A Rapidly Evolving Polybasic Motif Modulates Bacterial Detection by Guanylate Binding Proteins
A Rapidly Evolving Polybasic Motif Modulates Bacterial Detection by Guanylate Binding Proteins
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DOI：
10.1128/mbio.00340-20
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发表时间：
2020-05-01
期刊：
影响因子：
6.4
通讯作者：
Barber, Matthew F.
中科院分区：
文献类型：
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作者：
Kohler, Kristin M.;Kutsch, Miriam;Barber, Matthew F.
细胞自主免疫依赖于宿主蛋白对入侵病原体的快速检测。鸟苷酸结合蛋白（GBP）因其识别多种细胞内病原体和含有病原体的细胞区室的能力而成为脊椎动物免疫防御的关键介质。尽管病原体特异性的分子决定因素仍不清楚，但人类和小鼠 GBP 已被证明可以针对不同的微生物群。我们发现灵长类 GBP 中 C 端多碱基基序 (PBM) 的快速多样化控制着对模型胞质细菌病原体福氏志贺氏菌的识别。通过在灵长类 GBP 直系同源物之间交换这种膜结合基序，我们发现针对福氏链霉的能力在新世界灵长类的特定谱系中得到了增强和丧失。 GBP1 PBM 快速进化位点中的单个替换足以消除或恢复细菌检测能力，说明上位性在病原体识别进化中的作用。我们进一步证明，松鼠猴 GBP2 C 末端结构域最近通过逐步的趋同进化过程获得了靶向福氏链霉的能力。这些发现揭示了 PBM 的加速进化改变 GBP 靶标特异性的机制，并有助于解决细胞自主免疫防御中 GBP 功能的分子基础。 重要性 许多传染病是由进入宿主细胞并在宿主细胞内存活的微生物引起的。鸟苷酸结合蛋白（GBP）是一组识别和抑制多种细胞内病原微生物的免疫蛋白。我们发现 GBP 内检测细菌所需的一个短序列，即多碱基基序 (PBM)，在灵长类动物物种之间迅速进化。通过在灵长类 GBP1 基因之间交换 PBM，我们能够证明特定序列既可以降低也可以提高 GBP1 靶向细胞内细菌的能力。我们还表明，南美猴的 GBP2 包封细菌的能力是独立进化的。综合这些结果，本报告说明了灵长类 GBP 如何适应防御传染性病原体。
Cell-autonomous immunity relies on the rapid detection of invasive pathogens by host proteins. Guanylate binding proteins (GBPs) have emerged as key mediators of vertebrate immune defense through their ability to recognize a diverse array of intracellular pathogens and pathogen-containing cellular compartments. Human and mouse GBPs have been shown to target distinct groups of microbes, although the molecular determinants of pathogen specificity remain unclear. We show that rapid diversification of a C-terminal polybasic motif (PBM) in primate GBPs controls recognition of the model cytosolic bacterial pathogen Shigella flexneri. By swapping this membrane-binding motif between primate GBP orthologs, we found that the ability to target S. flexneri has been enhanced and lost in specific lineages of New World primates. Single substitutions in rapidly evolving sites of the GBP1 PBM are sufficient to abolish or restore bacterial detection abilities, illustrating a role for epistasis in the evolution of pathogen recognition. We further demonstrate that the squirrel monkey GBP2 C-terminal domain recently gained the ability to target S. flexneri through a stepwise process of convergent evolution. These findings reveal a mechanism by which accelerated evolution of a PBM shifts GBP target specificity and aid in resolving the molecular basis of GBP function in cell-autonomous immune defense.IMPORTANCE Many infectious diseases are caused by microbes that enter and survive within host cells. Guanylate binding proteins (GBPs) are a group of immune proteins which recognize and inhibit a variety of intracellular pathogenic microbes. We discovered that a short sequence within GBPs required for the detection of bacteria, the polybasic motif (PBM), has been rapidly evolving between primate species. By swapping PBMs between primate GBP1 genes, we were able to show that specific sequences can both reduce and improve the ability of GBP1 to target intracellular bacteria. We also show that the ability to envelop bacteria has independently evolved in GBP2 of South American monkeys. Taking the results together, this report illustrates how primate GBPs have adapted to defend against infectious pathogens.