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Chapter 2 : Extracellular Peptide Signaling and Quorum Responses in Development, Self-Recognition, and Horizontal Gene Transfer in

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Abstract:

This chapter focuses on the mechanisms of extracellular peptide signaling that utilizes to control gene expression involved in sporulation, the ComA-mediated general quorum response, and horizontal gene transfer. This signaling provides mechanisms for the cell to monitor population density and to distinguish whether neighboring cells are similar or different. All the responses described are stimulated by high population densities. The focus of the chapter is cell-cell signaling mediated by peptides. Horizontal gene transfer plays an important role in bacterial evolution. It is often regulated by cell-cell signaling, including the pheromone-responsive conjugal plasmids of , the autoinducer-sensing conjugal plasmids of , and competence development in and species. Self-recognition during competence development likely serves to limit competence development to conditions when DNA from closely related bacteria will be present. Cell-cell signaling influences the activity of integrative and conjugative element (ICE) in two ways. First, signaling via host-encoded regulators indicates a high population density and the proximity of potential mating partners. Second, the signaling pentapeptide PhrI is produced by ICE-containing cells and is used to inhibit transfer to potential partners that already contain the element. competence and sporulation are also regulated by two regulators, ComK and Spo0A, that are parts of multiple autoregulatory loops. They involve both positive and negative feedback regulation and help establish and maintain stable subpopulations of cells that exhibit specific patterns of gene expression and follow specific developmental fates.

Citation: Auchtung J, Grossman A. 2008. Extracellular Peptide Signaling and Quorum Responses in Development, Self-Recognition, and Horizontal Gene Transfer in , p 13-30. In Winans S, Bassler B (ed), Chemical Communication among Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815578.ch2

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Mobile Genetic Elements
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Image of FIGURE 1
FIGURE 1

Regulation of the transcription factor Spo0A by the phosphorelay and extracellular peptide signaling. The response regulator and transcription factor Spo0A is activated by a phosphorelay that transfers phosphate from histidine protein kinases, KinA to KinE, to the response regulator Spo0F, then to Spo0B, and finally to Spo0A. Spo0A~P directly activates (→) transcription of some genes and represses (⊣) transcription of others. The phosphatases RapA, RapB, RapE, and RapH promote dephosphorylation of Spo0F~P, thereby inhibiting the activation of Spo0A. The activity of RapA, RapB, RapE, and RapH is inhibited by the PhrA, PhrC (CSF), PhrE, and PhrH pentapeptides, respectively. ComA~P binds to sites upstream from and to activate transcription.

Citation: Auchtung J, Grossman A. 2008. Extracellular Peptide Signaling and Quorum Responses in Development, Self-Recognition, and Horizontal Gene Transfer in , p 13-30. In Winans S, Bassler B (ed), Chemical Communication among Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815578.ch2
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Image of FIGURE 2
FIGURE 2

Multiple and genes in . The 11 and 8 genes in the genome are indicated. All eight genes are downstream from and cotranscribed with a cognate . Six of the eight genes are known to be transcribed from at least one promoter that is sigma-H-dependent and internal to the cognate . The and operons are activated by ComA~P.

Citation: Auchtung J, Grossman A. 2008. Extracellular Peptide Signaling and Quorum Responses in Development, Self-Recognition, and Horizontal Gene Transfer in , p 13-30. In Winans S, Bassler B (ed), Chemical Communication among Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815578.ch2
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Image of FIGURE 3
FIGURE 3

Complex regulation, including autoregulatory loops, involving the transcription factor ComA and multiple extracellular signaling peptides. Stimulatory effects are indicated with arrows (→). Inhibitory effects are indicated by lines with bars (⊣). (A) ComA is activated by extracellular peptide signaling. The cell is represented by the contents of the large rectangular box with components that are intracellular, extracellular, or in the membrane. Numbers are for descriptive purposes and do not necessarily indicate sequential events. (a) The ComX pheromone is encoded together with a protein required for its production, ComQ, and the two-component signal transduction system, ComP-ComA, that regulates competence development and a quorum response. In addition to the promoter upstream from , there are likely to be minor promoters (not shown) internal to the operon. (b) After transcription and translation, a precursor to ComX pheromone (pre-ComX) is modified by ComQ and exported (c) by an unknown mechanism. (d) ComX interacts on the cell surface with the membrane receptor-histidine kinase ComP and stimulates auto-kinase activity of ComP. (e) Phosphate is transferred from ComP~P to ComA. (f) ComA~P activates expression of several genes, including , the only ComA-target that is required for competence development. The activity of ComA~P is antagonized by the indicated Rap proteins in the absence of sufficient concentrations of the cognate Phr pentapeptides. It is currently unclear whether RapG, RapH, and RapK affect ComA directly or indirectly. (g) PhrC, PhrF, PhrG, PhrH, and PhrK pentapeptides are encoded in operons with their cognate Rap proteins. (h) The pre-Phr peptides are exported and processed through an unknown mechanism. (i) Mature Phr pentapeptides are imported into the cell through the oligopeptide permease (Opp; a. k. a., Spo0K). (j) PhrC, PhrF, PhrG, PhrH, and PhrK stimulate ComA-dependent gene expression by antagonizing the activities of their cognate Rap proteins. (B) Complex regulation of ComA and Spo0A by multiple signals, including several extracellular peptides, allows for signal integration in the control of gene expression and many autoregulatory loops. Transcription of the genes is regulated by a variety of different proteins. The activities of these proteins are controlled by a variety of physiological signals, some of which are described in more detail in the text. Spo0A is regulated indirectly by the Rap proteins via the effects of the Raps on Spo0F. This diagram is an oversimplification of the regulatory circuits, and regulation of ComK by the Spo0A and ComA pathways is shown in Fig. 4 .

