Phage anti-CBASS protein simultaneously sequesters cyclic trinucleotides and dinucleotides.
Phage anti-CBASS protein simultaneously sequesters cyclic trinucleotides and dinucleotides.
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噬菌体抗 CBASS 蛋白同时隔离环状三核苷酸和二核苷酸。
DOI：
10.1101/2023.06.01.543220
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Feng,Yue
中科院分区：
文献类型：
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作者：
Cao,Xueli;Xiao,Yu;Huiting,Erin;Cao,Xujun;Li,Dong;Ren,Jie;Guan,Linlin;Wang,Yu;Li,Lingyin;Bondy-Denomy,Joseph;Feng,Yue
基于环状寡核苷酸的抗噬菌体信号系统（CBASS）是一种常见的免疫系统，它使用环状寡核苷酸信号来限制噬菌体复制。反过来，噬菌体编码抗 CBASS (Acb) 蛋白，例如 Acb2，它可以隔离一些环状二核苷酸 (CDN) 并限制下游效应子激活。在这里，我们发现 Acb2 隔离了 CBASS 系统产生的许多 CDN，并抑制人类细胞中干扰素基因刺激物 (STING) 的活性。令人惊讶的是，Acb2 六聚体还在与 CDN 不同的位点以高亲和力与 CBASS 环状三核苷酸 (CTN) 3'3'3'-环状 AMP-AMP-AMP 和 3'3'3'-cAAG 结合。一个Acb2六聚体可以同时结合两个CTN和三个CDN。噬菌体编码的 Acb2 可针对使用 cA3 信号分子的 III-C 型 CBASS 提供保护。此外，对不同噬菌体和原噬菌体编码的超过 2,000 个 Acb2 同源物的系统发育分析表明，大多数预计会结合 CTN 和 CDN。总之，Acb2 通过两个不同的结合袋隔离几乎所有已知的 CBASS 信号分子，因此可作为基于 cGAS 的免疫的广谱抑制剂。
Cyclic-oligonucleotide-based anti-phage signaling system (CBASS) is a common immune system that uses cyclic oligonucleotide signals to limit phage replication. In turn, phages encode anti-CBASS (Acb) proteins such as Acb2, which can sequester some cyclic dinucleotides (CDNs) and limit downstream effector activation. Here, we identified that Acb2 sequesters many CDNs produced by CBASS systems and inhibits stimulator of interferon genes (STING) activity in human cells. Surprisingly, the Acb2 hexamer also binds with high affinity to CBASS cyclic trinucleotides (CTNs) 3′3′3′-cyclic AMP-AMP-AMP and 3′3′3′-cAAG at a distinct site from CDNs. One Acb2 hexamer can simultaneously bind two CTNs and three CDNs. Phage-encoded Acb2 provides protection from type III-C CBASS that uses cA3signaling molecules. Moreover, phylogenetic analysis of >2,000 Acb2 homologs encoded by diverse phages and prophages revealed that most are expected to bind both CTNs and CDNs. Altogether, Acb2 sequesters nearly all known CBASS signaling molecules through two distinct binding pockets and therefore serves as a broad-spectrum inhibitor of cGAS-based immunity.