scholarly journals Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

2020 ◽  
Author(s):  
Chorong Park ◽  
Chen Peng ◽  
M. Julhasur Rahman ◽  
Sherry L. Haller ◽  
Loubna Tazi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Kinase ◽  
Vaccinia Virus ◽  
Related Species ◽  
Translation Initiation Factor ◽  
Virus Species ◽  
Specific Inhibition ◽  
Antiviral Protein ◽  
Closely Related Species ◽  
Species Specific

AbstractThe antiviral protein kinase R (PKR) is an important host restriction factor, which poxviruses must overcome to productively infect host cells. To inhibit PKR, many poxviruses encode a pseudosubstrate mimic of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), designated K3 in vaccinia virus. Although the interaction between PKR and eIF2α is highly conserved, some K3 orthologs were previously shown to inhibit PKR in a species-specific manner. To better define this host range function, we compared the sensitivity of PKR from 17 mammals to inhibition by K3 orthologs from closely related orthopoxviruses. The K3 orthologs showed species-specific inhibition of PKR and exhibited three distinct inhibition profiles. In some cases, PKR from closely related species showed dramatic differences in their sensitivity to K3 orthologs. Vaccinia virus expressing the camelpox virus K3 ortholog replicated more than three orders of magnitude better in human and sheep cells than a virus expressing vaccinia virus K3, but both viruses replicated comparably well in cow cells. Strikingly, in site-directed mutagenesis experiments between the variola virus and camelpox virus K3 orthologs, we found that different amino acid combinations were necessary to mediate improved or diminished inhibition of PKR derived from different host species. Because there is likely a limited number of possible variations in PKR that affect K3-interactions but still maintain PKR/eIF2α interactions, by chance PKR from some potential new hosts may be susceptible to K3-mediated inhibition from a virus it has never previously encountered. We conclude that neither the sensitivity of host proteins to virus inhibition nor the effectiveness of viral immune antagonists can be inferred from their phylogenetic relatedness but must be experimentally determined.Authors summaryMost virus families are composed of large numbers of virus species. However, in general, only a few prototypic viruses are experimentally studied in-depth, and it is often assumed that the obtained results are representative of other viruses in the same family. In order to test this assumption, we compared the sensitivity of the antiviral protein kinase PKR from various mammals to inhibition by multiple orthologs of K3, a PKR inhibitor expressed by several closely related orthopoxviruses. We found strong differences in PKR inhibition by the K3 orthologs, demonstrating that sensitivity to a specific inhibitor was not indicative of broad sensitivity to orthologs of these inhibitors from closely related viruses. We also show that PKR from even closely related species displayed markedly different sensitivities to these poxvirus inhibitors. Furthermore, we identified amino acid residues in these K3 orthologs that are critical for enhanced or decreased PKR inhibition and found that distinct amino acid combinations affected PKRs from various species differently. Our study shows that even closely related inhibitors of an antiviral protein can vary dramatically in their inhibitory potential, and cautions that results from host-virus interaction studies of a prototypic virus genus member cannot necessarily be extrapolated to other viruses in the same genus without experimental verification.

scholarly journals Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

2021 ◽  
Vol 17 (1) ◽  
pp. e1009183
Author(s):  
Chorong Park ◽  
Chen Peng ◽  
M. Julhasur Rahman ◽  
Sherry L. Haller ◽  
Loubna Tazi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Vaccinia Virus ◽  
Host Range ◽  
Translation Initiation Factor ◽  
Host Cells ◽  
Initiation Factor ◽  
Specific Inhibition ◽  
Antiviral Protein ◽  
Range Function ◽  
Species Specific

The antiviral protein kinase R (PKR) is an important host restriction factor, which poxviruses must overcome to productively infect host cells. To inhibit PKR, many poxviruses encode a pseudosubstrate mimic of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), designated K3 in vaccinia virus. Although the interaction between PKR and eIF2α is highly conserved, some K3 orthologs from host-restricted poxviruses were previously shown to inhibit PKR in a species-specific manner. To better define this host range function, we compared the sensitivity of PKR from 17 mammals to inhibition by K3 orthologs from closely related orthopoxviruses, a genus with a generally broader host range. The K3 orthologs showed species-specific inhibition of PKR and exhibited three distinct inhibition profiles. In some cases, PKR from closely related species showed dramatic differences in their sensitivity to K3 orthologs. Vaccinia virus expressing the camelpox virus K3 ortholog replicated more than three orders of magnitude better in human and sheep cells than a virus expressing vaccinia virus K3, but both viruses replicated comparably well in cow cells. Strikingly, in site-directed mutagenesis experiments between the variola virus and camelpox virus K3 orthologs, we found that different amino acid combinations were necessary to mediate improved or diminished inhibition of PKR derived from different host species. Because there is likely a limited number of possible variations in PKR that affect K3-interactions but still maintain PKR/eIF2α interactions, it is possible that by chance PKR from some potential new hosts may be susceptible to K3-mediated inhibition from a virus it has never previously encountered. We conclude that neither the sensitivity of host proteins to virus inhibition nor the effectiveness of viral immune antagonists can be inferred from their phylogenetic relatedness but must be experimentally determined.

