Recurrent Loss of Macrodomain Activity in Host Immunity and Viral Proteins.
Recurrent Loss of Macrodomain Activity in Host Immunity and Viral Proteins.
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宿主免疫和病毒蛋白中大域活性的复发性丧失。
DOI：
10.3390/pathogens12050674
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发表时间：
2023-05-03
期刊：
影响因子：
--
通讯作者：
Daugherty MD
中科院分区：
文献类型：
--
作者：
Delgado-Rodriguez SE;Ryan AP;Daugherty MD
蛋白质翻译后修饰（PTM）是宿主先天免疫系统和病毒之间进行的进化军备竞赛的重要战场。一个这样的PTM，ADP-核糖基化，最近出现作为宿主抗病毒免疫的重要介质。对于该PTM的宿主-病毒冲突重要的是通过PARP蛋白添加ADP-核糖和通过含有大结构域的蛋白去除ADP-核糖。有趣的是，几种宿主蛋白质，称为macroPARP，含有macrodomains以及PARP结构域，这些蛋白质对于宿主抗病毒免疫应答和在非常强的正（多样化）进化选择下进化都很重要。此外，包括甲病毒和冠状病毒在内的几种病毒编码一个或多个宏结构域。尽管存在保守的宏结构域折叠，但许多这些蛋白质的酶活性尚未被表征。在这里，我们进行进化和功能分析，以表征macroPARP和病毒macrodomains的活性。我们跟踪macroPARP在后生动物的进化历史，并显示PARP 9和PARP 14包含一个单一的活性宏域，而PARP 15不包含。有趣的是，我们还揭示了哺乳动物PARP 14内的几个独立的宏结构域酶活性损失，包括蝙蝠，有蹄类动物和食肉动物谱系。与macroPARP类似，冠状病毒含有多达三个宏结构域，只有第一个显示催化活性。有趣的是，我们还揭示了甲病毒组病毒内宏结构域活性的经常性丧失，包括昆虫特异性甲病毒中的酶失活以及两种人类感染病毒中的独立酶失活。总之，我们的进化和功能数据揭示了宿主抗病毒蛋白和病毒蛋白中宏域活性的意外周转。
Protein post-translational modifications (PTMs) are an important battleground in the evolutionary arms races that are waged between the host innate immune system and viruses. One such PTM, ADP-ribosylation, has recently emerged as an important mediator of host antiviral immunity. Important for the host–virus conflict over this PTM is the addition of ADP-ribose by PARP proteins and removal of ADP-ribose by macrodomain-containing proteins. Interestingly, several host proteins, known as macroPARPs, contain macrodomains as well as a PARP domain, and these proteins are both important for the host antiviral immune response and evolving under very strong positive (diversifying) evolutionary selection. In addition, several viruses, including alphaviruses and coronaviruses, encode one or more macrodomains. Despite the presence of the conserved macrodomain fold, the enzymatic activity of many of these proteins has not been characterized. Here, we perform evolutionary and functional analyses to characterize the activity of macroPARP and viral macrodomains. We trace the evolutionary history of macroPARPs in metazoans and show that PARP9 and PARP14 contain a single active macrodomain, whereas PARP15 contains none. Interestingly, we also reveal several independent losses of macrodomain enzymatic activity within mammalian PARP14, including in the bat, ungulate, and carnivore lineages. Similar to macroPARPs, coronaviruses contain up to three macrodomains, with only the first displaying catalytic activity. Intriguingly, we also reveal the recurrent loss of macrodomain activity within the alphavirus group of viruses, including enzymatic loss in insect-specific alphaviruses as well as independent enzymatic losses in two human-infecting viruses. Together, our evolutionary and functional data reveal an unexpected turnover in macrodomain activity in both host antiviral proteins and viral proteins.
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