Recombinant myxoma virus lacking all poxvirus ankyrin-repeat proteins stimulates multiple cellular anti-viral pathways and exhibits a severe decrease in virulence

Lamb, Stephanie A.; Rahman, Masmudur M.; McFadden, Grant

doi:10.1016/j.virol.2014.06.021

Cited by 13 publications

(14 citation statements)

References 42 publications

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“…The advantage for maintenance of multiple yet subtly different ANK/F-box genes within poxviral genomes is not yet known, however several studies have illustrated the importance of the complete set of ankyrin proteins to a successful infection. This has been shown with myxoma virus where in vivo studies showed increased viral attenuation with knockout of ANK repeat protein M-T5 in comparison to knockouts of the ANK/F-box proteins M148R, M149R, and M150R, [ 84 , 95 , 101 ] reflecting a more potent role for M-T5 in enabling a virulent and systemic infection. A prominent role in virulence and host-range for the ANK repeat proteins is also shown by the characterisation of attenuated strains generated by extensive cell-passage, which frequently and apparently preferentially, result in deletion or mutation of ANK repeat proteins, as shown with attenuated strains of myxoma virus, sheeppox virus, fowlpox virus, and orf virus [ 33 , 101 , 102 , 103 ].…”

Section: Poxviral Ank/f-box Protein Phylogeneticsmentioning

confidence: 84%

“… Interactions of ANK/F-box proteins are known from several poxviral species of the Avipoxviru s (AVPV) [ 117 , 122 ], Parapoxvirus (PPOV) [ 78 ], Orthopoxvirus (OPXV) genera [ 79 , 80 , 81 , 82 , 83 , 106 , 109 , 115 , 116 ], and also the Leporipoxvirus super-group (LSG) genera [ 84 , 101 , 123 ]. These poxviral proteins bind to Skp1 via F-box domains, and in some cases also interact with other cellular proteins or have an effect on other cellular systems, most frequently the canonical activation of NF-κB1 transcriptional regulation.…”

Section: Role Of Poxviral Ankyrin Proteinsmentioning

confidence: 99%

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Poxviral Ankyrin Proteins

Herbert

Squire

Mercer

2015

Viruses

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Multiple repeats of the ankyrin motif (ANK) are ubiquitous throughout the kingdoms of life but are absent from most viruses. The main exception to this is the poxvirus family, and specifically the chordopoxviruses, with ANK repeat proteins present in all but three species from separate genera. The poxviral ANK repeat proteins belong to distinct orthologue groups spread over different species, and align well with the phylogeny of their genera. This distribution throughout the chordopoxviruses indicates these proteins were present in an ancestral vertebrate poxvirus, and have since undergone numerous duplication events. Most poxviral ANK repeat proteins contain an unusual topology of multiple ANK motifs starting at the N-terminus with a C-terminal poxviral homologue of the cellular F-box enabling interaction with the cellular SCF ubiquitin ligase complex. The subtle variations between ANK repeat proteins of individual poxviruses suggest an array of different substrates may be bound by these protein-protein interaction domains and, via the F-box, potentially directed to cellular ubiquitination pathways and possible degradation. Known interaction partners of several of these proteins indicate that the NF-κB coordinated anti-viral response is a key target, whilst some poxviral ANK repeat domains also have an F-box independent affect on viral host-range.

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Section: Poxviral Ank/f-box Protein Phylogeneticsmentioning

confidence: 84%

Section: Role Of Poxviral Ankyrin Proteinsmentioning

confidence: 99%

Poxviral Ankyrin Proteins

Herbert

Squire

Mercer

2015

Viruses

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“…Inoculation of sheep with this variant produced lesions that were reduced in size and resolved more quickly than wild-type lesions, but it was not possible to determine if ov008 contributed to these differences. Future studies may need to consider the deletion of multiple combinations of the 5 ORFV ANK protein-encoding genes (49).…”

Section: Discussionmentioning

confidence: 99%

Ankyrin Repeat Proteins of Orf Virus Influence the Cellular Hypoxia Response Pathway