Citation: Auchtung J, Grossman A. 2008. Extracellular Peptide Signaling and Quorum Responses in Development, Self-Recognition, and Horizontal Gene Transfer in , p 13-30. In Winans S, Bassler B (ed), Chemical Communication among Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815578.ch2
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Image of FIGURE 4
FIGURE 4

Complex regulation of the transcription factor ComK. ComK is the master transcriptional regulator of competence development. Both its stability (A) and transcription (B) are regulated by extracellular peptide signaling. For simplicity in the figure, genes (e. g., ) and proteins (e. g., ComK) are not distinguished. (A) Control of the stability of ComK. (a) At low cell density, MecA binds to ComK and targets it for degradation by the ClpCP protease complex. (b) As cell density increases, ComA is activated by quorum sensing, and activates transcription of (c) ComS disrupts the complex between ComK and MecA, liberating ComK. (d) ComK is free to activate transcription of genes that are required for competence. (e) ComS and MecA are degraded by ClpCP. (B) Control of transcription of . ComK activates its own expression. Its activity is controlled by quorum sensing via ComA and ComS (see above). Several other proteins also regulate transcription, including Spo0A and DegU, whose activities are also regulated by cell-cell signaling. The regulatory network that controls transcription is described more fully in the text.

Citation: Auchtung J, Grossman A. 2008. Extracellular Peptide Signaling and Quorum Responses in Development, Self-Recognition, and Horizontal Gene Transfer in , p 13-30. In Winans S, Bassler B (ed), Chemical Communication among Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815578.ch2
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Image of FIGURE 5
FIGURE 5

The integrative and conjugative element ICE and its regulation by peptide signaling. (A) The genetic map of ICE. Open reading frame and direction of transcription are indicated by thick black arrows. The ends of the element are marked by 60-bp direct repeats (black rectangles at the ends). Genes whose functions are known experimentally include and , toward the right end of the element; , encoding integrase that is needed for site-specific integration and excision; , encoding an antirepressor; , encoding a transcriptional repressor; and , encoding excisionase. The known promoters are indicated by lines with arrows above the genes. ImmR represses transcription from the promoter immediately upstream of , and both activates and represses its own promoter, which also drives transcription of and . The and genes in the central part of the element are coregulated with and encode most of the machinery needed for conjugal transfer. (B) Regulation of transcription of ICE by peptide signaling and the SOS response. Expression of the ICE excisionase () and conjugation genes is repressed by ImmR. ImmA appears to antagonize the activity of ImmR, thereby stimulating expression of the excisionase and conjugation genes and causing excision and transfer. The activity of ImmA is stimulated by RapI. However, and are not significantly expressed at low cell densities and in the presence of abundant nutrients due to repression by AbrB. When cells are at high cell density and starved, Spo0A~P accumulates and inhibits , leading to increased transcription of and is also transcribed by RNA polymerase containing sigma-H, an alternative sigma factor whose activity increases as cells enter stationary phase. The activity of RapI is inhibited by the PhrI pentapeptide, thereby inhibiting excision and transfer of ICE. The concentration of the PhrI pentapeptide (encoded in ICE) reflects the concentration of surrounding cells that contain ICE. ImmA is also activated by RecA under conditions that induce the SOS response. The RecA and RapI pathways are independent of each other.

Citation: Auchtung J, Grossman A. 2008. Extracellular Peptide Signaling and Quorum Responses in Development, Self-Recognition, and Horizontal Gene Transfer in , p 13-30. In Winans S, Bassler B (ed), Chemical Communication among Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555815578.ch2
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