Protein kinase R reveals an evolutionary model for defeating viral mimicry

Abstract

Poxviruses, such as small pox, undermine host defences by producing a protein called K3L, which closely mimics the substrate of protein kinase R (PKR), an important component of the vertebrate innate immunity system. Elde et al. show that PKR evolved under dramatic episodes of positive selection in primates, substituting amino acids at sites where K3L and PKR meet. The evolutionary changes increase the chances of the host defeating the mimic and see the two protagonists locked in a molecular 'arms race' trying to out-smart and out-evolve each other. This paper documents the evolutionary interaction between the innate immunity gene protein kinase R (PKR), its substrate elF2α, and its poxvirus mimic K3L. It is concluded that the rapid evolution of the PKR gene may be due to viral mimicry. 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.