Cyclic oligoadenylate signalling - a new type of antiviral response

所有生物都进化出了对环境变化做出反应的能力，以最大限度地提高自己的适应性。例如，细菌游向食物来源，远离有害化学物质。为了实现这一目标，它们需要一种方法将环境信号转化为细胞内的信号，而它们需要一种被称为“第二信使”的分子来实现这一目标。2017年，在细菌和古细菌中发现了一类全新的第二信使：环低聚腺苷酸（cOA）。辅酶a分子是通过将三磷酸腺苷（ATP）分子连接在一起形成由3、4、5和6个构建块组成的环而形成的。制造辅酶a的酶是一种环化酶，它是CRISPR系统中重要的大型复合体的一部分。这种效应复合物有几个名称（Csm、Cmr、III型），可以通过特异性地结合病毒的遗传物质来感知细胞中病毒的存在。当病毒RNA结合时，环化酶被激活，辅酶a第二信使被合成，向细胞发出被感染的信号。这引发了一系列抗病毒反应，包括基因表达的改变和核糖核酸酶（RNA切割酶）的激活，核糖核酸酶可以降解细胞内的RNA。这可能有助于为细胞杀死病毒争取一些时间，或者也可能使细胞进入休眠甚至死亡。这些结果中的任何一种，虽然不一定对细胞有益，但可能对细胞的邻居有益。由于这些邻居往往是有亲缘关系的，这一过程受到进化的青睐，因为它阻止了感染的传播。在这项资助中，我们建议在一种被称为solfataricus的模式生物中研究这种新的cOA信号系统，这种生物存在于火山池中，在高温和酸性条件下茁壮成长。磺胺虫是我们进行生物化学、遗传和结构研究的理想模型系统。它有一个很好理解的CRISPR系统和大量由cOA信号分子激活的蛋白质。我们将研究cOA是如何合成和降解的，以及它是如何结合并激活引发抗病毒反应的下游蛋白质的。这项工作将帮助我们了解这种令人兴奋的新型抗病毒信号系统的基本特性。由于许多作物和人类病原体都有CRISPR III型系统，这项工作最终可能会在对抗这些疾病的新方法中得到应用。该提案非常符合BBSRC的战略重点领域：综合微生物组研究。

All living things have evolved the ability to respond to changes in their environment in a way that maximises their fitness. For example, bacteria swim towards a food source, and away from a harmful chemical. To achieve this, they need a way to convert an environmental signal into a signal inside the cell, and they do this with a class of molecules called "second messengers". In 2017 an entirely new class of second messengers was discovered in bacteria and archaea: cyclic oligoadenylates (cOA). cOA molecules are made by joining together molecules of Adenosine triphosphate (ATP) to form rings of 3, 4, 5 and 6 building blocks. The enzyme that makes cOA is a cyclase that is part of a large complex important in the CRISPR system. This effector complex, which goes by several names (Csm, Cmr, Type III) can sense the presence of a virus in the cell by binding specifically to its genetic material. When the viral RNA is bound, the cyclase is switched on and cOA second messengers are synthesised to signal to the cell that it is infected. This sets in chain an antiviral response that includes changes in gene expression and activation of ribonucleases (RNA cutting enzymes) that degrade RNA in the cell. This might help buy some time for the cell to kill the virus, or alternatively might push the cell into dormancy or even death. Any of these outcomes, while not necessarily good for the cell, can be good for the cell's neighbours. And as these neighbours tend to be related, this process is favoured by evolution as it stops infection spreading.In this grant, we propose to study this new cOA signalling system in a model organism known as Sulfolobus solfataricus - which is found in volcanic pools, thriving at high temperatures and acidic conditions. Sulfolobus is an ideal model system for the biochemical, genetic and structural studies we want to carry out. It has a well understood CRISPR system and a good number of proteins activated by the cOA signalling molecule. We will examine how cOA is synthesised and degraded, and how it binds to and activates the downstream proteins that elicit the antiviral response. The work will help us to understand the fundamental properties of this exciting new antiviral signalling system. Since many crop and human pathogens have CRISPR type III systems, this work could ultimately find application in new methods to combat these diseases. The proposal fits well with the BBSRC strategic priority area: Integrative Microbiome Research.