A novel immunity system for bacterial nucleic acid degrading toxins and its recruitment in various eukaryotic and DNA viral systems

Zhang, Dapeng; Iyer, Lakshminarayan M.; Aravind, L.

Other auxiliary domains which might play a role in resistance, trafficking or processing of toxins. Several other domain families were found to be encoded by genes having persistent association with the SUKH superfamily neighborhoods across distantly related bacterial species. One of these is the SuFu superfamily ( Figure 2 and Supplementary Data) prototyped by the Suppressor of Fused protein from Drosophila (69). In addition, we also detected members of this superfamily to be encoded by CDI-like operons, such as the one from N. gonorrhoeae that encodes a toxin with a distinct version of the HNH fold nuclease domain (toxin NGO1392, gi: 59801740; Supplementary Data). In these cases the SuFu superfamily gene occupies a position equivalent to that of the SUKH superfamily gene, suggesting that they might be functionally comparable. We also found several examples wherein the SuFu and SUKH domains are combined in the same polypeptide (Figures 1 and 5) . Based on these associations we propose that the SuFu domain represents a second widely conserved domain that function as an immunity protein for diverse nuclease toxins. Two other conserved protein families are encoded in the toxin neighborhoods (SUKH-neighborhood conserved family 1 and 2; SNCF1 and SNCF2, Supplementary Data) that occupy positions similar to the SUKH and SuFu superfamily genes ( Figure 2 ). They were not found in multi-domain architectures typical of the nuclease toxins and always occurred as proteins with standalone domains. This suggested that they were unlikely to be novel toxins but act as alternative immunity proteins just like the SuFu and SUKH superfamily proteins. The HINT domain, prototyped by the peptidase domains of the animal hedgehog proteins and protein-splicing inteins, is also frequently associated with SUKH superfamily neighborhoods (70) (71) (72) . These versions of the HINT domain are closer to those found in several bacterial surface proteins and the secreted animal proteins such as hedgehog and the C. elegans Hog proteins (70) . When present in a multidomain 'pro-toxin' protein, the HINT domain always occurs sandwiched between the PT domains such as PT-VENN and PT-TG and the nuclease toxin domain. This location of the HINT domain suggests that it is likely to serve as a peptidase that undergoes autoproteolytic cleavage, similar to what is observed in hedgehog and the inteins (70) , to release the C-terminal nuclease domain for uptake by the target cell. It is conceivable that this cleavage step is regulated by the interaction of the PT domains with the surface receptor on the target cell.