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

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 v...

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Autores principales: Park, Chorong, Peng, Chen, Rahman, M. Julhasur, Haller, Sherry L., Tazi, Loubna, Brennan, Greg, Rothenburg, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840043/
https://www.ncbi.nlm.nih.gov/pubmed/33444388
http://dx.doi.org/10.1371/journal.ppat.1009183
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author Park, Chorong
Peng, Chen
Rahman, M. Julhasur
Haller, Sherry L.
Tazi, Loubna
Brennan, Greg
Rothenburg, Stefan
author_facet Park, Chorong
Peng, Chen
Rahman, M. Julhasur
Haller, Sherry L.
Tazi, Loubna
Brennan, Greg
Rothenburg, Stefan
author_sort Park, Chorong
collection PubMed
description 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.
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spelling pubmed-78400432021-02-02 Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR Park, Chorong Peng, Chen Rahman, M. Julhasur Haller, Sherry L. Tazi, Loubna Brennan, Greg Rothenburg, Stefan PLoS Pathog Research Article 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. Public Library of Science 2021-01-14 /pmc/articles/PMC7840043/ /pubmed/33444388 http://dx.doi.org/10.1371/journal.ppat.1009183 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Park, Chorong
Peng, Chen
Rahman, M. Julhasur
Haller, Sherry L.
Tazi, Loubna
Brennan, Greg
Rothenburg, Stefan
Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR
title Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR
title_full Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR
title_fullStr Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR
title_full_unstemmed Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR
title_short Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR
title_sort orthopoxvirus k3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase pkr
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840043/
https://www.ncbi.nlm.nih.gov/pubmed/33444388
http://dx.doi.org/10.1371/journal.ppat.1009183
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