Tripartite toxin-antitoxin systems: expanding the paradigm of molecular interplay and antiphage defense.

Prokaryotic toxin-antitoxin (TA) systems are genetic modules involved in stress responses, including antiphage defense and the maintenance of mobile genetic elements. Although canonical TA systems consist of two neighboring genes encoding one toxin and one antitoxin, many have evolved into tripartite systems through the incorporation of a third component that serves as a chaperone, a regulator, or an additional antitoxin or toxin to increase functional diversity and regulatory potential. This review compares tripartite TA systems [TA-chaperone (TAC), TA-regulator (TAR), dual-antitoxin, and dual-toxin systems] with bipartite systems, summarizing their neutralizing mechanisms and phage-triggered activation pathways. The regulatory capacity and modularity of tripartite TAs illuminate the evolutionary trajectory of these 'selfish' genetic elements, reflecting complex coevolutionary dynamics among TA systems, host bacteria, and phages.