Chapter 18 : Regulation of Bacterial Type IV Secretion

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This chapter explores the question of how bacterial pathogens regulate the biogenesis and function of their type IV secretion systems (T4SSs) in pathogenic settings. First, it describes a regulatory cascade involving the perception of multiple signals exchanged between and its plant host. This signaling dialogue leads not only to infection of plant tissue but also to enhanced conjugative transfer of the virulence-associated tumor-inducing (pTi) plasmid. Second, it summarizes the regulatory features of a large T4SS subfamily, the conjugation systems functioning in gram-negative and -positive species. The chapter then summarizes regulatory features of the well-characterized effector translocators of spp., , and spp., and also examines why and how these and other bacterial pathogens cross-regulate T4SSs and other surface motility or attachment devices such as flagella and type IV pili. Finally, the chapter discusses post-transcriptional regulation of substrate-T4SS docking reactions and donor-target cell contacts. The overarching goal of this chapter is to identify mechanistic themes and variations that have evolved to regulate the myriad of T4SS activities exploited by bacterial pathogens during infection. The conjugation systems are the largest subfamily, present in nearly all bacterial species and some archaeal species. Many bacterial pathogens rely on flagellar or type IV pilus-based motility to migrate to sites favorable for colonization within the host. For all T4SSs, transduction of exogenous or physiological signals ultimately converges on the regulatory machinery controlling transcription of machine subunits, DNA processing enzymes, or protein effectors.

Citation: Laverde-Gomez J, Sarkar M, Christie P. 2013. Regulation of Bacterial Type IV Secretion, p 335-362. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch18
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Figure 1

General architectures of T4SSs in gram-negative and -positive bacteria. The T4SSs of gram-negative bacteria are composed of a translocation channel and an extracellular filament, e.g., conjugative pilus, that may or may not be physically connected. These systems translocate substrates to prokaryotic or eukaryotic target cells by a contact-dependent mechanism. Conjugation systems translocate DNA substrates as ssDNA covalently bound at their 5′ ends to relaxase (yellow circle, green wavy line). Effector translocators deliver protein substrates (yellow circle) to target cells, often to aid in the infection process. Some T4SSs export DNA or protein substrates or take up DNA (green wavy line) from the extracellular milieu by a contactindependent mechanism. Gram-positive T4SSs elaborate surface adhesins, e.g., AS, rather than conjugative pili and conjugatively transfer DNA substrates to bacterial recipient cells through direct cell-to-cell contact. doi:10.1128/9781555818524.ch18f1

Citation: Laverde-Gomez J, Sarkar M, Christie P. 2013. Regulation of Bacterial Type IV Secretion, p 335-362. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch18
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Figure 2

Schematic of chemical signaling events between and the transformed plant cell. Signals released from wounded plant cells initiate the infection process through the VirA/VirG/ChvE and ChvG/ChvI sensory response systems, resulting in gene activation. The Vir proteins mediate T-DNA processing, assembly of the VirB/VirD4 T4SS, and T-DNA translocation to susceptible plant cells. VirA/VirG also induces expression of the Ti plasmid genes, resulting in elevated Ti plasmid copy number. Opines released from transformed plant cells activate opine catabolism functions for growth of infecting bacteria. Opines also activate synthesis of TraR for autoinducer (AAI) synthesis. TraR and AAI at a critical concentration activate the Ti plasmid conjugation functions. TlrR and TraM negatively regulate TraR activity, and AttM and AttJ negatively control AAI levels. doi:10.1128/9781555818524.ch18f2

Citation: Laverde-Gomez J, Sarkar M, Christie P. 2013. Regulation of Bacterial Type IV Secretion, p 335-362. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch18
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Figure 3

Pheromone-inducible regulation of pCF10 transfer. The pheromone-responsive pCF10 is shown, with locations for genes coding for regulation and transfer (), the origin of transfer sequence (), and Tn. Chromosomally encoded peptide pheromone cCF10 released by donor cells is sequestered by . cCF10 released by recipient cells is taken up through an oligopeptide permease transporter and when bound to PrgX stimulates transcription of the transfer genes. pCF10- encoded peptide inhibitor iCF10 negatively regulates transfer gene expression, limiting plasmid transfer potential in donor cell populations. Human plasma binds iCF10, indirectly promoting plasmid transfer in the human host. pCF10-encoded AS promotes bacterial aggregation and plasmid transfer and biofilm formation on human tissues. doi:10.1128/9781555818524.ch18f3

