Deletion of the Vaccinia Virus B1 Kinase Reveals Essential Functions of This Enzyme Complemented Partly by the Homologous Cellular Kinase VRK2

Olson, Annabel T.; Rico, Amber B.; Wang, Zhigang; Delhon, G.; Wiebe, Matthew S.

doi:10.1128/jvi.00635-17

Cited by 16 publications

(37 citation statements)

References 45 publications

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“…In fact, this protein has been recognized for its involvement in the viral infection processes [157, 158]. It has long been hypothesized that brain inflammation contributes to pathological alterations in SCZ, and a recent study indicates that Vrk2 can reduce the transcriptional response to interleukin-1b (IL-1b, encoded by IL-1B ) [115], a cytokine involved in inflammatory activity and psychiatric disorders [159-161].…”

Section: Functions Of Vrk2 In the Neurological Systemmentioning

confidence: 99%

VRK2, a Candidate Gene for Psychiatric and Neurological Disorders

Yue

2018

Complex Psychiatry

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Recent large-scale genetic approaches, such as genome-wide association studies, have identified multiple genetic variations that contribute to the risk of mental illnesses, among which single nucleotide polymorphisms (SNPs) within or near the vaccinia related kinase 2 (VRK2) gene have gained consistent support for their correlations with multiple psychiatric and neurological disorders including schizophrenia (SCZ), major depressive disorder (MDD), and genetic generalized epilepsy. For instance, the genetic variant rs1518395 in VRK2 showed genome-wide significant associations with SCZ (35,476 cases and 46,839 controls, p = 3.43 × 10^–8) and MDD (130,620 cases and 347,620 controls, p = 4.32 × 10^–12) in European populations. This SNP was also genome-wide significantly associated with SCZ in Han Chinese population (12,083 cases and 24,097 controls, p = 3.78 × 10^–13), and all associations were in the same direction of allelic effects. These studies highlight the potential roles of VRK2 in the central nervous system, and this gene therefore might be a good candidate to investigate the shared genetic and molecular basis between SCZ and MDD, as it is one of the few genes known to show genome-wide significant associations with both illnesses. Furthermore, the VRK2 gene was found to be involved in multiple other congenital deficits related to the malfunction of neurodevelopment, adding further support for the involvement of this gene in the pathogenesis of these neurological and psychiatric illnesses. While the precise function of VRK2 in these conditions remains unclear, preliminary evidence suggests that it may affect neuronal proliferation and migration via interacting with multiple essential signaling pathways involving other susceptibility genes/proteins for psychiatric disorders. Here, we have reviewed the recent progress of genetic and molecular studies of VRK2, with an emphasis on its role in psychiatric illnesses and neurological functions. We believe that attention to this important gene is necessary, and further investigations of VRK2 may provide hints into the underlying mechanisms of SCZ and MDD.

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Section: Functions Of Vrk2 In the Neurological Systemmentioning

confidence: 99%

VRK2, a Candidate Gene for Psychiatric and Neurological Disorders

Yue

2018

Complex Psychiatry

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“…The vaccinia virus B1 kinase is expressed early during infection and promotes multiple facets of the vaccinia virus life cycle (6)(7)(8)(9)(10)(11). Genetic and biochemical investigations of the B1 kinase using temperature-sensitive viruses (7,9,(12)(13)(14) and a B1 deletion mutant virus (6,15) have provided insights into the essential roles played by B1 during vaccinia virus infection. Importantly, the severity of the phenotype resulting from B1 mutant virus infections in those studies was cell type dependent and was limited at the stages of DNA replication (13)(14)(15)(16)(17), intermediate transcription (7,11), or morphogenesis (9), signifying a function for B1 in promoting viral replication at each of these steps.…”

mentioning

confidence: 99%

“…Genetic and biochemical investigations of the B1 kinase using temperature-sensitive viruses (7,9,(12)(13)(14) and a B1 deletion mutant virus (6,15) have provided insights into the essential roles played by B1 during vaccinia virus infection. Importantly, the severity of the phenotype resulting from B1 mutant virus infections in those studies was cell type dependent and was limited at the stages of DNA replication (13)(14)(15)(16)(17), intermediate transcription (7,11), or morphogenesis (9), signifying a function for B1 in promoting viral replication at each of these steps. Explication of B1 mutant vaccinia virus infections demonstrated that B1 promotes replication by phosphorylating and inactivating the cellular host defense protein barrier to autointegration factor (BAF; encoded by the BANF1 gene) (7,8,16), which is otherwise capable of binding the viral genome and impeding its replication and transcription.…”

