Toxin ζ Triggers a Survival Response to Cope with Stress and Persistence.

María Moreno-Del Álamo,Mariangela Tabone,Juan C Alonso,Virginia S Lioy

doi:10.3389/fmicb.2017.01130

María Moreno-Del Álamo, Mariangela Tabone + Show 2 more

Open Access

https://doi.org/10.3389/fmicb.2017.01130

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Abstract

Bacteria have evolved complex regulatory controls in response to various environmental stresses. Protein toxins of the ζ superfamily, found in prominent human pathogens, are broadly distributed in nature. We show that ζ is a uridine diphosphate-N-acetylglucosamine (UNAG)-dependent ATPase whose activity is inhibited in vitro by stoichiometric concentrations of ε2 antitoxin. In vivo, transient ζ expression promotes a reversible multi-level response by altering the pool of signaling purine nucleotides, which leads to growth arrest (dormancy), although a small cell subpopulation persists rather than tolerating toxin action. High c-di-AMP levels (absence of phosphodiesterase GdpP) decrease, and low c-di-AMP levels (absence of diadenylate cyclase DisA) increase the rate of ζ persistence. The absence of CodY, a transition regulator from exponential to stationary phase, sensitizes cells to toxin action, and suppresses persisters formed in the ΔdisA context. These changes, which do not affect the levels of stochastic ampicillin (Amp) persistence, sensitize cells to toxin and Amp action. Our findings provide an explanation for the connection between ζ-mediated growth arrest (with alterations in the GTP and c-di-AMP pools) and persistence formation.

Highlights

The toxin-antitoxin (TA) systems are widely distributed in free-living bacteria, in their extrachromosomal elements, and in archaea (Gerdes, 2013; Unterholzner et al, 2013)
Toxin ζ represents a class of uridine diphosphate-N-acetylglucosamine (UNAG)-dependent ATPases (Figure 2A). As another mechanism to halt cell proliferation, toxin ζ catalyzes the transfer of part of the ATP γ-phosphate generated upon ATP hydrolysis to a fraction of UNAG, to yield unreactive UNAG-3P (Mutschler et al, 2011; Tabone et al, 2014a)
Stoichiometric concentrations of purified antitoxin ε2 are necessary and sufficient to inactivate toxin ζ action, which suggests that no other factor contributes to ζ inactivation in vitro

Summary

Introduction

The toxin-antitoxin (TA) systems are widely distributed in free-living bacteria, in their extrachromosomal elements, and in archaea (Gerdes, 2013; Unterholzner et al, 2013). The toxins of all known TA systems are proteins while the antitoxins are either proteins or non-coding RNAs. The TA systems are classified into five different TA types (Yamaguchi et al, 2011), being the most broadly distributed the type II TA system, where both the toxin and the antitoxin are proteins (Leplae et al, 2011; Gerdes, 2013). Toxins of the ζ/PezT superfamily, which are among the most broadly distributed in nature, are found in major human pathogens and in environmentally important bacteria of the phylum Firmicutes (Mutschler and Meinhart, 2013).

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