scholarly journals Species-specific inhibition of capripoxvirus replication by host antiviral protein kinase R

2018 ◽  
Vol 1438 (1) ◽  
pp. 3-17 ◽  
Author(s):  
Zhixun Zhao ◽  
Xueliang Zhu ◽  
Na Wu ◽  
Xiaodong Qin ◽  
Caiyun Huang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Specific Inhibition ◽  
Antiviral Protein ◽  
Protein Kinase R ◽  
Species Specific

Translation of the yeast transcriptional activator GCN4 is stimulated by purine limitation: implications for activation of the protein kinase GCN2

1993 ◽  
Vol 13 (8) ◽  
pp. 5099-5111
Author(s):  
R J Rolfes ◽  
A G Hinnebusch
Keyword(s):  
Amino Acid ◽  
Protein Kinase ◽  
Transcriptional Activation ◽  
Phosphorylation Site ◽  
Transcriptional Activator ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Single Amino Acid ◽  
Biosynthetic Genes ◽  
Transcriptional Activator Protein

The transcriptional activator protein GCN4 is responsible for increased transcription of more than 30 different amino acid biosynthetic genes in response to starvation for a single amino acid. This induction depends on increased expression of GCN4 at the translational level. We show that starvation for purines also stimulates GCN4 translation by the same mechanism that operates in amino acid-starved cells, being dependent on short upstream open reading frames in the GCN4 mRNA leader, the phosphorylation site in the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2 alpha), the protein kinase GCN2, and translational activators of GCN4 encoded by GCN1 and GCN3. Biochemical experiments show that eIF-2 alpha is phosphorylated in response to purine starvation and that this reaction is completely dependent on GCN2. As expected, derepression of GCN4 in purine-starved cells leads to a substantial increase in HIS4 expression, one of the targets of GCN4 transcriptional activation. gcn mutants that are defective for derepression of amino acid biosynthetic enzymes also exhibit sensitivity to inhibitors of purine biosynthesis, suggesting that derepression of GCN4 is required for maximal expression of one or more purine biosynthetic genes under conditions of purine limitation. Analysis of mRNAs produced from the ADE4, ADE5,7, ADE8, and ADE1 genes indicates that GCN4 stimulates the expression of these genes under conditions of histidine starvation, and it appeared that ADE8 mRNA was also derepressed by GCN4 in purine-starved cells. Our results indicate that the general control response is more global than was previously imagined in terms of the type of nutrient starvation that elicits derepression of GCN4 as well as the range of target genes that depend on GCN4 for transcriptional activation.

scholarly journals Repeated evolution of asymmetric genitalia and right-sided mating behavior in theDrosophila nannopteraspecies group

2019 ◽  
Author(s):  
Andrea Acurio ◽  
Flor T. Rhebergen ◽  
Sarah Paulus ◽  
Virginie Courtier-Orgogozo ◽  
Michael Lang
Keyword(s):  
Related Species ◽  
Current Data ◽  
The Other ◽  
Genital Morphology ◽  
Closely Related Species ◽  
Outgroup Species ◽  
Repeated Evolution ◽  
Drosophila Pachea ◽  
Species Specific ◽  
Group Species

AbstractBackgroundMale genitals have repeatedly evolved left-right asymmetries, and the causes of such evolution remain unclear. TheDrosophila nannopteragroup contains four species, among which three exhibit left-right asymmetries of distinct genital organs. In the most studied species,Drosophila pachea, males display asymmetric genital lobes and they mate right-sided on top of the female. Copulation position of the other species is unknown.ResultsTo assess whether the evolution of genital asymmetry could be linked to the evolution of one-sided mating, we examined phallus morphology and copulation position inD. pacheaand closely related species. The phallus was found to be symmetric in all investigated species exceptD. pachea, which display an asymmetric phallus with a right-sided gonopore, andD. acanthoptera, which harbor an asymmetrically bent phallus. In all examined species, males were found to position themselves symmetrically on top of the female, except inD. pacheaandD. nannoptera, where males mated right-sided, in distinctive, species-specific positions. In addition, the copulation duration was found to be increased innannopteragroup species compared to closely related outgroup species.ConclusionOur study shows that gains, and possibly losses, of asymmetry in genital morphology and mating position have evolved repeatedly in thenannopteragroup. Current data does not allow us to conclude whether genital asymmetry has evolved in response to changes in mating position, or vice versa.

