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dc.contributor.authorLinville, Alexandria C
dc.contributor.authorRico, Amber B
dc.contributor.authorTeague, Helena
dc.contributor.authorBinsted, Lucy E
dc.contributor.authorSmith, Geoffrey
dc.contributor.authorAlbarnaz, Jonas D
dc.contributor.authorWiebe, Matthew S
dc.date.accessioned2022-06-12T01:06:47Z
dc.date.available2022-06-12T01:06:47Z
dc.date.issued2022-06-08
dc.identifier.issn0022-538X
dc.identifier.other35543552
dc.identifier.otherPMC9175622
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338026
dc.description.abstractPoxvirus proteins remodel signaling throughout the cell by targeting host enzymes for inhibition and redirection. Recently, it was discovered that early in infection the vaccinia virus (VACV) B12 pseudokinase copurifies with the cellular kinase VRK1, a proviral factor, in the nucleus. Although the formation of this complex correlates with inhibition of cytoplasmic VACV DNA replication and likely has other downstream signaling consequences, the molecular mechanisms involved are poorly understood. Here, we further characterize how B12 and VRK1 regulate one another during poxvirus infection. First, we demonstrate that B12 is stabilized in the presence of VRK1 and that VRK1 and B12 coinfluence their respective solubility and subcellular localization. In this regard, we find that B12 promotes VRK1 colocalization with cellular DNA during mitosis and that B12 and VRK1 may be tethered cooperatively to chromatin. Next, we observe that the C-terminal tail of VRK1 is unnecessary for B12-VRK1 complex formation or its proviral activity. Interestingly, we identify a point mutation of B12 capable of abrogating interaction with VRK1 and which renders B12 nonrepressive during infection. Lastly, we investigated the influence of B12 on the host factor BAF and antiviral signaling pathways and find that B12 triggers redistribution of BAF from the cytoplasm to the nucleus. In addition, B12 increases DNA-induced innate immune signaling, revealing a new functional consequence of the B12 pseudokinase. Together, this study characterizes the multifaceted roles B12 plays during poxvirus infection that impact VRK1, BAF, and innate immune signaling. IMPORTANCE Protein pseudokinases comprise a considerable fraction of the human kinome, as well as other forms of life. Recent studies have demonstrated that their lack of key catalytic residues compared to their kinase counterparts does not negate their ability to intersect with molecular signal transduction. While the multifaceted roles pseudokinases can play are known, their contribution to virus infection remains understudied. Here, we further characterize the mechanism of how the VACV B12 pseudokinase and human VRK1 kinase regulate one another in the nucleus during poxvirus infection and inhibit VACV DNA replication. We find that B12 disrupts regulation of VRK1 and its downstream target BAF, while also enhancing DNA-dependent innate immune signaling. Combined with previous data, these studies contribute to the growing field of nuclear pathways targeted by poxviruses and provide evidence of unexplored roles of B12 in the activation of antiviral immunity.
dc.languageeng
dc.publisherAmerican Society for Microbiology
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 0113724
dc.sourceessn: 1098-5514
dc.subjectPoxvirus
dc.subjectProtein kinases
dc.subjectinnate immunity
dc.subjectVaccinia
dc.subjectBaf
dc.subjectHumans
dc.subjectPoxviridae
dc.subjectVaccinia virus
dc.subjectPoxviridae Infections
dc.subjectIntracellular Signaling Peptides and Proteins
dc.subjectDNA
dc.subjectAntiviral Agents
dc.subjectSignal Transduction
dc.subjectPhosphorylation
dc.subjectImmunity, Innate
dc.subjectProtein Serine-Threonine Kinases
dc.titleDysregulation of Cellular VRK1, BAF, and Innate Immune Signaling by the Vaccinia Virus B12 Pseudokinase.
dc.typeArticle
dc.date.updated2022-06-12T01:06:47Z
prism.issueIdentifier11
prism.publicationNameJ Virol
prism.volume96
dc.identifier.doi10.17863/CAM.85431
dcterms.dateAccepted2022-04-18
rioxxterms.versionofrecord10.1128/jvi.00398-22
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidSmith, Geoffrey [0000-0002-3730-9955]
dc.contributor.orcidWiebe, Matthew S [0000-0001-6337-6556]
dc.identifier.eissn1098-5514
pubs.funder-project-idWellcome Trust (090315/Z/09/Z)
pubs.funder-project-idWellcome Trust (203778/Z/16/Z)
cam.issuedOnline2022-05-11


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International