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Protein kinase R reveals an evolutionary model for defeating viral mimicry

Nature volume 457, pages 485–489 (2009)Cite this article

Abstract

Distinguishing self from non-self is a fundamental biological challenge. Many pathogens exploit the challenge of self discrimination by employing mimicry to subvert key cellular processes including the cell cycle, apoptosis and cytoskeletal dynamics1,2,3,4,5. Other mimics interfere with immunity6,7. Poxviruses encode K3L, a mimic of eIF2α, which is the substrate of protein kinase R (PKR), an important component of innate immunity in vertebrates8,9. The PKR–K3L interaction exemplifies the conundrum imposed by viral mimicry. To be effective, PKR must recognize a conserved substrate (eIF2α) while avoiding rapidly evolving substrate mimics such as K3L. Using the PKR–K3L system and a combination of phylogenetic and functional analyses, we uncover evolutionary strategies by which host proteins can overcome mimicry. We find that PKR has evolved under intense episodes of positive selection in primates. The ability of PKR to evade viral mimics is partly due to positive selection at sites most intimately involved in eIF2α recognition. We also find that adaptive changes on multiple surfaces of PKR produce combinations of substitutions that increase the odds of defeating mimicry. Thus, although it can seem that pathogens gain insurmountable advantages by mimicking cellular components, host factors such as PKR can compete in molecular ‘arms races’ with mimics because of evolutionary flexibility at protein interaction interfaces challenged by mimicry.

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Figure 1: Widespread positive selection has shaped PKR throughout primate evolution.
Figure 2: Distinct surfaces of the PKR kinase domain are crucial to K3L resistance.
Figure 3: PKR chimaeras reveal masking of K3L sensitivity by Leu 394.

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Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

Sequences of PKR have been deposited in Genbank under accession numbers EU733254–EU733271 and FJ374685.

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Acknowledgements

We thank T. Dever for yeast strains and advice; J. Tartaglia and B. Jacobs for valuable reagents; and S. Biggins and S. Furuyama for yeast expression plasmids and advice, and M. Emerman, S. Henikoff, S. Biggins, A. Turkewitz, D. Gottschling, D. Koshland, E. Smith, J. Kerns, S. Sawyer and D. Vermaak for comments and suggestions. We are supported by NIH grant AI026672 (A.P.G.) and a Searle Scholar and Burroughs Wellcome Investigator Award (H.S.M.). N.C.E. is an Ellison Medical Foundation Fellow of the Life Sciences Research Foundation.

Author Contributions N.C.E. and H.S.M. designed the study. N.C.E. performed the evolutionary analysis and yeast growth assays. S.J.C. and A.P.G. designed and performed the vaccinia infection experiments. N.C.E. and H.S.M. wrote the paper. All authors discussed and edited the manuscript.

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Authors and Affiliations

  1. Division of Basic Sciences,,

    Nels C. Elde & Harmit S. Malik

  2. Division of Human Biology, and,

    Stephanie J. Child & Adam P. Geballe

  3. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA,

    Adam P. Geballe

  4. Departments of Medicine and Microbiology, University of Washington, Seattle, Washington 98115, USA,

    Adam P. Geballe

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  1. Nels C. Elde
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  4. Harmit S. Malik
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Correspondence to Harmit S. Malik.

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Elde, N., Child, S., Geballe, A. et al. Protein kinase R reveals an evolutionary model for defeating viral mimicry. Nature 457, 485–489 (2009). https://doi.org/10.1038/nature07529

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