Altitudinal Variation in, and Morphological Divergence between, Three Related Species of Grasshopper, Praxibulus sp., Kosciuscola cognatus and K. usitatus (Orthoptera:Acrididae)

1980 ◽  
Vol 28 (1) ◽  
pp. 103 ◽  
Author(s):  
NA Campbell ◽  
JM Dearn
Keyword(s):  
Related Species ◽  
Character Displacement ◽  
Altitudinal Variation ◽  
Multivariate Statistical ◽  
Closely Related Species ◽  
Genetic Changes ◽  
Parallel Change ◽  
Variable Character ◽  
Multivariate Statistical Approach ◽  
Species Specific

Morphological variation between and within the closely related species Praxibuius sp.. Kosciuscola cognatus and K. usiratus has been examined along three independent altitudinal transects, by a multivariate statistical approach. The analyses, which were restricted to males. show that there is complete morphological separation between the three species. Moreover. there are species-specific patterns of character correlation which are consistent and relatively invariant within species, and do not exhibit altitudinal variation. The results suggest that there exist both distinct invariant species-specific character patterns and variable character patterns showing intraspecific variation. It is concluded that speciation in these grasshoppers could have involved genetic changes quite distinct from those involved in local intraspecific adaptation. Two further results are: first. evidence has been obtained for character displacement between Kosciuscola cognaius and Praxibulus sp. in an area of extensive sympatry: second. populations of K. cognatus along one transect, with a karyotype intermediate between typical K. cognatus and X usiiatus, show a parallel change in morphology towards that characteristic of K. usiiatus.

scholarly journals Activation of Antiviral Protein Kinase Leads to Immunoglobulin E Class Switching in Human B Cells

1998 ◽  
Vol 72 (2) ◽  
pp. 1171-1176 ◽  
Author(s):  
Kelly J. Rager ◽  
Jeffrey O. Langland ◽  
Bertram L. Jacobs ◽  
David Proud ◽  
David G. Marsh ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Viral Infection ◽  
Vaccinia Virus ◽  
Viral Infections ◽  
Germ Line ◽  
Immunoglobulin E ◽  
Class Switching ◽  
Antiviral Protein ◽  
Asthma And Allergy

ABSTRACT An epidemiologic association between viral infections and the onset of asthma and allergy has been documented. Also, evidence from animal and human studies has suggested an increase in antigen-specific immunoglobulin E (IgE) production during viral infections, and elevated levels of IgE are characteristic of human asthma and allergy. Here, we provide molecular evidence for the roles of viral infection and of activation of the antiviral protein kinase (PKR) (double-stranded-RNA [dsRNA]-activated protein kinase) in the induction of IgE class switching. The presence of dsRNA, a known component of viral infection and an activator of PKR, induced IgE class switching as detected by the expression of germ line ɛ in the human Ramos B-cell line. Furthermore, dsRNA treatment of Ramos cells resulted in the activation of PKR and in vivo activation of the NF-κB complex. Interestingly, infection of Ramos cells with rhinovirus (common cold virus) serotypes 14 and 16 resulted in the induction of germ line ɛ expression. To further evaluate the role of PKR in the viral induction of IgE class switching, we infected Ramos cells with two different vaccinia virus (cowpox virus) strains. Infection with wild-type vaccinia virus failed to induce germ line ɛ expression; however, a deletion mutant of vaccinia virus (VP1080) lacking the PKR-inhibitory polypeptide E3L induced the expression of germ line ɛ. Collectively, the results of our study define a common molecular mechanism underlying the role of viral infections in IgE class switching and subsequent induction of IgE-mediated disorders such as allergy and asthma.

scholarly journals Excessive Parallelism in Protein Evolution of Lake Baikal Amphipod Species Flock

2020 ◽  
Vol 12 (9) ◽  
pp. 1493-1503
Author(s):  
Valentina Burskaia ◽  
Sergey Naumenko ◽  
Mikhail Schelkunov ◽  
Daria Bedulina ◽  
Tatyana Neretina ◽  
...  
Keyword(s):  
Amino Acid ◽  
Lake Baikal ◽  
Related Species ◽  
Parallel Evolution ◽  
Amino Acid Level ◽  
Species Flock ◽  
Amphipod Species ◽  
Closely Related Species ◽  
Epistatic Interactions ◽  
Synonymous Sites

