Single phage proteins sequester TIR- and cGAS-generated signaling molecules.
Single phage proteins sequester TIR- and cGAS-generated signaling molecules.
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单噬菌体蛋白隔离 TIR 和 cGAS 生成的信号分子。
DOI：
10.1101/2023.11.15.567273
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Feng,Yue
中科院分区：
文献类型：
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作者：
Li,Dong;Xiao,Yu;Xiong,Weijia;Fedorova,Iana;Wang,Yu;Liu,Xi;Huiting,Erin;Ren,Jie;Gao,Zirui;Zhao,Xingyu;Cao,Xueli;Zhang,Yi;Bondy-Denomy,Joseph;Feng,Yue
原核抗噬菌体免疫系统利用Toll/IL-1受体和cGAS(环状GMP-AMP合成酶)产生1“-3‘/1”-2’糖环ADPR(GcADPR)和环状二/三核苷酸(CDN和CTN)信号分子，分别限制噬菌体复制1-3。然而，噬菌体如何中和这些共同的系统在很大程度上是未知的。在这里，我们证明了Thoeris抗防御蛋白Tad1 4和Tad2 5都通过同时隔离CBass环寡核苷酸而具有抗CBass活性。值得注意的是，除了结合Thoeris信号1“-3‘和1”-2’gcADPR外，Tad1还以高亲和力结合大量的CBass CDN/CTN，在体内和体外抑制使用这些分子的CBass系统。六聚体Tad1有6个CDN或gcADPR结合位点，它们独立于CTN的两个高亲和力结合位点。除gcADPR分子外，Tad2还隔离各种CDN，抑制使用这些CDN的CBASS系统。然而，CDNS和gcADPR的结合口袋在Tad2中是不同的，因此一个四聚体可以同时结合两个CDN和两个gcADPR分子。总而言之，Tad1和Tad2都是双管齐下的抑制剂，与抗CBass蛋白2一起，建立了一个噬菌体蛋白范例，灵活地隔离了参与TIR和cGAS抗噬菌体免疫的大量环核苷酸。
Prokaryotic anti-phage immune systems use TIR (toll/interleukin-1 receptor) and cGAS (cyclic GMP-AMP synthase) enzymes to produce 1”-3’/1”-2’ glycocyclic ADPR (gcADPR) and cyclid di-/trinucleotides (CDNs and CTNs) signaling molecules that limit phage replication, respectively 1–3. However, how phages neutralize these common systems is largely unknown. Here, we show that Thoeris anti-defense proteins Tad1 4 and Tad2 5 both have anti-CBASS activity by simultaneously sequestering CBASS cyclic oligonucleotides. Strikingly, apart from binding Thoeris signals 1”-3’ and 1”-2’ gcADPR, Tad1 also binds numerous CBASS CDNs/CTNs with high affinity, inhibiting CBASS systems using these molecules in vivo and in vitro. The hexameric Tad1 has six binding sites for CDNs or gcADPR, which are independent from two high affinity binding sites for CTNs. Tad2 also sequesters various CDNs in addition to gcADPR molecules, inhibiting CBASS systems using these CDNs. However, the binding pockets for CDNs and gcADPR are different in Tad2, whereby a tetramer can bind two CDNs and two gcADPR molecules simultaneously. Taken together, Tad1 and Tad2 are both two-pronged inhibitors that, alongside anti-CBASS protein 2, establish a paradigm of phage proteins that flexibly sequester a remarkable breadth of cyclic nucleotides involved in TIR- and cGAS-based anti-phage immunity.