Bacterial Toxin–Antitoxin Systems: More Than Selfish Entities?
Laurence Van Melderen and Manuel Saavedra De Bast

Bacterial Toxin-Antitoxin systems are diverse and widespread in the prokaryotic world. They are composed of two components, a toxin that can harm the host and its corresponding antitoxin that is needed by the host to prevent cell death. TA systems that are found on chromosomes are hypothesized to have been acquired by horizontal gene transfer. Some bacteria are known to have around 50 putative TA systems such as Nitrosomonas europeae, and Sinorhizobium meliloti. Others have none or a few TA systems. Plasmid encoded TA systems act as addiction modules and help in maintaining plasmid-containing cells. Thus, while the function of plasmid encoded TA systems is well known, those found on chromosomes are not as well understood. There are several theories on the physiological roles of chromosomal TA systems. Following are some of these proposed models:
1) The programmed cell death model: This model is based on the chromosomally located mazEF system of E. coli [1]. Under conditions of stress such as amino acid starvation, high temperature or presence of antibiotics, transcription of mazEF is affected. This is followed by degradation of MazE (antitoxin) by an ATP-dependent protease and subsequent toxification by previously produced MazF (toxin). This in turn leads to cell death.
2) The growth modulation model: This model is based on the relBE system of E coli [2,3]. The primary difference between this model and the previous one is that this model proposes cell growth inhibition under conditions of amino acid starvation and not cell death.
3) The developmental model: This model was proposed for the toxin gene in Myxococcus xanthus [4] an organism that forms fruiting bodies under nutrient starved conditions. The genome of this organism has a homologue of the mazF toxin gene. During fruiting body formation, MazF protein is produced which induces cell death. In fact, nearly 80% of the cells that undergo fruiting body formation die by lysis. However, MazF has also been found to be essential for fruiting body formation.
4) The stabilization model: The model proposes that TA systems could help stabilize some regions of the genome that are unstable and prone to being lost [5]. Such TA systems are often found on structures called super integrons that carry many essential and non-essential genes. The TA systems stabilize the super integrons as well as unstable plasmids or genomic regions.
5) The anti-addiction model: This model proposes that chromosomal TA systems can benefit their hosts during post seggregational killing [6]. The chromosomal TA system of Erwinia chrysanthemi 3937 was found to prevent post seggregational killing of bacterial cell after loss of plasmid.
The above models show the different ways in which TA systems can confer a selective advantage to their hosts.
Thus TA systems on chromosomes are diverse and have evolved multiple roles from being simple addiction modules to more complex systems involved in cell physiology.
References:
[1] Engelberg-Kulka H, Amitai S, Kolodkin-Gal I, Hazan R. Bacterial programmed cell death and multicellular behavior in bacteria. PLoS Genet. 2006;2:e135. doi:10.1371/journal.pgen.0020135.
[2] Christensen SK, Mikkelsen M, Pedersen K, Gerdes K. RelE, a global inhibitor of translation, is activated during nutritional stress. Proc Natl Acad Sci U S A. 2001;98: 14328–14333.
[3] Christensen SK, Pedersen K, Hansen FG, Gerdes K. Toxin-antitoxin loci as stress-response-elements: ChpAK/MazF and ChpBK cleave translated RNAs and are counteracted by tmRNA. J Mol Biol. 2003; 332:809–819.
[4] Nariya H, Inouye M. MazF, an mRNA interferase, mediates programmed cell death during multicellular Myxococcus development. Cell. 2008;132:55–66.
[5] Rowe-Magnus DA, Guerout AM, Biskri L, Bouige P, Mazel D. Comparative analysis of superintegrons: engineering extensive genetic diversity in the Vibrionaceae. Genome Res. 2003;13:428–442.
[6] Saavedra De Bast M, Mine N, Van Melderen L. Chromosomal toxin-antitoxin systems may act as antiaddiction modules. J Bacteriol. 2008;190:4603–4609.


DIYA SEN
GRADUATE STUDENT
BIOLOGICAL SCIENCES
UNIVERSITY OF IDAHO