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

Dong Li, Yu Xiao, Iana Fedorova, Weijia Xiong, Yu Wang, Xi Liu, Erin Huiting, Jie Ren, Zirui Gao, Xingyu Zhao, Xueli Cao, Yi Zhang, Joseph Bondy-Denomy () and Yue Feng ()
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Dong Li: Beijing University of Chemical Technology
Yu Xiao: Chinese Academy of Sciences
Iana Fedorova: San Francisco
Weijia Xiong: Beijing University of Chemical Technology
Yu Wang: Beijing University of Chemical Technology
Xi Liu: Beijing University of Chemical Technology
Erin Huiting: San Francisco
Jie Ren: Chinese Academy of Agricultural Sciences
Zirui Gao: Beijing University of Chemical Technology
Xingyu Zhao: Beijing University of Chemical Technology
Xueli Cao: Beijing University of Chemical Technology
Yi Zhang: Beijing University of Chemical Technology
Joseph Bondy-Denomy: San Francisco
Yue Feng: Beijing University of Chemical Technology

Nature, 2024, vol. 635, issue 8039, 719-727

Abstract: 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 replication1–3. 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 (Acb26–8), establish a paradigm of phage proteins that use distinct binding sites to flexibly sequester a considerable breadth of cyclic nucleotides.

Date: 2024
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DOI: 10.1038/s41586-024-08122-4

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