Non-cognate immunity proteins provide broader defenses against interbacterial effectors in microbial communities

Abstract Dense microbial communities, like the gut and soil microbiomes, are dynamic societies. Bacteria can navigate these environments by deploying proteins (effectors) that alter foreign cells’ behavior. Immunity proteins preferentially protect neighboring sibling cells, in contrast to canonical toxin-antitoxin systems. A prevailing hypothesis is that when immunity proteins are bound to specific (cognate) protein partners, it is sufficient to disrupt their function; further, there is little-to-no crosstalk with other (non-cognate) effectors. Here, we build on sporadic reports challenging these hypotheses. We show that immunity proteins from a newly defined protein family can bind and protect against non-cognate PD-(D/E)XK-containing effectors from diverse phyla. We describe the domains essential for binding and function and show that binding alone is insufficient for protective activity. Moreover, we found that these effector and immunity genes co-occur in individual human microbiomes. These results expand the growing repertoire of bacterial protection mechanisms and force us to reconsider how non-cognate interactions impact community structure within complex ecosystems.