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

• DOI: 10.1371/journal.ppat.1009183
• Publication Date: 2021-01-14T19:53:35Z
• Authors: Chorong Park; Chen Peng; M. Julhasur Rahman; Sherry L. Haller; Loubna Tazi; Greg Brennan; Stefan Rothenburg
• Keywords: Protein kinase R; EIF-2 kinase; Antiviral protein; Orthopoxvirus

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