Induction of apoptosis limits cytomegalovirus cross-species infection

Jurak, Igor; Brune, Wolfram

doi:10.1038/sj.emboj.7601133

Cited by 93 publications

(114 citation statements)

References 69 publications

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“…For example, rhesus CMV (RhCMV) can replicate in human cells as well as rhesus cells (2,29). Although in some cases modification of a single gene can allow a virus to cross a species barrier (24,38,40), the limited host range of CMV replication likely involves multiple viral genes that have adapted to support replication in the specific host over millions of years of coevolution. Understanding the changes that have occurred in both host and viral factors has importance for identifying conserved features of the viral life cycle, for assessing the power and limitations of animal models, and for evaluating the risks and barriers to cross-species transmission of viruses.…”

mentioning

confidence: 99%

Species Specificity of Protein Kinase R Antagonism by Cytomegalovirus TRS1 Genes

Child

Brennan

Braggin

et al. 2012

J Virol

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The host antiviral protein kinase R (PKR) has rapidly evolved during primate evolution, likely in response to challenges posed by many different viral antagonists, such as the TRS1 gene of cytomegaloviruses (CMVs). In turn, viral antagonists have adapted to changes in PKR. As a result of this "arms race," modern TRS1 alleles in CMVs may function differently in cells derived from alternative species. We have previously shown that human CMV TRS1 (HuTRS1) blocks the PKR pathway and rescues replication of a vaccinia virus mutant lacking its major PKR antagonist in human cells. We now demonstrate that HuTRS1 does not have these activities in Old World monkey cells. Conversely, the rhesus cytomegalovirus homologue of HuTRS1 (RhTRS1) fulfills these functions in African green monkey cells, but not rhesus or human cells. Both TRS1 proteins bind to double-stranded RNA and, in the cell types in which they can rescue VV⌬E3L replication, they also bind to PKR and prevent phosphorylation of the ␣-subunit of eukaryotic initiation factor 2. However, while HuTRS1 binds to inactive human PKR and prevents its autophosphorylation, RhTRS1 binds to phosphorylated African green monkey PKR. These studies reveal that evolutionary adaptations in this critical host defense protein have altered its binding interface in a way that has resulted in a qualitatively altered mechanism of PKR antagonism by viral TRS1 alleles from different CMVs. These results suggest that PKR antagonism is likely one of the factors that contributes to species specificity of cytomegalovirus replication.

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confidence: 99%

Species Specificity of Protein Kinase R Antagonism by Cytomegalovirus TRS1 Genes

Child

Brennan

Braggin

et al. 2012

J Virol

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“…By using deletion mutants of antiapoptotic genes, apoptosis control has been shown to be an important in vitro determinant of host cell tropism and host species specificity of CMVs, restricting replication to defined cell types of the authentic host (5,29) and preventing replication in cells of a heterologous host species (21).…”

Section: Discussionmentioning

confidence: 99%

Dominant-Negative FADD Rescues the In Vivo Fitness of a Cytomegalovirus Lacking an Antiapoptotic Viral Gene

Čičin‐Šain¹,

Ruzsics²,

Podlech

et al. 2008

J Virol

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“…Southern blots were performed with chemiluminescent detection, as described previously (58). A probe that encompassed the entire UL83 ORF was used to detect viral DNA.…”

Section: Methodsmentioning

confidence: 99%

Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase

Kamil¹,

Hume

Jurak³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Several different families of DNA viruses encode proteins that inactivate the cellular retinoblastoma tumor suppressor protein (pRb), which normally functions to bind E2F transcription factors and restrict expression of genes necessary for cellular processes including DNA replication. Human cytomegalovirus (HCMV) UL97, a protein kinase functionally orthologous to cellular cyclin-dependent kinases, phosphorylates pRb on inactivating residues during HCMV infection. To assess if such phosphorylation is biologically relevant, we tested whether the human papillomavirus type 16 E7 protein, which inactivates pRb family proteins by direct binding and destabilization, could substitute for UL97 during HCMV infection. In the absence of UL97, expression of wild-type E7 protein, but not a mutant E7 unable to bind pRb family proteins, restored E2F-responsive cellular gene expression, late viral gene expression, and viral DNA synthesis to levels normally observed during wildtype virus infection of quiescent cells. UL97-null mutants exhibited more pronounced defects in virus production and DNA synthesis in quiescent cells as compared to serum-fed, cycling cells. E7 expression substantially enhanced infectious virus production in quiescent cells, but did not complement the defects observed during UL97-null virus infection of cycling cells. Thus, a primary role of UL97 is to inactivate pRb family proteins during infection of quiescent cells, and this inactivation likely abets virus replication by induction of cellular E2F-responsive genes. Our findings have implications for human cytomegalovirus disease and for drugs that target UL97.E2F ͉ cyclin-dependent kinase ͉ cell cycle ͉ antiviral drugs ͉ retinoblastoma protein

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Induction of apoptosis limits cytomegalovirus cross-species infection

Cited by 93 publications

References 69 publications

Species Specificity of Protein Kinase R Antagonism by Cytomegalovirus TRS1 Genes

Species Specificity of Protein Kinase R Antagonism by Cytomegalovirus TRS1 Genes

Dominant-Negative FADD Rescues the In Vivo Fitness of a Cytomegalovirus Lacking an Antiapoptotic Viral Gene

Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase

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