RNA-based regulation in type I toxin–antitoxin systems and its implication for bacterial persistence
RNA‑based regulation in type I toxin-antitoxin systems and its implication for bacterial persistence
Bork A. Berghoff 0 1
E. Gerhart H. Wagner 0
0 Department of Cell and Molecular Biology, Uppsala University , 75124 Uppsala , Sweden
1 Institut für Mikrobiologie und Molekularbiologie, Justus-Liebig-Universität , 35392 Giessen , Germany
2 E. Gerhart H. Wagner
Bacterial dormancy is a valuable survival strategy upon challenging environmental conditions. Dormant cells tolerate the consequences of high stress levels and may re-populate the environment upon return to favorable conditions. Antibiotic-tolerant bacteria-termed persisters-regularly cause relapsing infections, increase the likelihood of antibiotic resistance, and, therefore, earn increasing attention. Their generation often depends on toxins from chromosomal toxin-antitoxin systems. Here, we review recent insights concerning RNA-based control of toxin synthesis, and discuss possible implications for persister generation. Communicated by M. Kupiec. * Bork A. Berghoff
Toxin-antitoxin; Antisense RNA; 5′ UTR structure; Persistence; Depolarization; SOS response
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Every organism’s future is unwritten and to a large extent
unpredictable. We—as human beings—are aware of this
unpleasant fact and try to safeguard ourselves by sanitary
and monetary protection. Even though simple organisms
like bacteria are not “aware” of the inevitable risks of life,
they have inherited genetic programs that have ensured
their survival in the past and will do so in the future.
Generating phenotypic heterogeneity in a clonal population
of bacteria is considered a successful survival strategy,
often referred to as bet-hedging (Veening et al. 2008). For
example, most bacteria generate subpopulations of
nongrowing (i.e., dormant) cells that can withstand
unfavorable environmental conditions (Lennon and Jones 2011).
According to the “microbial scout” hypothesis, cells
leave dormancy stochastically to sample the environment
(Buerger et al. 2012; Sturm and Dworkin 2015). If
conditions are favorable, these pioneering cells can re-populate
the environment. Even the smallest subpopulation that
rides out a catastrophe can ensure continuity of the
bacterial species as such. In line with this concept, pathogenic
bacteria generate multidrug-tolerant phenotypic variants
that have been denoted persisters due to their ability to
survive antibiotic treatment (Bigger 1944). Persisters
regularly cause relapsing infections and are considered
a major risk to public health (Lewis 2010). In contrast
to resistant cells, persisters are unable to multiply in the
presence of antibiotics, but rather reside in a dormant
state which renders them tolerant towards the action of
most antibiotics. Multiple pathways by which persisters
arise have been described, most often ultimately resulting
in slowed down growth via corruption of essential
cellular processes. For example, persistence can be triggered
by ATP depletion (Conlon et al. 2016; Shan et al. 2017),
nutrient shifts, and metabolic perturbations (Amato et al.
2013; Amato and Brynildsen 2014; Radzikowski et al.
2016), stochastic induction of (p)ppGpp (Maisonneuve
et al. 2013; Germain et al. 2015), or indole-activated
stress responses (Vega et al. 2012). Distinct pathways
might be either essential or rather negligible for persister
formation, depending on the
experimental/environmental conditions. For example, it was recently challenged
whether (p)ppGpp-activated pathways are the dominant
source of persister cells (Chowdhury et al. 2016; Shan
et al. 2017), and clearly, more experiments are needed
to understand the complex nature of persister
formation. A recurrent scheme for inducing the persistent state
involves toxins from chromosomal toxin–antitoxin (TA)
systems (e.g., Dörr et al. 2010; Kim and Wood 2010;
Maisonneuve et al. 2011). In unstressed cells,
antitoxins normally inhibit either translation or activity of their
toxin counterparts. However, when stress occurs, the
inhibiting effect is released and cellular processes are
impeded by the action of one or several toxins. The
different TA systems are classified according to the
specific mechanism by which the antitoxin inhibits the toxin
directly, or its synthesis. In total, six different TA system
types have been described so far (reviewed in Page and
Peti 2016). Translational repression of toxin mRNA by
an antisense RNA (type I) and inhibition of toxin activity
by an antitoxin via protein–protein interaction (type II)
are the predominant mechanisms. The first
persistencerelated toxin gene was hipA in Escherichia coli (Moyed
and Bertrand 1983). HipA belongs to the type II TA
system HipAB. Its mode of action was recently deciphered:
HipA phosphorylates glutamyl-tRNA synthetase,
causing uncharged tRNA accumulation, thereby triggering
the synthesis of the alarmone (p)ppGpp (Germain et al.
2013, 2015; Kaspy et al. 2013). Accumulation of (p)
ppGpp results in activation of Lon protease, which, in
turn (...truncated)