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Peer-reviewedCC BY 4.0Journal of Virology

Insights into molecular mechanisms of poxvirus evolution and host range through studies of poxvirus inhibitors of protein kinase R

  • Stefan Rothenburg1
  • Dewi Megawati2
  • Ryan Bruneau3
  • Loubna Tazi1
  1. 1Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, California, USA
  2. 2Department of Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Warmadewa University, Bali, Indonesia
  3. 3Biotechnology and Bioengineering, Sandia National Laboratories, Livermore, California, USA
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Abstract

Protein kinase R (PKR) acts both as a sensor for virus infections, by detecting double-stranded (ds) RNA, and as an antiviral effector by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). Consequently, viruses have evolved many mechanisms to evade this potent antiviral protein, which in turn led to the fast evolution of PKR. There is an emerging understanding that these molecular arms races have important implications for the virulence and host range of viruses, which was in part propelled by research on PKR and poxvirus PKR inhibitors. At least four direct PKR pathway inhibitors, which either prevent PKR activation, inhibit interaction with eIF2α, or reverse eIF2α phosphorylation, evolved independently in different poxvirus clades, while poxvirus decapping enzymes provide another mechanism to subdue PKR activation via the reduction of dsRNA formation. In addition to discussing the functions and distributions of poxvirus PKR pathway inhibitors, we focus on host species-specific PKR-inhibitor interactions and their consequences for virus host range and virulence, including differential NF-κB pathway activation. We further highlight how research with PKR inhibitor-deficient poxviruses led to seminal discoveries elucidating molecular mechanisms for virus evolution, including gene amplification and horizontal gene transfer.

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Cite

BibTeXRIS
BibTeX
@article{rothenburg2026insights,
  title = {{Insights into molecular mechanisms of poxvirus evolution and host range through studies of poxvirus inhibitors of protein kinase R}},
  author = {Stefan Rothenburg and Dewi Megawati and Ryan Bruneau and Loubna Tazi},
  journal = {Journal of Virology},
  year = {2026},
  month = sep,
  doi = {10.1128/jvi.01768-24},
  url = {https://doi.org/10.1128/jvi.01768-24},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Insights into molecular mechanisms of poxvirus evolution and host range through studies of poxvirus inhibitors of protein kinase R
AU  - Stefan Rothenburg
AU  - Dewi Megawati
AU  - Ryan Bruneau
AU  - Loubna Tazi
PY  - 2026
DA  - 2026/09/25
JO  - Journal of Virology
DO  - 10.1128/jvi.01768-24
UR  - https://doi.org/10.1128/jvi.01768-24
AB  - Protein kinase R (PKR) acts both as a sensor for virus infections, by detecting double-stranded (ds) RNA, and as an antiviral effector by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). Consequently, viruses have evolved many mechanisms to evade this potent antiviral protein, which in turn led to the fast evolution of PKR. There is an emerging understanding that these molecular arms races have important implications for the virulence and host range of viruses, which was in part propelled by research on PKR and poxvirus PKR inhibitors. At least four direct PKR pathway inhibitors, which either prevent PKR activation, inhibit interaction with eIF2α, or reverse eIF2α phosphorylation, evolved independently in different poxvirus clades, while poxvirus decapping enzymes provide another mechanism to subdue PKR activation via the reduction of dsRNA formation. In addition to discussing the functions and distributions of poxvirus PKR pathway inhibitors, we focus on host species-specific PKR-inhibitor interactions and their consequences for virus host range and virulence, including differential NF-κB pathway activation. We further highlight how research with PKR inhibitor-deficient poxviruses led to seminal discoveries elucidating molecular mechanisms for virus evolution, including gene amplification and horizontal gene transfer.
SN  - 0022-538X
SN  - 1098-5514
ER  -