Host proteostasis modulates influenza evolution
Host proteostasis modulates influenza evolution
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DOI：
10.7554/elife.28652
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发表时间：
2017-09
期刊：
影响因子：
7.7
通讯作者：
Angela M. Phillips;Luna O Gonzalez;Emmanuel E. Nekongo;A. I. Ponomarenko;Seán McHugh;Vincent L. Butty;S. Levine;Yu-Shan Lin;L. Mirny;M. Shoulders
中科院分区：
文献类型：
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作者：
Angela M. Phillips;Luna O Gonzalez;Emmanuel E. Nekongo;A. I. Ponomarenko;Seán McHugh;Vincent L. Butty;S. Levine;Yu-Shan Lin;L. Mirny;M. Shoulders
预测和限制RNA病毒的进化需要了解定义这些病原体可获得的突变格局的分子因素。RNA病毒通常有很高的突变率，导致频繁产生生物物理特性受损的蛋白质变体。它们的进化必然受到随之而来的蛋白质折叠和功能挑战的限制。我们假设宿主蛋白稳定机制可能是病毒蛋白变体适合性的重要决定因素，是塑造病毒进化的关键力量。在这里，我们通过在宿主细胞中传播流感来检验这一假设，该宿主细胞表现出化学控制的、不同的蛋白稳定环境。我们发现，在流感基因组上选择的性质和特定突变轨迹的可及性都受到宿主蛋白平衡的显著影响。这些发现为塑造病毒进化的宿主-病原体相互作用的特征提供了新的见解，并为耐药的宿主蛋白抑制靶向抗病毒疗法的潜在设计提供了新的见解。
Predicting and constraining RNA virus evolution require understanding the molecular factors that define the mutational landscape accessible to these pathogens. RNA viruses typically have high mutation rates, resulting in frequent production of protein variants with compromised biophysical properties. Their evolution is necessarily constrained by the consequent challenge to protein folding and function. We hypothesized that host proteostasis mechanisms may be significant determinants of the fitness of viral protein variants, serving as a critical force shaping viral evolution. Here, we test that hypothesis by propagating influenza in host cells displaying chemically-controlled, divergent proteostasis environments. We find that both the nature of selection on the influenza genome and the accessibility of specific mutational trajectories are significantly impacted by host proteostasis. These findings provide new insights into features of host–pathogen interactions that shape viral evolution, and into the potential design of host proteostasis-targeted antiviral therapeutics that are refractory to resistance.