Functional diversity of phage sponge proteins that sequester host immune signals

Many bacterial immune systems use signalling molecules that activate the immune response following phage infection. Phages counteract bacterial immune signalling using sponge proteins that bind and sequester the immune signals, but their functional diversity and versatility have not been fully explored. Here we study Acb2, Tad1 and Tad2, three families of sponge proteins known to inhibit CBASS (cyclic oligonucleotide-based anti-phage signalling system) and Thoeris signalling. Eighty-four proteins representing the phylogenetic diversity of these sponge families were tested for their ability to inhibit immunity by sequestering seven distinct signals from CBASS, Thoeris and Pycsar defence systems. While Acb2 proteins were so far reported to inhibit only CBASS, we found Acb2 homologues that bind 3'cADPR and inhibit Thoeris defence. We also discovered sponge proteins that inhibit Pycsar and type IV Thoeris by binding cUMP and N7-cADPR, respectively. Using crystal structures, structural modelling and biochemical analyses, we explain the molecular basis for signal-binding specificities in these sponge families.