Chen

Fabrizio

Wilkins

et al. 2017

J Virol

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Hypoxia-inducible factor (HIF) is a transcriptional activator with a central role in regulating cellular responses to hypoxia. It is also emerging as a major target for viral manipulation of the cellular environment. Under normoxic conditions, HIF is tightly suppressed by the activity of oxygen-dependent prolyl and asparaginyl hydroxylases. The asparaginyl hydroxylase active against HIF, factor inhibiting HIF (FIH), has also been shown to hydroxylate some ankyrin repeat (ANK) proteins. Using bioinformatic analysis, we identified the five ANK proteins of the parapoxvirus orf virus (ORFV) as potential substrates of FIH. Consistent with this prediction, coimmunoprecipitation of FIH was detected with each of the ORFV ANK proteins, and for one representative ORFV ANK protein, the interaction was shown to be dependent on the ANK domain. Immunofluorescence studies revealed colocalization of FIH and the viral ANK proteins. In addition, mass spectrometry confirmed that three of the five ORFV ANK proteins are efficiently hydroxylated by FIH in vitro. While FIH levels were unaffected by ORFV infection, transient expression of each of the ORFV ANK proteins resulted in derepression of HIF-1␣ activity in reporter gene assays. Furthermore, ORFV-infected cells showed upregulated HIF target gene expression. Our data suggest that sequestration of FIH by ORFV ANK proteins leads to derepression of HIF activity. These findings reveal a previously unknown mechanism of viral activation of HIF that may extend to other members of the poxvirus family.IMPORTANCE The protein-protein binding motif formed from multiple repeats of the ankyrin motif is common among chordopoxviruses. However, information on the roles of these poxviral ankyrin repeat (ANK) proteins remains limited. Our data indicate that the parapoxvirus orf virus (ORFV) is able to upregulate hypoxia-inducible factor (HIF) target gene expression. This response is mediated by the viral ANK proteins, which sequester the HIF regulator FIH (factor inhibiting HIF). This is the first demonstration of any viral protein interacting directly with FIH. Our data reveal a new mechanism by which viruses reprogram HIF, a master regulator of cellular metabolism, and also show a new role for the ANK family of poxvirus proteins.KEYWORDS factor inhibiting HIF, hypoxia-inducible factor, ankyrin repeat, orf virus, parapoxvirus C ells must be able to respond rapidly to low oxygen levels in order to survive, and triggering of the heterodimeric transcription factor hypoxia-inducible factor (HIF) is key to the cellular adaptation to hypoxia. Under normoxic conditions, the HIF alpha subunits (HIF-1␣ and HIF-2␣) are tightly suppressed by posttranslational modifications, which are relaxed with decreasing oxygen availability. These posttranslational modifi-

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“…Six-week-old female New Zealand White rabbits (weight, 1.8 to 2.0 kg; Charles River Laboratories) were inoculated intradermally with 1,000 focus-forming units (FFU) of MYXV in 100 l sterile phosphate-buffered saline (PBS). The rabbits were then monitored for the course and severity of disease as previously described (27). In short, the animals were scored daily for each of 14 variables: posture, eating and drinking, attitude, hydration, eyes, ears, nose, respiration, heart rate, temperature, weight, feces, primary lesion, and secondary lesions.…”

Section: Methodsmentioning

confidence: 99%

“…New Zealand White rabbits were injected intradermally with 1 ϫ 10 3 FFU of either vGFP (n ϭ 3), vM083 (n ϭ 3), or vM083 invert (n ϭ 3). The course of disease was then monitored daily, as previously described (27) (Fig. 4A).…”

Section: Creation Of Myxv Lacking M083lmentioning

confidence: 99%

Myxoma Virus M083 Is a Virulence Factor Which Mediates Systemic Dissemination

Wolfe

Dunlap

Smith

et al. 2018

J Virol

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Poxviruses are large, DNA viruses whose protein capsid is surrounded by one or more lipid envelopes. Embedded into these lipid envelopes are three conserved viral proteins which are thought to mediate binding of virions to target cells. While the function of these proteins has been studied , their specific roles during the pathogenesis of poxviral disease remain largely unclear. Here we present data demonstrating that the putative chondroitin binding protein M083 from the leporipoxvirus myxoma virus is a significant virulence factor during infection of susceptible rabbits. Removal of M083 results in a reduced capacity of virus to spread beyond the regional lymph nodes and completely eliminates infection-mediated mortality. , removal of M083 results in only minor intracellular replication defects but causes a significant reduction in the ability of myxoma virus to spread from infected epithelial cells onto primary lymphocytes. We hypothesize that the physiological role of M083 is therefore to mediate the spread of myxoma virus onto rabbit lymphocytes, allowing these cells to disseminate virus throughout infected rabbits. Poxviruses represent both a class of human pathogens and potential therapeutic agents for the treatment of human malignancy. Understanding the basic biology of these agents is therefore significant to human health in a variety of ways. While the mechanisms mediating poxviral binding have been well studied , how these mechanisms impact poxviral pathogenesis remains unclear. The current study advances our understanding of how poxviral binding impacts viral pathogenesis by demonstrating that the putative chondroitin binding protein M083 plays a critical role during the pathogenesis of myxoma virus in susceptible rabbits by impacting viral dissemination through changes in the transfer of virions onto primary splenocytes.

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Recombinant myxoma virus lacking all poxvirus ankyrin-repeat proteins stimulates multiple cellular anti-viral pathways and exhibits a severe decrease in virulence

Cited by 13 publications

References 42 publications

Poxviral Ankyrin Proteins

Poxviral Ankyrin Proteins

Ankyrin Repeat Proteins of Orf Virus Influence the Cellular Hypoxia Response Pathway

Myxoma Virus M083 Is a Virulence Factor Which Mediates Systemic Dissemination

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