Post-Segregational Killing, Altruistic Cell Death, and Other Toxin/Antitoxin Fallacies

Abstract

The toxin/antitoxin (TA) field, born of controversy, is plagued by several prevailing misperceptions.For example, some TA systems stabilize plasmids and other genomic regions; however, the evidence of post-segregational killing by toxins of TA systems is weak. In addition, there are few credible reports of cell death via TA systems like MazF/MazE and via phage exclusion systems. Although many aspects of 5 the biological roles of TA systems remain enigmatic, there are now some clear, confirmed TA functions:(i) phage inhibition, (ii) plasmid maintenance, (iii) stress response (including regulation of loci distinct from the TA pair itself), (iv) biofilm formation, and (v) persistence. Therefore, this opinion piece aims to challenge the oft-repeated dogma related to TA systems with the goal of emphasizing their primary biological role: constraining metabolism in a reversible manner. Hence, their roles in their five confirmed 10 functions all stem from their ability to rapidly and reversibly reduce metabolic activity. REVIEWWe recently elucidated several misperceptions in a field related to toxin/antitoxin (TA) systems, persister cell biology Wood, 2016, 2017). Here, in the following sections, we aim to initiate a similar discussion about several dubious yet entrenched theories that are related to TA systems. Most of 15 these misperceptions are based on overproducing toxins; i.e., many toxins of TA systems appear lethal if produced from a strong promoter. However, conclusions based on overproducing proteins are seldom relevant for physiological conditions. Nebulous nomenclature. Historically, TA systems were deemed cytosolic (not secreted); hence, TA system toxins were considered primarily to affect the metabolism of the host that produced it rather than 20 as serving as a weapon against other cells, such as colicins (Rendueles, et al., 2014). With a better understanding of their biological function, growth diminution as opposed to cell death, TA systems would be more aptly named "growth inhibitors" and "silencers of growth inhibitors," rather than "toxins," which imply a poison used against competitors rather than an internal means to reduce metabolism. However, little would be served, and much confusion would ensue, if the name of the field was changed now. 25Moreover, TA system components have now starting to be found outside the cell. For example, the Song and Wood 3 type VII secretion system DNase toxin EsaD of the EsaD/EsaG TA system of Staphylococcus aureus (Cao, et al., 2016) is secreted for bacterial competitiveness; this is the second known toxin that is a DNase with RalR of the E. coli RalR/RalA TA system being the first (Guo, et al., 2014). The Xanthomonas oryzae type III secretion system toxin AvrRxo1 of the AvrRxo1/Arc1 TA system is also secreted into 30 plants and modifies nicotinamide adenine dinucleotide. Additionally, antitoxin MqsA of the MqsR/MqsA TA system of Xylella fastidiosa (Santiago, et al., 2016) is secreted via outer membrane vesicles.Therefore, the distinction between external to...

The coordination of anti-phage immunity mechanisms in bacterial cells

“…Abi systems have also been reported to induce a state of dormancy in infected cells by reducing their metabolic rate 5,12,17,44 . This behavior is usually interpreted as an alternative to suicidal death intended to buy time for the action of other immune mechanisms 12 .…”