Identification of sites phosphorylated by the vaccinia virus B1R kinase in viral protein H5R

Brown, Neil G.; Morrice, D Nick; Beaud, Georges; Hardie, Grahame; Leader, David P.

doi:10.1186/1471-2091-1-2

Cited by 16 publications

(3 citation statements)

References 19 publications

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“…Secondly, we posit that B1 may have substrates other than BAF that are also needed for optimal transcription, which are mediating this difference in gene expression. In this regard one possible candidate is the viral H5 protein, which is known to be phosphorylated by B1 and has been linked to transcriptional regulation in other studies (Black et al, 1998, Brown et al, 2000, D'Costa et al, 2008, D'Costa et al, 2010, Kovacs and Moss, 1996). Additional studies will be needed to distinguish between these two possibilities.…”

Section: Discussionmentioning

confidence: 98%

Barrier to autointegration factor (BAF) inhibits vaccinia virus intermediate transcription in the absence of the viral B1 kinase

et al. 2013

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Barrier to autointegration factor (BAF/BANF1) is a cellular DNA-binding protein found in the nucleus and cytoplasm. Cytoplasmic BAF binds to foreign DNA and can act as a defense against vaccinia DNA replication. To evade BAF, vaccinia expresses the B1 kinase, which phosphorylates BAF and blocks its ability to bind DNA. Interestingly, B1 is also needed for viral intermediate gene expression via an unknown mechanism. Therefore, we evaluated the impact of B1-BAF signaling on vaccinia transcription. Strikingly, the decrease in vaccinia transcription caused by loss of B1 can be rescued by depletion of BAF. The repressive action of BAF is greatest on a viral promoter, and is more modest when non-vaccinia promoters are employed, which suggests BAF acts in a gene specific manner. These studies expand our understanding of the role of the B1 kinase during infection and provide the first evidence that BAF is a defense against viral gene expression.

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Section: Discussionmentioning

confidence: 98%

Barrier to autointegration factor (BAF) inhibits vaccinia virus intermediate transcription in the absence of the viral B1 kinase

et al. 2013

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“…The activity of the B1R kinase (VPK1) has kinase activity that has been well characterized (Rempel and Traktman, 1992), and the H5R product is one of the many natural substrates of this enzyme (Brown et al, 2000). Both H5R and B1R co-localize as punctate sites in the cytoplasm that are precursors to sites of viral DNA synthesis (Domi and Beaud, 2000).…”

Section: Potential Molecular Targets In Orthopoxvirus Replication mentioning

confidence: 99%

Orthopoxvirus targets for the development of new antiviral agents

Prichard

Kern

2012

Antiviral Research

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Investments in the development of new drugs for orthopoxvirus infections have fostered new avenues of research, provided an improved understanding of orthopoxvirus biology and yielded new therapies that are currently progressing through clinical trials. These broad-based efforts have also resulted in the identification of new inhibitors of orthopoxvirus replication that target many different stages of viral replication cycle. This review will discuss progress in the development of new anti-poxvirus drugs and the identification of new molecular targets that can be exploited for the development of new inhibitors. The prototype of the orthopoxvirus group is vaccinia virus and its replication cycle will be discussed in detail noting specific viral functions and their associated gene products that have the potential to serve as new targets for drug development. Progress that has been achieved in recent years should yield new drugs for the treatment of these infections and might also reveal new approaches for antiviral drug development with other viruses.

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“…For example, it has been discovered that RACK1 (receptor for activated C kinase) is phosphorylated in a B1 dependent manner, triggering a selective advantage for translation of viral RNAs that is postulated to enhance viral fitness late in infection [23]. Some other known substrates of the B1 kinase include the ribosomal Sa and S2 proteins [24] as well as the viral H5 proteins [14, 25], each of which can be directly phosphorylated by B1 in vitro and is modified in a B1-dependent manner in infected cells. However, although it has been known for some time that these proteins are substrates of B1, whether their phosphorylation by B1 is beneficial during the poxvirus lifecycle remains unclear.…”

Section: Introductionmentioning

confidence: 99%

A poxvirus pseudokinase represses viral DNA replication via a pathway antagonized by its paralog kinase

et al. 2019

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Poxviruses employ sophisticated, but incompletely understood, signaling pathways that engage cellular defense mechanisms and simultaneously ensure viral factors are modulated properly. For example, the vaccinia B1 protein kinase plays a vital role in inactivating the cellular antiviral factor BAF, and likely orchestrates other pathways as well. In this study, we utilized experimental evolution of a B1 deletion virus to perform an unbiased search for suppressor mutations and identify novel pathways involving B1. After several passages of the ΔB1 virus we observed a robust increase in viral titer of the adapted virus. Interestingly, our characterization of the adapted viruses reveals that mutations correlating with a loss of function of the vaccinia B12 pseudokinase provide a striking fitness enhancement to this virus. In support of predictions that reductive evolution is a driver of poxvirus adaptation, this is clear experimental evidence that gene loss can be of significant benefit. Next, we present multiple lines of evidence demonstrating that expression of full length B12 leads to a fitness reduction in viruses with a defect in B1, but has no apparent impact on wild-type virus or other mutant poxviruses. From these data we infer that B12 possesses a potent inhibitory activity that can be masked by the presence of the B1 kinase. Further investigation of B12 attributes revealed that it primarily localizes to the nucleus, a characteristic only rarely found among poxviral proteins. Surprisingly, BAF phosphorylation is reduced under conditions in which B12 is present in infected cells without B1, indicating that B12 may function in part by enhancing antiviral activity of BAF. Together, our studies of B1 and B12 present novel evidence that a paralogous kinase-pseudokinase pair can exhibit a unique epistatic relationship in a virus, perhaps serving to enhance B1 conservation during poxvirus evolution and to orchestrate yet-to-be-discovered nuclear events during infection.

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Identification of sites phosphorylated by the vaccinia virus B1R kinase in viral protein H5R

Cited by 16 publications

References 19 publications

Barrier to autointegration factor (BAF) inhibits vaccinia virus intermediate transcription in the absence of the viral B1 kinase

Barrier to autointegration factor (BAF) inhibits vaccinia virus intermediate transcription in the absence of the viral B1 kinase

Orthopoxvirus targets for the development of new antiviral agents

A poxvirus pseudokinase represses viral DNA replication via a pathway antagonized by its paralog kinase

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