小柯机器人

美国德克萨斯大学陈志坚研究团队发现，细菌cGAS介导的泛素样偶联增强抗噬菌体防御。相关论文于2023年2月27日在线发表在《自然》杂志上。

研究人员表示，cGAS是一种演化上保守的酶，在抵抗感染的免疫防御中起着关键的作用。在脊椎动物中，cGAS被DNA激活，产生环状GMP-AMP（cGAMP），从而导致抗菌基因的表达。在细菌中，已经发现基于环状二核苷酸（CDN）的抗噬菌体信号系统（CBASS）。这些系统由类似cGAS的酶和各种效应蛋白组成，在噬菌体感染时杀死细菌，从而阻止噬菌体传播。在报道的CBASS系统中，约39%含有Cap2和Cap3，它们分别编码与泛素结合（E1/E2）和解结合（DUB）酶同源的蛋白。尽管这些蛋白是防止某些噬菌体感染所需的，但其酶活性发挥抗噬菌体作用的机制尚不清楚。

研究人员表明Cap2与cGAS的C端甘氨酸形成硫酯键，并促进cGAS与目标蛋白的偶联，这一过程类似于泛素偶联。cGAS的共价偶联增加了cGAMP的产生。通过遗传筛选，研究人员发现噬菌体蛋白Vs.4通过与cGAMP紧密结合（Kd ~30nM）并将其封存来拮抗cGAS信号。与cGAMP结合的Vs.4的晶体结构显示，Vs.4形成一个六聚体，与三个分子的cGAMP结合。这些结果揭示了一种类似于泛素的偶联机制，调节细菌中cGAS的活性，并说明了细菌和病毒之间通过控制CDN水平进行的军备竞赛。

附：英文原文

Title: Ubiquitin-like Conjugation by Bacterial cGAS Enhances Anti-phage Defence

Author: Jenson, Justin M., Li, Tuo, Du, Fenghe, Ea, Chee-Kwee, Chen, Zhijian J.

Issue&Volume: 2023-02-27

Abstract: cGAS is an evolutionarily conserved enzyme that plays a pivotal role in immune defense against infection1-3. In vertebrate animals, cGAS is activated by DNA to produce cyclic GMP-AMP (cGAMP)4,5, which leads to the expression of antimicrobial genes6,7. In bacteria, cyclic dinucleotide (CDN)-based anti-phage signaling systems (CBASS) have been discovered8-11. These systems are composed of cGAS-like enzymes and various effector proteins that kill bacteria upon phage infection, thereby stopping phage spread. Of the CBASS systems reported, ~39% contain Cap2 and Cap3, which encode proteins with homology to ubiquitin conjugating (E1/E2) and deconjugating (DUB) enzymes, respectively8,12. Although these proteins are required to prevent infection of some bacteriophages8, the mechanism by which the enzymatic activities exert anti-phage effect is unknown. Here, we show that Cap2 forms a thioester bond with the C-terminal glycine of cGAS and promotes conjugation of cGAS to target proteins in a process that resembles ubiquitin conjugation. The covalent conjugation of cGAS increased the production of cGAMP. Through a genetic screen, we found that the phage protein Vs.4 antagonized cGAS signaling by binding tightly to cGAMP (Kd ~30 nM) and sequestering it. A crystal structure of Vs.4 bound to cGAMP showed that Vs.4 formed a hexamer that bound to three molecules of cGAMP. These results reveal a ubiquitin-like conjugation mechanism that regulates cGAS activity in bacteria and illustrate an arms race between bacteria and viruses through controlling CDN levels.

DOI: 10.1038/s41586-023-05862-7

Source: https://www.nature.com/articles/s41586-023-05862-7

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