Overlapping Patterns of Rapid Evolution in the Nucleic Acid Sensors cGAS and OAS1 Suggest a Common Mechanism of Pathogen Antagonism and Escape.
Overlapping Patterns of Rapid Evolution in the Nucleic Acid Sensors cGAS and OAS1 Suggest a Common Mechanism of Pathogen Antagonism and Escape.
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DOI：
10.1371/journal.pgen.1005203
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发表时间：
2015-05
期刊：
影响因子：
4.5
通讯作者：
Elde NC
中科院分区：
文献类型：
--
作者：
Hancks DC;Hartley MK;Hagan C;Clark NL;Elde NC
模式识别受体（PRR）的不同子集检测病原体相关的核酸，以启动宿主生物体中的关键先天免疫反应。反映了它们对宿主防御的重要性，病原体编码各种对策来逃避或抑制这些免疫效应物。与病原体抑制剂直接相关的PRR通常在反复发生的正选择下进化，这被描述为分子“军备竞赛”。环GMP-AMP合酶（cGAS）最近被鉴定为关键PRR。在结合来自各种病毒的细胞质双链DNA（dsDNA）后，cGAS产生小核苷酸第二信使cGAMP以发出先天防御激活的信号。在这里，我们报告了cGAS在灵长类谱系中具有周期性正选择的进化历史。最近的研究表明，cGAS和2'-5'-寡腺苷酸合酶1（OAS 1）（一种检测双链RNA（dsRNA）的PRR）之间具有高度的结构相似性，尽管各自基因之间的序列同一性较低。我们提出了全面的比较进化分析cGAS和OAS1灵长类序列，并观察到积极的选择在核酸结合界面和分布在整个两个基因。我们的数据显示同源区域具有强烈的正选择特征，表明未知病原体编码的抑制剂和类似的逃避拮抗作用的模式所采用的共同机制。我们对cGAS多样化的分析还鉴定了在正选择下缺失多个位点的交替剪接形式。对灵长类动物中OAS家族（包括OAS1、OAS2、OAS3和OASL）的选择的进一步分析表明了一种假设，即基因重复和结构域融合事件导致旁系同源物，这些旁系同源物提供了逃避病原体抑制剂的另一种手段。我们对cGAS和OAS的比较进化分析为先天免疫系统的关键分子哨兵适应规避病毒编码的抑制剂的不同机制提供了新的见解。病原体在物种内部和跨物种感染新个体的能力主要是由其劫持细胞机器和克服免疫系统的能力驱动的。病原体已经进化出多种手段来逃避和关闭宿主免疫力。通常，灭活机制涉及宿主和病原体因子之间的直接相互作用。为了逃避世代过程中的抑制，宿主因子经常以破坏与病原体因子在特定界面处的相互作用的方式进化。同样地，病原体也会通过适应来恢复这种相互作用，而这些遗传拔河被描述为"分子军备竞赛"。在这里，我们专注于适应两个关键的宿主免疫因子，cGAS和OAS，尽管非常有限的遗传相似性，但它们在蛋白质结构中具有相同性。我们的分析确定了各种方式，包括蛋白质表面的氨基酸变化，这些宿主因子似乎逃脱病原体介导的抑制。令人惊讶的是，一些氨基酸取代位于等同位点，表明cGAS和OAS可能已经适应于逃避常见病原体编码的抑制剂。这些数据还确定了病毒靶向的蛋白质表面，以抑制宿主免疫力。综上所述，我们的结果表明存在关键的，尚未确定的cGAS和OAS的病毒拮抗剂。
A diverse subset of pattern recognition receptors (PRRs) detects pathogen-associated nucleic acids to initiate crucial innate immune responses in host organisms. Reflecting their importance for host defense, pathogens encode various countermeasures to evade or inhibit these immune effectors. PRRs directly engaged by pathogen inhibitors often evolve under recurrent bouts of positive selection that have been described as molecular ‘arms races.’ Cyclic GMP-AMP synthase (cGAS) was recently identified as a key PRR. Upon binding cytoplasmic double-stranded DNA (dsDNA) from various viruses, cGAS generates the small nucleotide secondary messenger cGAMP to signal activation of innate defenses. Here we report an evolutionary history of cGAS with recurrent positive selection in the primate lineage. Recent studies indicate a high degree of structural similarity between cGAS and 2’-5’-oligoadenylate synthase 1 (OAS1), a PRR that detects double-stranded RNA (dsRNA), despite low sequence identity between the respective genes. We present comprehensive comparative evolutionary analysis of cGAS and OAS1 primate sequences and observe positive selection at nucleic acid binding interfaces and distributed throughout both genes. Our data revealed homologous regions with strong signatures of positive selection, suggesting common mechanisms employed by unknown pathogen encoded inhibitors and similar modes of evasion from antagonism. Our analysis of cGAS diversification also identified alternately spliced forms missing multiple sites under positive selection. Further analysis of selection on the OAS family in primates, which comprises OAS1, OAS2, OAS3 and OASL, suggests a hypothesis where gene duplications and domain fusion events result in paralogs that provide another means of escaping pathogen inhibitors. Together our comparative evolutionary analysis of cGAS and OAS provides new insights into distinct mechanisms by which key molecular sentinels of the innate immune system have adapted to circumvent viral-encoded inhibitors. A pathogen’s ability to infect new individuals within and across species is largely driven by its capacity to hijack cellular machinery and overcome the immune system. Pathogens have evolved multiple means to evade and shut down host immunity. Typically, mechanisms of inactivation involve direct interactions between host and pathogen factors. To escape inhibition over the course of generations, host factors frequently evolve in a manner that disrupts interactions at specific interfaces with pathogen factors. Likewise, pathogens adapt to restore such interactions, and these genetic tug-of-wars have been described as “molecular-arms races.” Here we focus on the adaptation of two critical host immune factors, cGAS and OAS that share identity in protein structures despite very limited genetic similarity. Our analysis identifies a variety of ways, including amino acid changes on protein surfaces, by which these host factors appear to escape pathogen-mediated inhibition. Surprisingly, some amino acid substitutions are located at equivalent sites suggesting that cGAS and OAS may have adapted to evade common pathogen encoded inhibitors. These data also identify protein surfaces that are targeted by viruses to inhibit host immunity. Taken together our results indicate the existence of critical, yet-to-be identified viral antagonists of cGAS and OAS.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1038/nri3719
发表时间：
2014-08
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Hornung V;Hartmann R;Ablasser A;Hopfner KP
通讯作者：
Hopfner KP
影响因子：
7
作者：
George, Renee D.;McVicker, Graham;Thomas, James H.
通讯作者：
Thomas, James H.
影响因子：
64.8
作者：
Elde NC;Child SJ;Geballe AP;Malik HS
通讯作者：
Malik HS
影响因子：
16
作者：
Hartmann, R;Justesen, J;Yee, VC
通讯作者：
Yee, VC