Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence.
Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence.
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DOI：
10.1038/s41586-023-05862-7
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发表时间：
2023-04
期刊：
影响因子：
64.8
通讯作者：
Chen ZJ
中科院分区：
文献类型：
--
作者：
Jenson JM;Li T;Du F;Ea CK;Chen ZJ
cGAS是一种进化保守的酶，在免疫防御感染中起着关键作用。在脊椎动物中，cGAS被DNA激活产生环状GMP-AMP (cGAMP)，导致抗菌基因的表达。在细菌中，基于环二核苷酸（CDN）的抗噬菌体信号系统（CBASS）已经被发现。这些系统由cgas样酶和各种效应蛋白组成，这些效应蛋白在噬菌体感染时杀死细菌，从而阻止噬菌体扩散。在报道的CBASS系统中，大约39%含有Cap2和Cap3，它们分别编码与泛素偶联酶（E1/E2）和解偶联酶同源的蛋白质。虽然这些蛋白质是防止某些噬菌体感染所必需的，但酶活性发挥抗噬菌体作用的机制尚不清楚。本研究表明，Cap2与cGAS的c端甘氨酸形成硫酯键，并促进cGAS与靶蛋白的结合，其过程类似于泛素结合。cGAS的共价偶联增加了cGAMP的产生。通过基因筛选，我们发现噬菌体蛋白Vs.4通过与cGAMP紧密结合（解离常数约为30 nM）并将其隔离，从而拮抗cGAS信号。结合cGAMP的v .4晶体结构表明，v .4形成了一个六聚体，与三个cGAMP分子结合。这些结果揭示了细菌中调控cGAS活性的泛素样偶联机制，并说明了细菌和病毒之间通过控制CDN水平进行军备竞赛。基于环二核苷酸的抗噬菌体免疫系统的Cap2通过泛素样偶联机制调节cGAS活性。
cGAS is an evolutionarily conserved enzyme that has a pivotal role in immune defence against infection. In vertebrate animals, cGAS is activated by DNA to produce cyclic GMP–AMP (cGAMP), which leads to the expression of antimicrobial genes. In bacteria, cyclic dinucleotide (CDN)-based anti-phage signalling systems (CBASS) have been discovered. These systems are composed of cGAS-like enzymes and various effector proteins that kill bacteria on phage infection, thereby stopping phage spread. Of the CBASS systems reported, approximately 39% contain Cap2 and Cap3, which encode proteins with homology to ubiquitin conjugating (E1/E2) and deconjugating enzymes, respectively. Although these proteins are required to prevent infection of some bacteriophages, the mechanism by which the enzymatic activities exert an 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 increases the production of cGAMP. Using a genetic screen, we found that the phage protein Vs.4 antagonized cGAS signalling by binding tightly to cGAMP (dissociation constant of approximately 30 nM) and sequestering it. A crystal structure of Vs.4 bound to cGAMP showed that Vs.4 formed a hexamer that was bound to three molecules of cGAMP. These results reveal a ubiquitin-like conjugation mechanism that regulates cGAS activity in bacteria and illustrates an arms race between bacteria and viruses through controlling CDN levels. Cap2 of the cyclic dinucleotide-based anti-phage immune system functions through a ubiquitin-like conjugation mechanism to regulate cGAS activity.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
28.3
作者：
Millman A;Melamed S;Amitai G;Sorek R
通讯作者：
Sorek R
影响因子：
14.9
作者：
Letunic I;Bork P
通讯作者：
Bork P
影响因子：
64.8
作者：
Ichimura, Y;Kirisako, T;Ohsumi, Y
通讯作者：
Ohsumi, Y
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.