Cyclic oligoadenylate signalling - a new type of antiviral response

环状寡腺苷酸信号传导 - 一种新型抗病毒反应

• 批准号: BB/S000313/1
• 负责人: Malcolm White
• 金额: $ 57.84万
• 依托单位: University of St Andrews
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS000313%2F1
• 关键词: Cyclic; oligoadenylate; signalling; new; type

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.

所有生物都进化出了对环境变化做出反应的能力，以最大限度地提高它们的适应性。例如，细菌游向食物来源，远离有害的化学物质。为了实现这一目标，他们需要一种方法将环境信号转换为细胞内的信号，他们用一类称为“第二信使”的分子来做到这一点。2017年，在细菌和古细菌中发现了一类全新的第二信使：环状寡腺苷酸（cOA）。cOA分子是通过将三磷酸腺苷（ATP）分子连接在一起形成3、4、5和6个结构单元的环而制成的。制造cOA的酶是一种环化酶，是CRISPR系统中重要的大型复合物的一部分。这种效应复合物有几个名字（Csm，Cmr，III型），可以通过特异性结合其遗传物质来感知细胞中病毒的存在。当病毒RNA被结合时，环化酶被打开，cOA第二信使被合成，向细胞发出它被感染的信号。这就引发了一系列的抗病毒反应，包括基因表达的变化和细胞内降解RNA的核糖核酸酶（RNA切割酶）的激活。这可能有助于为细胞杀死病毒争取一些时间，或者可能使细胞进入休眠甚至死亡。这些结果中的任何一个，虽然不一定对细胞有利，但对细胞的邻居都有好处。由于这些邻居往往是相关的，这一过程是有利于进化的，因为它阻止了感染的传播。在这项资助中，我们建议在一种名为Sulfolobus solfataricus的模式生物中研究这种新的cOA信号系统-这种模式生物在火山池中发现，在高温和酸性条件下蓬勃发展。硫化叶菌是我们想要进行的生化、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，以及它如何结合并激活引发抗病毒反应的下游蛋白质。这项工作将帮助我们了解这种令人兴奋的新的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具有CRISPR III型系统，这项工作最终可能会应用于对抗这些疾病的新方法。该提案非常符合BBSRC的战略优先领域：综合微生物组研究。

项目成果

Cyclic oligoadenylate signalling and regulation by ring nucleases during type III CRISPR defence.

• DOI: 10.1261/rna.078739.121
• 发表时间: 2021-05-13
• 期刊: RNA (New York, N.Y.)
• 作者: Athukoralage JS;White MF
• 通讯作者: White MF

Cyclic Nucleotide Signaling in Phage Defense and Counter-Defense

• DOI: 10.1146/annurev-virology-100120-010228
• 发表时间: 2022-01-01
• 期刊: ANNUAL REVIEW OF VIROLOGY
• 影响因子: 11.3
• 作者: Athukoralage, Januka S.;White, Malcolm F.
• 通讯作者: White, Malcolm F.

Tetramerisation of the CRISPR ring nuclease Csx3 facilitates cyclic oligoadenylate cleavage

• DOI: 10.1101/2020.04.28.066118
• 发表时间: 2020-04
• 期刊: bioRxiv
• 作者: Januka S. Athukoralage;S. McQuarrie;S. Grüschow;S. Graham;T. Gloster;M. F. White

The dynamic interplay of host and viral enzymes in type III CRISPR-mediated cyclic nucleotide signalling

• DOI: 10.1101/2020.02.12.946046
• 发表时间: 2020-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: Januka S. Athukoralage;S. Graham;Christophe Rouillon;S. Grüschow;C. Czekster;M. F. White

A Type III CRISPR Ancillary Ribonuclease Degrades Its Cyclic Oligoadenylate Activator

• DOI: 10.1101/582114
• 发表时间: 2019-03
• 期刊: Journal of Molecular Biology
• 影响因子: 5.6
• 作者: Januka S. Athukoralage;S. Graham;Sabine Grueschow;Christophe Rouillon;M. F. White