Poxviral Ankyrin Proteins

Herbert, Michael; Squire, C.J.; Mercer, Andrew A.

doi:10.3390/v7020709

Cited by 59 publications

(59 citation statements)

References 146 publications

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“…The combination of ANK repeats and F-box-like domains (called Ank/PRANC) is found in proteins encoded by nearly all poxvirus genera (55). However, in very few cases have the interactions of the poxvirus ANK repeats been determined (56). The rapid equilibrium between existing SCF complexes that can occur following cell lysis (52, 57) may contribute to the difficulty in analysis.…”

Section: Discussionmentioning

confidence: 99%

Vaccinia Virus C9 Ankyrin Repeat/F-Box Protein Is a Newly Identified Antagonist of the Type I Interferon-Induced Antiviral State

Liu

Moss

2018

J Virol

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Type I interferons (IFNs) induce expression of more than 300 cellular genes that provide protection against viruses and other pathogens. For survival, viruses evolved defenses to prevent the IFN response or counteract the IFN-induced antiviral state. However, because viruses and cells coevolved, the dynamic relationship between virus and host is difficult to discern. In the present study, we demonstrated that vaccinia virus with a large deletion near the left end of the genome had a diminished ability to replicate in cells that had been pretreated with beta interferon (IFN-β), suggesting that one or more of the missing 17 open reading frames (ORFs) encode an antagonist of the IFN-induced antiviral state. By systematically deleting groups of ORFs and then individual ORFs, the C9L gene was shown to be required for IFN resistance. Replication of the C9L deletion mutant (vΔC9) was impaired in human cells that had been pretreated with IFN-β. Expression of viral early genes occurred, but subsequent events, including genome uncoating, genome replication, and postreplicative gene expression, were inhibited. Expression of the C9 protein occurred prior to genome replication, consistent with an early role in counteracting the IFN-induced antiviral state. C9 contains six ankyrin repeat motifs and a near C-terminal F-box. Mass spectrometry and immunoblotting identified host proteins that copurified with a functional epitope-tagged C9. The most abundant proteins were components of the SCF (CUL1, SKP1, F-box) and signalosome/deneddylation complexes, which interact with each other, suggesting a possible role in proteolysis of one or more interferon-induced proteins. IMPORTANCE Poxviruses comprise a family of large DNA viruses that replicate in the cytoplasm of vertebrate and insect hosts and cause human and zoonotic diseases. In most cases the primary infection is moderated by innate immune defenses. Vertebrates, including fish, amphibians, reptiles, birds, and mammals, all produce type I interferon homologs. In humans, interferon stimulates the synthesis of more than 300 proteins thought to have roles in host defense. Conversely, viruses have evolved means to thwart the host defenses. We are attempting to deconstruct the established virus-host relationship in order to better understand the molecular mechanisms involved. In the present study, we identified a vaccinia virus gene that prevents interferon-mediated inhibition of very early stages of viral replication and is conserved in orthopoxviruses. The viral protein was shown to interact with host proteins involved in proteolysis, suggesting that vaccinia virus may subvert the cellular apparatus for its own defense.

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Section: Discussionmentioning

confidence: 99%

Vaccinia Virus C9 Ankyrin Repeat/F-Box Protein Is a Newly Identified Antagonist of the Type I Interferon-Induced Antiviral State

Liu

Moss

2018

J Virol

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“…K1 possesses 9 ankyrin repeat domains (ARDs), motifs that mediate proteinprotein interactions (17). While poxviruses encode multiple ARD proteins (18), K1 lacks a C-terminal F box present in nearly all other poxvirus ARDs (18). This suggests that K1 may have physiological properties unique among poxviral ARDs.…”

