Rapid evolution of PARP genes suggests a broad role for ADP-ribosylation in host-virus conflicts.
Rapid evolution of PARP genes suggests a broad role for ADP-ribosylation in host-virus conflicts.
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DOI：
10.1371/journal.pgen.1004403
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发表时间：
2014
期刊：
影响因子：
4.5
通讯作者：
Malik HS
中科院分区：
文献类型：
--
作者：
Daugherty MD;Young JM;Kerns JA;Malik HS
翻译后蛋白质修饰，如磷酸化和泛素化是病毒与其宿主之间冲突的常见分子靶点。然而，其他翻译后修饰，如ADP-核糖基化，在宿主-病毒相互作用的作用是不太好的特点。ADP-核糖基化由PARP（也称为ARTD）基因家族编码的蛋白质进行。17个人类PARP基因中的大多数特征不佳。然而，一种PARP蛋白，PARP 13/ZAP，具有广泛的抗病毒活性，并在灵长类动物中的正（多样化）选择下进化。这种进化是典型的领域，锁定在敌对的“军备竞赛”与病毒因子。为了鉴定可能参与宿主-病毒相互作用的其他PARP基因，我们对所有灵长类动物PARP基因进行了进化分析，以寻找快速进化的特征。与大多数PARP基因参与“管家”功能的预期相反，我们发现近三分之一的PARP基因在强烈的循环正选择下进化。我们鉴定了PARP 4的一个>300个氨基酸的无序区域，该区域是细胞质穹窿结构的一个组分，在几种哺乳动物谱系中快速进化，表明该区域作为重要的宿主-病原体特异性界面。我们还发现了PARP 9、14和15的正选择，这是仅有的三个同时含有PARP结构域和宏结构域的人类基因。宏结构域独特地识别，并且在某些情况下可以逆转蛋白质单ADP核糖基化，并且我们在整个宏PARP宏结构域中观察到强烈的复发性正选择特征。此外，PARP 14和PARP 15在脊椎动物进化过程中经历了重复的基因诞生和丢失，与周期性基因创新一致。与以前的研究，涉及几个PARP的免疫，以及那些证明了病毒编码的宏结构域在宿主免疫逃避的作用，我们的进化分析表明，添加，识别和去除ADP-核糖基化是一个关键的，低估的货币在宿主病毒的冲突。病毒感染的结果由特定动物物种中抗病毒基因的库和特异性决定。候选免疫基因和机制的鉴定是描述这一谱系的关键步骤。尽管基因组测序取得了进展，但抗病毒基因的鉴定在很大程度上仍然依赖于证明它们对候选病毒的活性。然而，直接与病毒靶点或拮抗剂相互作用的抗病毒蛋白也具有反复进化适应的特征，可用于鉴定候选抗病毒药物。在这里，我们发现，17个基因中有5个含有一个可以催化ADP-核糖翻译后添加到蛋白质的结构域，这些基因具有这种经常性遗传创新的特征。特别是，我们发现，所有编码ADP-核糖添加（通过PARP结构域）以及识别和/或去除（通过宏结构域）活动的基因都在哺乳动物中进化了非常强大的多样化选择。此外，这些基因在整个哺乳动物进化过程中经历了多次基因复制和丢失。结合一些病毒还编码宏结构域以抵消宿主免疫的知识，我们的进化分析因此暗示ADP-核糖基化是哺乳动物基因组中抗病毒防御中未被充分认识的关键步骤。
Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. However, the role of other post-translational modifications, such as ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation is carried out by proteins encoded by the PARP (also called ARTD) gene family. The majority of the 17 human PARP genes are poorly characterized. However, one PARP protein, PARP13/ZAP, has broad antiviral activity and has evolved under positive (diversifying) selection in primates. Such evolution is typical of domains that are locked in antagonistic ‘arms races’ with viral factors. To identify additional PARP genes that may be involved in host-virus interactions, we performed evolutionary analyses on all primate PARP genes to search for signatures of rapid evolution. Contrary to expectations that most PARP genes are involved in ‘housekeeping’ functions, we found that nearly one-third of PARP genes are evolving under strong recurrent positive selection. We identified a >300 amino acid disordered region of PARP4, a component of cytoplasmic vault structures, to be rapidly evolving in several mammalian lineages, suggesting this region serves as an important host-pathogen specificity interface. We also found positive selection of PARP9, 14 and 15, the only three human genes that contain both PARP domains and macrodomains. Macrodomains uniquely recognize, and in some cases can reverse, protein mono-ADP-ribosylation, and we observed strong signatures of recurrent positive selection throughout the macro-PARP macrodomains. Furthermore, PARP14 and PARP15 have undergone repeated rounds of gene birth and loss during vertebrate evolution, consistent with recurrent gene innovation. Together with previous studies that implicated several PARPs in immunity, as well as those that demonstrated a role for virally encoded macrodomains in host immune evasion, our evolutionary analyses suggest that addition, recognition and removal of ADP-ribosylation is a critical, underappreciated currency in host-virus conflicts. The outcome of viral infections is determined by the repertoire and specificity of the antiviral genes in a particular animal species. The identification of candidate immunity genes and mechanisms is a key step in describing this repertoire. Despite advances in genome sequencing, identification of antiviral genes has largely remained dependent on demonstration of their activity against candidate viruses. However, antiviral proteins that directly interact with viral targets or antagonists also bear signatures of recurrent evolutionary adaptation, which can be used to identify candidate antivirals. Here, we find that five out of seventeen genes that contain a domain that can catalyze the post-translational addition ADP-ribose to proteins bear such signatures of recurrent genetic innovation. In particular, we find that all the genes that encode both ADP-ribose addition (via PARP domains) as well as recognition and/or removal (via macro domains) activities have evolved under extremely strong diversifying selection in mammals. Furthermore, such genes have undergone multiple episodes of gene duplications and losses throughout mammalian evolution. Combined with the knowledge that some viruses also encode macro domains to counteract host immunity, our evolutionary analyses therefore implicate ADP-ribosylation as an underappreciated key step in antiviral defense in mammalian genomes.
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