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Nature:痘病毒与先天免疫系统的角力

来源:Nature 2009-01-22 12:05

专题:Nature报道

痘病毒(如天花)通过产生一种被称为K3L的蛋白来破坏宿主防卫系统。该蛋白能够非常像地模仿“蛋白激酶R”(PKR)的基质,后者是脊椎动物先天免疫系统的一个重要组成部分。Elde等人发现,PKR是在灵长类引人注目的积极选择过程中、通过在K3L 和 PKR相遇处替换氨基酸形成的。这些演化性变化增加了宿主挫败模仿的机会,其中两个对手在进行一场分子“军备竞赛” ,试图通过斗智斗勇战胜对方。(生物谷Bioon.com)

生物谷推荐原始出处:

Nature 457, 485-489 (22 January 2009) | doi:10.1038/nature07529

Protein kinase R reveals an evolutionary model for defeating viral mimicry

Nels C. Elde1, Stephanie J. Child2, Adam P. Geballe2,3,4 & Harmit S. Malik1

1 Division of Basic Sciences,
2 Division of Human Biology, and,
3 Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
4 Departments of Medicine and Microbiology, University of Washington, Seattle, Washington 98115, USA

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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