Toxin-antitoxin systems as multilevel interaction systems

Abstract

Toxin-antitoxin (TA) systems are small genetic modules usually composed of a toxin and an antitoxin counteracting the activity of the toxic protein. These systems are widely spread in bacterial and archaeal genomes. TA systems have been assigned many functions, ranging from persistence to DNA stabilization or protection against mobile genetic elements. They are classified in five types, depending on the nature and mode of action of the antitoxin. In type I and III, antitoxins are RNAs that either inhibit the synthesis of the toxin or sequester it. In type II, IV and V, antitoxins are proteins that either sequester, counterbalance toxin activity or inhibit toxin synthesis. In addition to these interactions between the antitoxin and toxin components (RNA-RNA, protein-protein, RNA-protein), TA systems interact with a variety of cellular factors, e.g., toxins target essential cellular components, antitoxins are degraded by RNAses or ATP-dependent proteases. Hence, TA systems have the capacity to interact with each other at different levels. In this review, we will discuss the different interactions in which TA systems are involved and their implications in TA system functions and evolution.

Figure 1

The addiction phenomenon. Toxin-antitoxin (TA) systems participate in plasmid maintenance in growing bacterial populations by a mechanism called addiction or post-segregational killing. Addiction relies on the differential stability of the toxin and antitoxin. A: Daughter-bacteria that inherit a plasmid copy encoding the ccd (control of cell death) toxin-antitoxin system grow normally. B: Daughter-bacteria that do not inherit a plasmid copy still have antitoxin-toxin complexes in their cytoplasm. C: The CcdA antitoxin (light green) is degraded by the Lon protease, while the CcdB toxin (dark green) is stable. CcdB is, therefore, liberated from the CcdA-CcdB complex and is able to interact with DNA-gyrase, a class II topoisomerase. The interaction of CcdB with DNA-gyrase inhibits DNA replication and leads eventually to cell death. Addiction leads to the selective killing of plasmid-free daughter bacteria and increases plasmid prevalence in the bacterial population.

Figure 2

Interactions between TA systems. (A) In most cases, antitoxins and toxins only interact with their cognate partners; (B) chromosomal systems can interact with homologous systems, such as for anti-addiction; (C) TA systems can bind non-canonical antitoxins and toxins, which can lead to network formation and (D) a toxin can be inhibited by a protein not related to TA systems, as in the case of Dmd of the T4 phage.