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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Murphy, P. M. Molecular mimicry and the generation of host defense protein diversity. Cell 72, 823–826 (1993)
Angot, A., Vergunst, A., Genin, S. & Peeters, N. Exploitation of eukaryotic ubiquitin signaling pathways by effectors translocated by bacterial type III and type IV secretion systems. PLoS Pathog. 3, e3 (2007)
Benedict, C. A., Norris, P. S. & Ware, C. F. To kill or be killed: viral evasion of apoptosis. Nature Immunol. 3, 1013–1018 (2002)
Izard, T., Tran Van Nhieu, G. & Bois, P. R. Shigella applies molecular mimicry to subvert vinculin and invade host cells. J. Cell Biol. 175, 465–475 (2006)
Stebbins, C. E. & Galan, J. E. Structural mimicry in bacterial virulence. Nature 412, 701–705 (2001)
Alcami, A. Viral mimicry of cytokines, chemokines and their receptors. Nature Rev. Immunol. 3, 36–50 (2003)
Finlay, B. B. & McFadden, G. Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell 124, 767–782 (2006)
Meurs, E. et al. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell 62, 379–390 (1990)
Dever, T. E., Dar, A. C. & Sicheri, F. in Translational Control in Biology and Medicine (eds Mathews, M. B., Sonenberg, N. & Hershey, J. W. B.) 319–344 (Cold Spring Harbor Laboratory Press, 2007)
Langland, J. O., Cameron, J. M., Heck, M. C., Jancovich, J. K. & Jacobs, B. L. Inhibition of PKR by RNA and DNA viruses. Virus Res. 119, 100–110 (2006)
Sawyer, S. L., Emerman, M. & Malik, H. S. Ancient adaptive evolution of the primate antiviral DNA-editing enzyme APOBEC3G. PLoS Biol. 2, E275 (2004)
Nielsen, R. et al. A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol. 3, e170 (2005)
Yang, Z. PAML 4: phylogenetic analysis by maximum likelihood. Mol. Biol. Evol. 24, 1586–1591 (2007)
Scheffler, K., Martin, D. P. & Seoighe, C. Robust inference of positive selection from recombining coding sequences. Bioinformatics 22, 2493–2499 (2006)
Dar, A. C., Dever, T. E. & Sicheri, F. Higher-order substrate recognition of eIF2α by the RNA-dependent protein kinase PKR. Cell 122, 887–900 (2005)
Li, Y. et al. On the origin of smallpox: correlating variola phylogenics with historical smallpox records. Proc. Natl Acad. Sci. USA 104, 15787–15792 (2007)
Babkin, I. V. & Shchelkunov, S. N. The time scale in poxvirus evolution. [In Russian.]. Mol. Biol. (Mosk.) 40, 20–24 (2006)
Sawyer, S. L., Wu, L. I., Emerman, M. & Malik, H. S. Positive selection of primate TRIM5α identifies a critical species-specific retroviral restriction domain. Proc. Natl Acad. Sci. USA 102, 2832–2837 (2005)
Kaiser, S. M., Malik, H. S. & Emerman, M. Restriction of an extinct retrovirus by the human TRIM5α antiviral protein. Science 316, 1756–1758 (2007)
Chong, K. L. et al. Human p68 kinase exhibits growth suppression in yeast and homology to the translational regulator GCN2. EMBO J. 11, 1553–1562 (1992)
Dey, M. et al. Mechanistic link between PKR dimerization, autophosphorylation, and eIF2α substrate recognition. Cell 122, 901–913 (2005)
Dever, T. E. et al. Mammalian eukaryotic initiation factor 2α kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast. Proc. Natl Acad. Sci. USA 90, 4616–4620 (1993)
Kawagishi-Kobayashi, M., Silverman, J. B., Ung, T. L. & Dever, T. E. Regulation of the protein kinase PKR by the vaccinia virus pseudosubstrate inhibitor K3L is dependent on residues conserved between the K3L protein and the PKR substrate eIF2alpha. Mol. Cell. Biol. 17, 4146–4158 (1997)
