小柯机器人

英国圣安德鲁斯大学Malcolm F. White团队近期取得重要工作进展，他们研究发现了通过ATP和SAM偶联的抗病毒III型CRISPR信号转导。相关研究成果2023年10月18日在线发表于《自然》杂志上。

据介绍，CRISPR系统在原核生物世界中广泛存在，提供针对可移动遗传元件的适应性免疫。具有特征基因cas10的III型CRISPR系统使用CRISPR RNA检测非自身RNA，激活酶促cas10亚基，直接通过完整的组氨酸-天冬氨酸（HD）核酸酶结构域或间接通过合成环状寡腺苷酸第二信使来激活各种辅助效应物，从而保护细胞免受可移动遗传元件的侵害。III型CRISPR系统的一个子集编码一种未表征的CorA家族膜蛋白和一种相关的NrN家族磷酸二酯酶，预计它们在抗病毒防御中发挥作用。

研究人员证明了脆弱拟杆菌的CorA相关III-B型（Cmr）CRISPR系统在大肠杆菌中表达时提供了对可移动遗传元件的免疫力。然而，B.fragilis Cmr在激活时不合成环状寡腺苷酸，而是通过磷酸二酯键将ATP与SAM偶联来产生S-腺苷甲硫氨酸（SAM）-AMP（SAM也称为AdoMet）。一旦合成，SAM-AMP就会与CorA效应物结合，可能会通过破坏膜完整性导致细胞休眠或死亡。SAM-AMP被CRISPR相关的磷酸二酯酶或SAM-AMP裂解酶降解，可能提供类似于环状寡腺苷酸特异性环核酸酶的“关闭开关”。

因此，SAM-AMP代表了一类新的抗病毒信号第二信使，它可能在不同的细胞环境中发挥不同的作用。

附：英文原文

Title: Antiviral type III CRISPR signalling via conjugation of ATP and SAM

Author: Chi, Haotian, Hoikkala, Ville, Grschow, Sabine, Graham, Shirley, Shirran, Sally, White, Malcolm F.

Issue&Volume: 2023-10-18

Abstract: CRISPR systems are widespread in the prokaryotic world, providing adaptive immunity against mobile genetic elements1,2. Type III CRISPR systems, with the signature gene cas10, use CRISPR RNA to detect non-self RNA, activating the enzymatic Cas10 subunit to defend the cell against mobile genetic elements either directly, via the integral histidine–aspartate (HD) nuclease domain3,4,5 or indirectly, via synthesis of cyclic oligoadenylate second messengers to activate diverse ancillary effectors6,7,8,9. A subset of type III CRISPR systems encode an uncharacterized CorA-family membrane protein and an associated NrN family phosphodiesterase that are predicted to function in antiviral defence. Here we demonstrate that the CorA-associated type III-B (Cmr) CRISPR system from Bacteroides fragilis provides immunity against mobile genetic elements when expressed in Escherichia coli. However, B. fragilis Cmr does not synthesize cyclic oligoadenylate species on activation, instead generating S-adenosyl methionine (SAM)-AMP (SAM is also known as AdoMet) by conjugating ATP to SAM via a phosphodiester bond. Once synthesized, SAM-AMP binds to the CorA effector, presumably leading to cell dormancy or death by disruption of the membrane integrity. SAM-AMP is degraded by CRISPR-associated phosphodiesterases or a SAM-AMP lyase, potentially providing an ‘off switch’ analogous to cyclic oligoadenylate-specific ring nucleases10. SAM-AMP thus represents a new class of second messenger for antiviral signalling, which may function in different roles in diverse cellular contexts.

DOI: 10.1038/s41586-023-06620-5

Source: https://www.nature.com/articles/s41586-023-06620-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html