Antiviral function and viral antagonism of the rapidly evolving dynein activating adaptor NINL.
Antiviral function and viral antagonism of the rapidly evolving dynein activating adaptor NINL.
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DOI：
10.7554/elife.81606
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发表时间：
2022-10-12
期刊：
影响因子：
7.7
通讯作者：
Daugherty MD
中科院分区：
文献类型：
--
作者：
Stevens DA;Beierschmitt C;Mahesula S;Corley MR;Salogiannis J;Tsu BV;Cao B;Ryan AP;Hakozawki H;Reck-Peterson SL;Daugherty MD
病毒与细胞内转运机制相互作用以促进病毒复制。这种宿主-病毒相互作用可以驱动宿主基因适应，在宿主基因组中留下病原体驱动进化的特征。在这里，我们利用这些遗传特征来识别动力蛋白激活适配器，ninein样（NINL），作为抗病毒先天免疫反应的关键组成部分，并作为病毒拮抗作用的靶点。在编码活性动力蛋白复合物组分的基因中，NINL是独特的，它在反复的正选择（多样化）下进化，特别是在其羧基末端的货物结合区。与NINL在宿主免疫中的作用一致，我们证明NINL敲除细胞对干扰素的反应受损，导致对病毒复制的容许性增加。此外，我们表明，由不同小核糖核酸病毒和冠状病毒编码的蛋白酶以宿主和病毒特异性的方式切割并破坏NINL功能。我们的工作揭示了NINL在抗病毒反应中的重要性，以及使用宿主病毒遗传冲突的签名来发现抗病毒免疫的新组分和病毒拮抗作用的靶点的实用性。人类和病毒陷入了一场进化的军备竞赛。病毒劫持细胞，利用它们的资源和蛋白质来构建更多的病毒颗粒;细胞进行反击，调用免疫系统来抵御攻击。双方都必须不断迅速发展，以跟上对方的步伐。这种遗传冲突已经发生了数百万年，它在基因上留下的不可磨灭的标记可以用来揭示病毒如何与它们入侵的生物体相互作用。宿主-病毒冲突的一个热点是帮助细胞内运输货物的复杂分子网络。这个系统传输免疫系统的元素，但病毒也可以利用它来制造更多的自己。科学家们对病毒和细胞内运输机制如何相互作用以及这如何影响病毒复制和免疫反应仍然知之甚少。因此，Stevens等人开始利用进化过程中留在宿主基因组中的线索来确定病毒与运输系统之间的新相互作用。他们专注于动力蛋白，这是这种机制的核心组成部分，有助于将分子演员拉过细胞。为了做到这一点，动力蛋白依赖于衔接分子，如“Ninein样”，或简称NINL。在灵长类动物中仔细检查NINL的基因序列，突出了宿主-病毒遗传冲突的进化特征;这表明该蛋白质可能被病毒用于繁殖，或被细胞用于抵御感染。事实上，缺乏NINL基因的人类细胞防御能力较弱，使病毒比正常情况下生长得更快。进一步的研究表明，NINL对于一种主要类型的抗病毒免疫应答是重要的。作为破坏这种防御机制的潜在手段，一些病毒在特定位点切割NINL并破坏其在细胞内转运中的作用。需要更好的抗病毒治疗来帮助人类抵抗旧敌人和新威胁。Stevens等人的工作展示了如何利用宿主基因组中包含的信息来了解是什么驱动了对感染的易感性，并确定了可能成为治疗靶点的分子因素。
Viruses interact with the intracellular transport machinery to promote viral replication. Such host–virus interactions can drive host gene adaptation, leaving signatures of pathogen-driven evolution in host genomes. Here, we leverage these genetic signatures to identify the dynein activating adaptor, ninein-like (NINL), as a critical component in the antiviral innate immune response and as a target of viral antagonism. Unique among genes encoding components of active dynein complexes, NINL has evolved under recurrent positive (diversifying) selection, particularly in its carboxy-terminal cargo-binding region. Consistent with a role for NINL in host immunity, we demonstrate that NINL knockout cells exhibit an impaired response to interferon, resulting in increased permissiveness to viral replication. Moreover, we show that proteases encoded by diverse picornaviruses and coronaviruses cleave and disrupt NINL function in a host- and virus-specific manner. Our work reveals the importance of NINL in the antiviral response and the utility of using signatures of host–virus genetic conflicts to uncover new components of antiviral immunity and targets of viral antagonism. Humans and viruses are locked in an evolutionary arms race. Viruses hijack cells, using their resources and proteins to build more viral particles; the cells fight back, calling in the immune system to fend off the attack. Both actors must constantly and quickly evolve to keep up with each other. This genetic conflict has been happening for millions of years, and the indelible marks it has left on genes can serve to uncover exactly how viruses interact with the organisms they invade. One hotspot in this host-virus conflict is the complex network of molecules that help to move cargo inside a cell. This system transports elements of the immune system, but viruses can also harness it to make more of themselves. Scientists still know very little about how viruses and the intracellular transport machinery interact, and how this impacts viral replication and the immune response. Stevens et al. therefore set out to identify new interactions between viruses and the transport system by using clues left in host genomes by evolution. They focused on dynein, a core component of this machinery which helps to haul molecular actors across a cell. To do so, dynein relies on adaptor molecules such as 'Ninein-like', or NINL for short. Closely examining the gene sequence for NINL across primates highlighted an evolutionary signature characteristic of host-virus genetic conflicts; this suggests that the protein may be used by viruses to reproduce, or by cells to fend off infection. And indeed, human cells lacking the NINL gene were less able to defend themselves, allowing viruses to grow much faster than normal. Further work showed that NINL was important for a major type of antiviral immune response. As a potential means to sabotage this defence mechanism, some viruses cleave NINL at specific sites and disrupt its role in intracellular transport. Better antiviral treatments are needed to help humanity resist old foes and new threats alike. The work by Stevens et al. demonstrates how the information contained in host genomes can be leveraged to understand what drives susceptibility to an infection, and to pinpoint molecular actors which could become therapeutic targets.