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

• 成果类型: Article
• 署名作者: 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
• 署名单位: Beijing University of Chemical Technology; Chinese Academy of Sciences; Tsinghua University; University of California System; University of California San Francisco; Chinese Academy of Agricultural Sciences; Institute of Plant Protection, CAAS; University of California System; University of California San Francisco
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5980
• DOI: 10.1038/s41586-024-08122-4
• 发表日期: 2024-11-21
• 页码: 719-+
• 关键词: antiviral immunity; pseudomonas; bacteria

摘要

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 replication(1-3). However, how phages neutralize these distinct and common systems is largely unclear. Here we show that the Thoeris anti-defence proteins Tad1(4) and Tad2(5) 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 (Acb2(6-8)), establish a paradigm of phage proteins that use distinct binding sites to flexibly sequester a considerable breadth of cyclic nucleotides.