Section: Abstract K1l Poxvirus Vaccines Vaccinia Virus Viral Pathmentioning

confidence: 99%

Deletion of the K1L Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity

Cruz

Han

Roy

et al. 2017

J Virol

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All viruses strategically alter the antiviral immune response to their benefit. The vaccinia virus (VACV) K1 protein has multiple immunomodulatory effects in tissue culture models of infection, including NF-B antagonism. However, the effect of K1 during animal infection is poorly understood. We determined that a K1L-less vaccinia virus (vΔK1L) was less pathogenic than wild-type VACV in intranasal and intradermal models of infection. Decreased pathogenicity was correlated with diminished virus replication in intranasally infected mice. However, in intradermally inoculated ears, vΔK1L replicated to levels nearly identical to those of VACV, implying that the decreased immune response to vΔK1L infection, not virus replication, dictated lesion size. Several lines of evidence support this theory. First, vΔK1L induced slightly less edema than vK1L, as revealed by histopathology and noninvasive quantitative ultrasound technology (QUS). Second, infiltrating immune cell populations were decreased in vΔK1L-infected ears. Third, cytokine and chemokine gene expression was decreased in vΔK1L-infected ears. While these results identified the biological basis for smaller lesions, they remained puzzling; because K1 antagonizes NF-B in vitro, antiviral gene expression was expected to be higher during vΔK1L infection. Despite these diminished innate immune responses, vΔK1L vaccination induced a protective VACV-specific CD8 ϩ T cell response and protected against a lethal VACV challenge. Thus, vΔK1L is the first vaccinia virus construct reported that caused a muted innate immune gene expression profile and decreased immune cell infiltration in an intradermal model of infection yet still elicited protective immunity. IMPORTANCE The vaccinia virus (VACV) K1 protein inhibits NF-B activation among its other antagonistic functions.A virus lacking K1 (vΔK1L) was predicted to be less pathogenic because it would trigger a more robust antiviral immune response than VACV. Indeed, vΔK1L was less pathogenic in intradermally infected mouse ear pinnae. However, vΔK1L infection unexpectedly elicited dramatically reduced infiltration of innate immune cells into ears. This was likely due to decreased expression of cytokine and chemokine genes in vΔK1L-infected ears. As such, our finding contradicted observations from cell culture systems. Interestingly, vΔK1L conferred protective immunity against lethal VACV challenge. This suggests that the muted immune response triggered during vΔK1L infection remained sufficient to mount an effective protective response. Our results highlight the complexity and unpredictable nature of virus-host interactions, a relationship that must be understood to better comprehend virus pathogenesis or to manipulate viruses for use as vaccines.

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“…Many of the larger poxviruses contain multiple members of this group of proteins (Herbert et al, 2015). The PTPVAus-008 predicted protein has several ankyrin-like motifs within the N-terminal domain and a cellular F-box-like sequence (Mercer et al, 2005) at the C-terminus, an arrangement known as a Pfam PRANC (Pox proteins Repeats of Ankyrin -C terminal) domain.…”

Section: Pteropox Virus Proteins Of Special Interestmentioning

confidence: 99%

“…The PTPV protein is highly diverged from all other poxvirus ankyrin-like proteins, it shares approximately 25 % aa identity with a variety of ankyrin-like proteins from a number of other poxviruses, but it is not possible to determine which is most closely related with any certainty. The poxvirus ankyrin-like proteins are not part of the essential set of core poxvirus proteins and several have been shown to play a role in host range and modulation of the host's antiviral immune response (Herbert et al, 2015).…”

Section: Pteropox Virus Proteins Of Special Interestmentioning

confidence: 99%

Genomic characterization of a novel poxvirus from a flying fox: evidence for a new genus?

O’Dea

Pang

et al. 2016

Journal of General Virology

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The carcass of an Australian little red flying fox (Pteropus scapulatus) which died following entrapment on a fence was submitted to the laboratory for Australian bat lyssavirus exclusion testing, which was negative. During post-mortem, multiple nodules were noted on the wing membranes, and therefore degenerate PCR primers targeting the poxvirus DNA polymerase gene were used to screen for poxviruses. The poxvirus PCR screen was positive and sequencing of the PCR product demonstrated very low, but significant, similarity with the DNA polymerase gene from members of the Poxviridae family. Next-generation sequencing of DNA extracted from the lesions returned a contig of 132 353 nucleotides (nt), which was further extended to produce a near full-length viral genome of 133 492 nt. Analysis of the genome revealed it to be AT-rich with inverted terminal repeats of at least 1314 nt and to contain 143 predicted genes. The genome contains a surprisingly large number (29) of genes not found in other poxviruses, one of which appears to be a homologue of the mammalian TNF-related apoptosis-inducing ligand (TRAIL) gene. Phylogenetic analysis indicates that the poxvirus described here is not closely related to any other poxvirus isolated from bats or other species, and that it likely should be placed in a new genus.

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Poxviral Ankyrin Proteins

Cited by 59 publications

References 146 publications

Vaccinia Virus C9 Ankyrin Repeat/F-Box Protein Is a Newly Identified Antagonist of the Type I Interferon-Induced Antiviral State

Vaccinia Virus C9 Ankyrin Repeat/F-Box Protein Is a Newly Identified Antagonist of the Type I Interferon-Induced Antiviral State

Deletion of the K1L Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity

Genomic characterization of a novel poxvirus from a flying fox: evidence for a new genus?

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