mentioning

confidence: 99%

“…While B1 has been shown to be critical for vaccinia virus replication in every cell line tested, the cell type-dependent severity of the mutant B1 phenotype indicated that the functional activity of B1 and/or its substrates may be impacted by complementing host kinases. Indeed, a group of three conserved cellular Ser/Thr kinases, the vaccinia virus-related kinases (VRKs) (21,22), exhibit similarity (33 to 41% amino acid identity) to the vaccinia virus B1 kinase (2) and can complement loss of B1 function (15,23,24). For example, seminal studies demonstrated that the expression of VRK1 from the viral genome can rescue a B1 mutant phenotype (23), paving the way for the discovery that VRK1 and B1 both regulate BAF.…”

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confidence: 99%

“…For example, seminal studies demonstrated that the expression of VRK1 from the viral genome can rescue a B1 mutant phenotype (23), paving the way for the discovery that VRK1 and B1 both regulate BAF. More recently, studies in VRK knockout (KO) cell lines demonstrated that endogenous VRK2 can complement loss of B1 during ΔB1 virus DNA replication (15). Importantly, although the replication block resulting from B1 and VRK2 deletion inhibited the vaccinia virus life cycle at the stage of DNA replication, BAF depletion only modestly rescued ΔB1 virus DNA replication in VRK2 knockout (VRK2KO) cell lines.…”

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confidence: 99%

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The Vaccinia Virus (VACV) B1 and Cellular VRK2 Kinases Promote VACV Replication Factory Formation through Phosphorylation-Dependent Inhibition of VACV B12

Rico

Wang

Olson

et al. 2019

J Virol

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Comparative examination of viral and host protein homologs reveals novel mechanisms governing downstream signaling effectors of both cellular and viral origin. The vaccinia virus B1 protein kinase is involved in promoting multiple facets of the virus life cycle and is a homolog of three conserved cellular enzymes called vaccinia virus-related kinases (VRKs). Recent evidence indicates that B1 and VRK2 mediate a common pathway that is largely uncharacterized but appears independent of previous VRK substrates. Interestingly, separate studies described a novel role for B1 in inhibiting vaccinia virus protein B12, which otherwise impedes an early event in the viral lifecycle. Herein, we characterize the B1/VRK2 signaling axis to better understand their shared functions. First, we demonstrate that vaccinia virus uniquely requires VRK2 for viral replication in the absence of B1, unlike other DNA viruses. Employing loss-of-function analysis, we demonstrate that vaccinia virus’s dependence on VRK2 is only observed in the presence of B12, suggesting that B1 and VRK2 share a pathway controlling B12. Moreover, we substantiate a B1/VRK2/B12 signaling axis by examining coprecipitation of B12 by B1 and VRK2. Employing execution point analysis, we reveal that virus replication proceeds normally through early protein translation and uncoating but stalls at replication factory formation in the presence of B12 activity. Finally, structure/function analyses of B1 and VRK2 demonstrate that enzymatic activity is essential for B1 or VRK2 to inhibit B12. Together, these data provide novel insights into B1/VRK signaling coregulation and support a model in which these enzymes modulate B12 in a phosphorylation-dependent manner. IMPORTANCE Constraints placed on viral genome size require that these pathogens must employ sophisticated, yet parsimonious mechanisms to effectively integrate with host cell signaling pathways. Poxviruses are no exception and employ several methods to balance these goals, including encoding single proteins that impact multiple downstream pathways. This study focuses on the vaccinia virus B1 protein kinase, an enzyme that promotes virus replication at multiple phases of the viral lifecycle. Herein, we demonstrate that in addition to its previously characterized functions, B1 inhibits vaccinia virus B12 protein via a phosphorylation-dependent mechanism and that this function of B1 can be complemented by the cellular B1 homolog VRK2. Combined with previous data implicating functional overlap between B1 and an additional cellular B1 homolog, VRK1, these data provide evidence of how poxviruses can be multifaceted in their mimicry of cellular proteins through the consolidation of functions of both VRK1 and VRK2 within the viral B1 protein kinase.

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