北京化工大学生命科学与技术学院冯越等共同合作，近期取得重要工作进展。他们研究发现，单个噬菌体蛋白可隔离来自TIR和cGAS类酶的信号。相关研究成果2024年10月30日在线发表于《自然》杂志上。

据介绍，原核生物抗噬菌体免疫系统利用TIR和cGAS样酶分别产生1′′-3′-糖环状ADP-核糖（1′′-3′-gcADPR）以及环状二核苷酸（CDN）和环状三核苷酸（CTN）信号分子，从而限制噬菌体复制。然而，噬菌体如何中和这些不同且常见的系统在很大程度上仍不清楚。

研究人员发现Thoeris抗防御蛋白Tad1和Tad2均通过同时结合CBASS环状寡核苷酸来实现抗环状寡核苷酸抗噬菌体信号系统（anti-CBASS）活性。除了与Thoeris信号1′′-3′-gcADPR和1′′-2′-gcADPR结合外，Tad1还高亲和力地结合了多种CBASS CDN和CTN，抑制了在体内和体外使用这些分子的CBASS系统。

六聚体Tad1具有六个CDN或gcADPR结合位点，这些位点独立于两个CTN的高亲和力结合位点。Tad2形成四聚体，除gcADPR分子外，还通过不同的结合位点同时结合多种CDN。因此，Tad1和Tad2都是双重抑制剂，与anti-CBASS蛋白2（Acb2）一起，建立了一个噬菌体蛋白范式，即通过不同的结合位点灵活地结合和隔离大量环状核苷酸。

附：英文原文

Title: Single phage proteins sequester signals from TIR and cGAS-like enzymes

Author: Li, Dong, Xiao, Yu, Fedorova, Iana, Xiong, Weijia, Wang, Yu, Liu, Xi, Huiting, Erin, Ren, Jie, Gao, Zirui, Zhao, Xingyu, Cao, Xueli, Zhang, Yi, Bondy-Denomy, Joseph, Feng, Yue

Issue&Volume: 2024-10-30

Abstract: Prokaryotic anti-phage immune systems use TIR and cGAS-like enzymes to produce 1′′-3′-glycocyclic ADP-ribose (1′′-3′-gcADPR) and cyclic dinucleotide (CDN) and cyclic trinucleotide (CTN) signalling molecules, respectively, which limit phage replication1,2,3. However, how phages neutralize these distinct and common systems is largely unclear. Here we show that the Thoeris anti-defence proteins Tad14 and Tad25 both achieve anti-cyclic-oligonucleotide-based anti-phage signalling system (anti-CBASS) activity by simultaneously sequestering CBASS cyclic oligonucleotides. Apart from binding to the Thoeris signals 1′′-3′-gcADPR and 1′′-2′-gcADPR, Tad1 also binds to numerous CBASS CDNs and CTNs with high affinity, inhibiting CBASS systems that use these molecules in vivo and in vitro. The hexameric Tad1 has six binding sites for CDNs or gcADPR, which are independent of the two high-affinity binding sites for CTNs. Tad2 forms a tetramer that also sequesters various CDNs in addition to gcADPR molecules, using distinct binding sites to simultaneously bind to these signals. Thus, Tad1 and Tad2 are both two-pronged inhibitors that, alongside anti-CBASS protein 2 (Acb26,7,8), establish a paradigm of phage proteins that use distinct binding sites to flexibly sequester a considerable breadth of cyclic nucleotides.

DOI: 10.1038/s41586-024-08122-4

Source: https://www.nature.com/articles/s41586-024-08122-4