Protein kinase R reveals an evolutionary model for defeating viral mimicry.
Protein kinase R reveals an evolutionary model for defeating viral mimicry.
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DOI：
10.1038/nature07529
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发表时间：
2009-01-22
期刊：
影响因子：
64.8
通讯作者：
Malik HS
中科院分区：
文献类型：
--
作者：
Elde NC;Child SJ;Geballe AP;Malik HS
区分自我和非自我是一项基本的生物学挑战。许多病原体通过模仿来颠覆关键的细胞过程，包括细胞周期、细胞凋亡和细胞骨架动力学，从而利用自我歧视的挑战。其他模仿者会干扰免疫力。痘病毒编码 K3L，它是 eIF2α 的模拟物，而 eIF2α 是蛋白激酶 R (PKR) 的底物，而蛋白激酶 R 是脊椎动物先天免疫的重要组成部分。 PKR-K3L 相互作用体现了病毒拟态带来的难题。为了发挥作用，PKR 必须识别保守底物 (eIF2α)，同时避免快速进化的底物模拟物（如 K3L）。使用 PKR-K3L 系统并结合系统发育和功能分析，我们揭示了宿主蛋白克服拟态的进化策略。我们发现 PKR 是在灵长类动物积极选择的戏剧性事件中进化而来的。 PKR 逃避病毒模拟物的能力部分归因于与 eIF2α 识别最密切相关的位点的正选择。我们还发现 PKR 多个表面上的适应性变化会产生替代组合，从而增加击败拟态的几率。因此，虽然病原体通过模仿细胞成分获得了难以克服的优势，但像 PKR 这样的宿主因子可以与模仿者进行分子“军备竞赛”，因为受到模仿挑战的蛋白质相互作用界面具有显着的进化灵活性。
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 dynamics. Other mimics interfere with immunity. Poxviruses encode K3L, a mimic of eIF2α, which is the substrate of Protein Kinase R (PKR), an important component of innate immunity in vertebrates. 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 like 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 dramatic 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, while it can appear that pathogens gain insurmountable advantages by mimicking cellular components, host factors like PKR can compete in molecular ‘arms races’ with mimics because of remarkable evolutionary flexibility at protein interaction interfaces challenged by mimicry.
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