates: type 1 Lang (T1L), type 2 Jones (T2J) and type 3 Dearing (T3D). The whole genome sequences of all 3 prototype reovirus strains have been reported [4][5][6]. The lengths of 6 of the 10 genome segments (L1, L3, M2, S2, S3 and S4) are invariant among the three prototype isolates.…”

Section: Introductionmentioning

confidence: 98%

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Genetic characterization of a new mammalian reovirus, type 2 Winnipeg (T2W)

Hermann

Coombs

2006

Virus Genes

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We previously described isolation of a potentially new reovirus strain from the central nervous system of an 8-week-old female infant with a history of active varicella, oral thrush, hypoalbuminemia, intermittent fevers, diarrhea and feeding intolerance [Hermann et al., Ped. Inf. Dis J. 23, 373 (2004)]. This reovirus strain was tentatively identified as a member of the serotype 2 group by virus neutralization and RNA-gel electrophoresis studies and has been named type 2 Winnipeg (T2W). For this study we determined the nucleotide sequences of the T2W S1, S2, S3 and S4 genome segments to allow molecular comparison with other reoviruses. Comparative segment alignments of T2W S1 gene sequence with other reovirus S1 sequences showed T2W belongs to reovirus serotype 2. T2W S1 is most similar to the S1 genes of reovirus strains T2/Human/Netherlands/1,984 and T2/Human/Netherlands/1,973 with nucleotide identity >93%. The T2W S2 gene showed highest identity to reovirus T1 Lang S2 (approximately 75%). The T2W S3 gene showed highest identity to the S3 gene of T3/Human/Netherlands/1,983 (approximately 74%), and the T2W S4 gene showed highest identity to the T2 Jones S4 gene (approximately 73%). Pairwise protein comparisons between T2W sigma proteins and all available reovirus sigma proteins ranged from <21% identity for the sigma1 comparisons to more than 95% identity for sigma2 comparisons. The predicted T2W sigma1, sigma2 and sigma3 protein sequences were confirmed by mass spectrometry.

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Reoviruses

Coombs

2011

Encyclopedia of Life Sciences

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Reoviruses are infectious agents, transmitted by respiratory and faecal – oral routes. The mammalian reoviruses (MRV) are the prototypic viruses of a large group of infectious agents, many of which are highly pathogenic to their natural hosts, although the MRV are not significant human pathogens. The MRV are distinguished by having a genome of 10 segments of double‐stranded ribonucleic acid (dsRNA) that is located inside a double‐layered, spherical nonenveloped protein capsid. The capsid is incompletely uncoated during viral replication and the inner capsid (core) serves as an enzymatic ‘machine’ producing progeny mRNA. The virus is being studied as a potential anticancer oncolytic therapy. The virus is also quite stable and therefore is useful as a ‘bio‐indicator’ for assessing water quality and wastewater disinfection. Key Concepts: The reoviruses have served as models for understanding biology of double‐stranded RNA and RNA transcription signals. Mammalian reoviruses are ubiquitous in nature and virtually all mammalian species are infected by these agents. Reoviruses have a segmented genome and different genome segments from different virus types can mix to create hybrid progeny viruses called ‘reassortants’. Although most family members are highly pathogenic in their natural hosts, mammalian reoviruses are generally harmless to humans. Because the viruses are generally harmless, and because they are unusually stable, they serve beneficially as anticancer agents and for monitoring water and wastewater disinfection.

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Cited by 44 publications

References 68 publications

An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB, Induction of Beta Interferon, and Viral Spread

An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB, Induction of Beta Interferon, and Viral Spread

Genetic characterization of a new mammalian reovirus, type 2 Winnipeg (T2W)

Reoviruses

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