Abstract Repeated emergence of similar adaptations is often explained by parallel evolution of underlying genes. However, evidence of parallel evolution at amino acid level is limited. When the analyzed species are highly divergent, this can be due to epistatic interactions underlying the dynamic nature of the amino acid preferences: The same amino acid substitution may have different phenotypic effects on different genetic backgrounds. Distantly related species also often inhabit radically different environments, which makes the emergence of parallel adaptations less likely. Here, we hypothesize that parallel molecular adaptations are more prevalent between closely related species. We analyze the rate of parallel evolution in genome-size sets of orthologous genes in three groups of species with widely ranging levels of divergence: 46 species of the relatively recent lake Baikal amphipod radiation, a species flock of very closely related cichlids, and a set of significantly more divergent vertebrates. Strikingly, in genes of amphipods, the rate of parallel substitutions at nonsynonymous sites exceeded that at synonymous sites, suggesting rampant selection driving parallel adaptation. At sites of parallel substitutions, the intraspecies polymorphism is low, suggesting that parallelism has been driven by positive selection and is therefore adaptive. By contrast, in cichlids, the rate of nonsynonymous parallel evolution was similar to that at synonymous sites, whereas in vertebrates, this rate was lower than that at synonymous sites, indicating that in these groups of species, parallel substitutions are mainly fixed by drift.

Review of the leafhopper genus Anaceratagallia Zachvatkin, 1946 (Homoptera: Auchenorrhyncha: Cicadellidae: Megophthalminae: Agalliini) from Russia, Kazakhstan, and Central Asia

Zootaxa ◽  
2020 ◽  
Vol 4821 (2) ◽  
pp. 250-276
Author(s):  
DMITRI YU. TISHECHKIN
Keyword(s):  
Central Asia ◽  
Related Species ◽  
Male Genitalia ◽  
Comparative Investigation ◽  
Allopatric Speciation ◽  
Closely Related Species ◽  
New Synonyms ◽  
Male Calling ◽  
Species Specific

In Russia, Kazakhstan, and Central Asia the genus Anaceratagallia includes 14 species from two subgenera; all species except one belong to the nominotypical subgenus and can be classified into four groups according to the structure of male genitalia. The illustrated descriptions for all species are given, with male calling signal oscillograms provided for nine species. Ten new synonyms are established. Comparative investigation of morphological and acoustic characters of Anaceratagallia species showed that small differences in the structure of male genitalia and 2nd abdominal apodemes are not species-specific traits. All species studied in nature appeared to be polyphagous feeding on different species of herbaceous dicotyledons. It is assumed that closely related species within each group of the subgenus Anaceratagallia arose as a result of allopatric speciation and became secondarily sympatric due to subsequent range expansions.

Mutations activating the yeast eIF-2 alpha kinase GCN2: isolation of alleles altering the domain related to histidyl-tRNA synthetases

1992 ◽  
Vol 12 (12) ◽  
pp. 5801-5815
Author(s):  
M Ramirez ◽  
R C Wek ◽  
C R Vazquez de Aldana ◽  
B M Jackson ◽  
B Freeman ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Kinase ◽  
Translation Initiation ◽  
Trna Synthetase ◽  
Amino Acid Starvation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Atp Binding ◽  
Sequence Motif ◽  
Trna Synthetases

The protein kinase GCN2 stimulates expression of the yeast transcriptional activator GCN4 at the translational level by phosphorylating the alpha subunit of translation initiation factor 2 (eIF-2 alpha) in amino acid-starved cells. Phosphorylation of eIF-2 alpha reduces its activity, allowing ribosomes to bypass short open reading frames present in the GCN4 mRNA leader and initiate translation at the GCN4 start codon. We describe here 17 dominant GCN2 mutations that lead to derepression of GCN4 expression in the absence of amino acid starvation. Seven of these GCN2c alleles map in the protein kinase moiety, and two in this group alter the presumed ATP-binding domain, suggesting that ATP binding is a regulated aspect of GCN2 function. Six GCN2c alleles map in a region related to histidyl-tRNA synthetases, and two in this group alter a sequence motif conserved among class II aminoacyl-tRNA synthetases that directly interacts with the acceptor stem of tRNA. These results support the idea that GCN2 kinase function is activated under starvation conditions by binding uncharged tRNA to the domain related to histidyl-tRNA synthetase. The remaining GCN2c alleles map at the extreme C terminus, a domain required for ribosome association of the protein. Representative mutations in each domain were shown to depend on the phosphorylation site in eIF-2 alpha for their effects on GCN4 expression and to increase the level of eIF-2 alpha phosphorylation in the absence of amino acid starvation. Synthetic GCN2c double mutations show greater derepression of GCN4 expression than the parental single mutations, and they have a slow-growth phenotype that we attribute to inhibition of general translation initiation. The phenotypes of the GCN2c alleles are dependent on GCN1 and GCN3, indicating that these two positive regulators of GCN4 expression mediate the inhibitory effects on translation initiation associated with activation of the yeast eIF-2 alpha kinase GCN2.

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