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. 2013 Apr;21(4):174-80.
doi: 10.1016/j.tim.2013.01.002. Epub 2013 Feb 16.

Bacterial Lifestyle Shapes Stringent Response Activation

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Bacterial Lifestyle Shapes Stringent Response Activation

Cara C Boutte et al. Trends Microbiol. .
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Bacteria inhabit enormously diverse niches and have a correspondingly large array of regulatory mechanisms to adapt to often inhospitable and variable environments. The stringent response (SR) allows bacteria to quickly reprogram transcription in response to changes in nutrient availability. Although the proteins controlling this response are conserved in almost all bacterial species, recent work has illuminated considerable diversity in the starvation cues and regulatory mechanisms that activate stringent signaling proteins in bacteria from different environments. In this review, we describe the signals and genetic circuitries that control the stringent signaling systems of a copiotroph, a bacteriovore, an oligotroph, and a mammalian pathogen -Escherichia coli, Myxococcus xanthus, Caulobacter crescentus, and Mycobacterium tuberculosis, respectively - and discuss how control of the SR in these species is adapted to their particular lifestyles.


Figure 1
Figure 1. Domain structure of RSH proteins
All RSH proteins contain – from N to C terminus – (p)ppGpp hydrolase, (p)ppGpp synthetase, TGS (conserved in Threonyl-tRNA synthetases, GTPases and SpoT ) and ACT domains (conserved in many proteins involved in small molecule metabolism; the ACT domain usually binds an amino acid or small molecule that allosterically regulates enzyme activity) [80]. The hydrolase domain of RelAEC contains sequence polymorphisms (indicated by vertical black line) that render it enzymatically inactive. We note there are several sites of sequence variation that distinguish RelAEC, SpoTEC and bifunctional Rel proteins besides the active sites of the catalytic domains; these are discussed in reference [12].
Figure 2
Figure 2. Lifestyle and stringent response (SR) signaling in four bacteria
Key events in SR activation signaling are diagrammed on the left; lifestyle transitions that affect SR signaling are diagrammed on the right. Arrowheads indicate positive regulation, perpendicular lines indicate negative regulation. A) In Escherichia coli, several starvation signals can individually activate the SR via either RelAEC or SpoTEC. RelAEC is activated at the ribosome when translation is halted due to the entry of an uncharged tRNA in the A site. SpoTEC is activated in lipid starvation through interactions with holo-acyl-carrier protein (Acp) and by several different starvation signals via unknown mechanisms. E. coli transitions from the nutrient-rich mammalian colon to nutrient-poor soil or aquatic environments; though it may also experience smaller variations in nutrient availability within these environments. In nutrient-rich conditions, cells are large and contain multiple replication forks, in nutrient-poor conditions cells are smaller and contain either one or zero replication forks. B) Myxococcus xanthus encodes a signal override system, involving both positive (CsgA) and negative (SocE) feedback loops, in its SR activation pathway that allows information about cell density and developmental progression to be integrated with information about nutrient availability. In the developmental progression of M. xanthus, vegetatively growing cells exhaust nutrients, activate the stringent response and A-signaling; cells then move in waves which coalesce into mounds that develop into mature, spore-forming fruiting bodies. (p)ppGpp levels remain high for the period indicated by the blue arrow, the green region indicates the time when the signal override is in effect. A-signaling is active during the period indicated by the purple arrow. C) The SR of Caulobacter crescentus has a higher threshold for activation than many other species, requiring both starvation for amino acids AND additional carbon or ammonium starvation signals. The amino acid starvation signal is transmitted through the ribosome, much like RelAEC. Information about the nutritional and developmental status of the cell are integrated at multiple levels: (p)ppGpp accumulation has a greater inhibitory effect on the swarmer-to-stalked transition than on the division of the stalked (purple) cell. In addition the swarmer cell (green) is more sensitive to starvation, producing higher levels of ppGpp than the stalked cell. Heavier lines indicate stronger regulation. D) Expression of Rel in mycobacteria is controlled through a complex signaling cascade that depends upon the amount of polyphosphate present in a cell, and results in populations of cells that have bistable expression of Rel. Cells that express high levels of Rel are thought to be biased toward a persister state (red), exhibiting slow growth and greater resistance to antibiotics and other stresses. Host-generated stresses that occur during infection likely fail to kill persister cells, which could then transition into vegetatively growing cells (blue) once stresses are alleviated.

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