Langland, J. O. & Jacobs, B. L. The role of the PKR-inhibitory genes, E3L and K3L, in determining vaccinia virus host range. Virology 299, 133–141 (2002)
Poon, A. F., Lewis, F. I., Pond, S. L. & Frost, S. D. An evolutionary-network model reveals stratified interactions in the V3 loop of the HIV-1 envelope. PLOS Comput. Biol. 3, e231 (2007)
Kerns, J. A., Emerman, M. & Malik, H. S. Positive selection and increased antiviral activity associated with the PARP-containing isoform of human zinc-finger antiviral protein. PLoS Genet. 4, e21 (2008)
Essbauer, S., Bremont, M. & Ahne, W. Comparison of the eIF-2α homologous proteins of seven ranaviruses (Iridoviridae). Virus Genes 23, 347–359 (2001)
Ortlund, E. A., Bridgham, J. T., Redinbo, M. R. & Thornton, J. W. Crystal structure of an ancient protein: evolution by conformational epistasis. Science 317, 1544–1548 (2007)
Dean, A. M. & Thornton, J. W. Mechanistic approaches to the study of evolution: the functional synthesis. Nature Rev. Genet. 8, 675–688 (2007)
Sawyer, S. L. & Malik, H. S. Positive selection of yeast nonhomologous end-joining genes and a retrotransposon conflict hypothesis. Proc. Natl Acad. Sci. USA 103, 17614–17619 (2006)
Comeron, J. M. K-Estimator: calculation of the number of nucleotide substitutions per site and the confidence intervals. Bioinformatics 15, 763–764 (1999)
Pond, S. L. & Frost, S. D. A genetic algorithm approach to detecting lineage-specific variation in selection pressure. Mol. Biol. Evol. 22, 478–485 (2005)
DeLano, W. L. The PyMOL User’s Manual (DeLano Scientific, 2004)
Gietz, R. D. & Woods, R. A. Transformation of yeast by lithium acetate/single-stranded carrier DNA/polyethylene glycol method. Methods Enzymol. 350, 87–96 (2002)
Kushnirov, V. V. Rapid and reliable protein extraction from yeast. Yeast 16, 857–860 (2000)
Tartaglia, J. et al. Highly attenuated poxvirus vectors. AIDS Res. Hum. Retroviruses 8, 1445–1447 (1992)
Beattie, E., Tartaglia, J. & Paoletti, E. Vaccinia virus-encoded eIF-2α homolog abrogates the antiviral effect of interferon. Virology 183, 419–422 (1991)
Earl, P. L., Cooper, N., Wyatt, L. S., Moss, B. & Carroll, M. W. Preparation of cell cultures and vaccinia virus stocks. Curr. Protocols Protein Sci. 5, Unit 5.12 10.1002/0471140864.ps0512s13 (2001)
Dar, A. C. & Sicheri, F. X-ray crystal structure and functional analysis of vaccinia virus K3L reveals molecular determinants for PKR subversion and substrate recognition. Mol. Cell 10, 295–305 (2002)
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.
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Supplementary Figures
This file contains Supplementary Figures S1-S8 with legends. (PDF 8793 kb)
Supplementary Tables
This file contains Supplementary Tables S1-S11 with descriptions. (PDF 415 kb)
Supplementary Data
This file contains Supplementary Data S1-S3 with descriptions. (PDF 288 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature07529
This article is cited by
-
Conservation and similarity of bacterial and eukaryotic innate immunity
Nature Reviews Microbiology (2024)
-
Multiple intermolecular interactions facilitate rapid evolution of essential genes
Nature Ecology & Evolution (2023)
-
What Do We Know About the Smallpox Virus? A Journey Between Clinic and Therapy
Pharmaceutical Research (2023)
-
A functional map of HIV-host interactions in primary human T cells
Nature Communications (2022)
-
Using oncolytic viruses to ignite the tumour immune microenvironment in bladder cancer
Nature Reviews Urology (2021)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.