Chapter 14 : The Stringent Response

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The (p)ppGpp nucleotides act as global transcriptional regulators by modulating directly or indirectly RNA polymerase (RNAP) activity. The major consequences are the immediate arrest of ribosome biogenesis and cell growth and the activation of stress survival genes. This chapter presents two points that are presented in two separate main sections. The first part reviews the current knowledge on the functioning of RelA/SpoT enzymes and how (p) ppGpp levels are controlled in the cell. The second part shows the role of (p)ppGpp in controlling the balance between growth and survival, first by describing its mode of action on RNAP and other enzymes and then by describing its global effects on the physiology of bacteria (from growth control to pathogenicity). The mechanism of rRNA transcription inhibition by (p)ppGpp is one of the most studied and rRNA promoters constitute the archetype of stringently inhibited promoters. In , it is the elongation itself that is controlled by (p)ppGpp because the replication forks are arrested during the stringent response. This arrest is caused by direct inhibition of the primase by (p)ppGpp, arresting the replication fork at any location when the stringent response occurs.

Citation: Bouveret E, Battesti A. 2011. The Stringent Response, p 231-250. In Storz G, Hengge R (ed), Bacterial Stress Responses, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816841.ch14
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Image of Figure 1.
Figure 1.

(p)ppGpp cycle. Products and substrates of the enzymatic reactions are indicated in regular characters. Genes are indicated in italic in gray boxes. codes for a RelA/SpoT homolog enzyme, for the Gpp phosphohydrolase, and for the nucleoside diphosphate kinase.

Citation: Bouveret E, Battesti A. 2011. The Stringent Response, p 231-250. In Storz G, Hengge R (ed), Bacterial Stress Responses, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816841.ch14
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Image of Figure 2.
Figure 2.

Structure/function of Rsh enzymes. (A) Domain organization of (p)ppGpp synthesis enzymes. From top to bottom, the following architectures are shown: canonical Rsh with the conserved domains as described in the PFam database (Finn et al., ); SpoT and RelA domain organization in β-and γ-proteobacteria; and a RelPQ-like protein. Below the domain description, the structure of the N-terminal domain of Rsh from (Hogg et al., ) is shown, highlighting the HD (darker gray) and RelA_SpoT (lighter gray) distinct structural domains. (B) Model of regulation of the enzymatic activities in the N-terminal domain by conformational modifications of the C-terminal domain (Mechold et al., ; Jain et al., ). R, regulation domain; S, (p)ppGpp synthesis activity; D, (p)ppGpp degradation activity.

Citation: Bouveret E, Battesti A. 2011. The Stringent Response, p 231-250. In Storz G, Hengge R (ed), Bacterial Stress Responses, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816841.ch14
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Image of Figure 3.
Figure 3.

Mechanisms of (p)ppGpp control in . RelA responds to amino acid starvation. RelA bound to ribosomes detects the presence of uncharged tRNA in the A site blocking translation, which activates its (p)ppGpp synthesis and, simultaneously, its release (Wendrich et al., ). SpoT responds to other types of starvation. The CgtA(Obg) small GTPase may maintain SpoT in a hydrolase ON/synthetase OFF conformation (Jiang et al., ; Raskin et al., ). Upon fatty acid metabolism perturbations, ACP-bound signals may put SpoT in a hydrolase OFF/synthetase ON conformation (Battesti and Bouveret, ). The mechanism of SpoT regulation in response to other starvation events is not known. R, regulation domain; S, (p)ppGpp synthesis activity; D, (p)ppGpp degradation activity.

Citation: Bouveret E, Battesti A. 2011. The Stringent Response, p 231-250. In Storz G, Hengge R (ed), Bacterial Stress Responses, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816841.ch14
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Image of Figure 4.
Figure 4.

Physiological effects of (p)ppGpp. Through regulation of gene expression, (p)ppGpp continuously controls the balance between proliferation and survival, depending on the nutritional quality of the environment. The regulations shown are described in the text or adapted from Traxler et al. ( ).

Citation: Bouveret E, Battesti A. 2011. The Stringent Response, p 231-250. In Storz G, Hengge R (ed), Bacterial Stress Responses, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816841.ch14
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