Citation: Laverde-Gomez J, Sarkar M, Christie P. 2013. Regulation of Bacterial Type IV Secretion, p 335-362. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch18
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Figure 4

Inducible transfer of ICE. Conditions stimulating ICE transfer include DNA-damaging agents, e.g., quinolone antibiotics, and a high density of potential recipient cells lacking the ICE (whose presence is sensed by the ICEencoded PhrL pheromone inhibitor [blue-shaded triangles]). Induction of the SOS response activates the ImmA protease, which, in turn, inactivates the ImmR repressor, leading to expression of the excision and transfer genes. At a high density of donor cells, PhlR accumulates in the extracellular milieu and upon internalization inactivates the RapI inducer (green-shadedovals). Arrows denote activation of gene expression; bars denote inactivation/repression. doi:10.1128/9781555818524.ch18f4

Citation: Laverde-Gomez J, Sarkar M, Christie P. 2013. Regulation of Bacterial Type IV Secretion, p 335-362. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch18
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Figure 5

Transfer of the F factor is controlled by environmental and physiological signals acting through the regulatory factors shown. Factors that repress F gene expression are boxed and red shaded; those inducing gene expression are circled. The CpxRA two-component system is green shaded. The F-borne main regulators , , and FinO/ fertility inhibition system and their promoter targets are shown. RNase E degrades antisense RNA in the absence of bound RNA chaperone FinO. The regulators activated in response to environmental and physiological cues control F gene expression as described in the text (see also ). Arrows denote activation of gene expression; lines denote repression. Dotted arrows represent unspecified sensing or transduction mechanisms. doi:10.1128/9781555818524.ch18f5

Citation: Laverde-Gomez J, Sarkar M, Christie P. 2013. Regulation of Bacterial Type IV Secretion, p 335-362. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch18
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Figure 6

The VirB T4SS genes are expressed in the phagosome in response to environmental signals and quorum signals. At neutral pH, IHF activates expression, whereas nutritional stress resulting in elevated levels of the alarmone (p)ppGpp promotes displacement of HutC for IHF. The BvrS/BvrR two-component system (green shaded) regulates expression directly and indirectly by controlling VjbR activity. VjbR and BlxR (blue shaded) control expression in response to sensing of unknown quorum signals. Arrows denote activation of gene expression; lines denote repression. Dashed arrows represent unspecified sensing or transduction mechanisms. doi:10.1128/9781555818524.ch18f6

Citation: Laverde-Gomez J, Sarkar M, Christie P. 2013. Regulation of Bacterial Type IV Secretion, p 335-362. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch18
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Figure 7

In the LCV, various signals regulate expression of genes coding for the Dot/Icm T4SS and the estimated 200 effectors. Signals are perceived by three two-component systems (green shaded), which act directly on gene expression or indirectly, e.g., through sRNAs and and the RNA-binding protein CsrA. A complex regulatory network coordinates T4SS machine biogenesis with production of effectors for translocation at the appropriate stage of the infection cycle. A putative quorum sensing system (blue shaded) activates the LuxR homolog, LqsR. Arrows denote activation of gene expression; lines denote repression. Dashed arrows represent predicted activities. doi:10.1128/9781555818524.ch18f7

Citation: Laverde-Gomez J, Sarkar M, Christie P. 2013. Regulation of Bacterial Type IV Secretion, p 335-362. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch18
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Figure 8

Coordinated regulation of T4SSs and other motility or attachment organelles. A pathogen may elaborate more than one T4SS for translocation of effectors to promote colonization at different stages of the infection cycle or for expansion of the infection niche. Conjugation systems function optimally in dense populations of nonmotile cells, e.g., biofilms; regulators induce genes and repress genes. Effector translocators coordinate the synthesis of T4SSs and flagella during the infection cycle through common environmentally responsive regulators. Most conjugation systems function efficiently among cells growing on solid surfaces; coregulation of type IV pili allows for sampling of the fluid environment for potential recipients for expanded transfer potential. In , the T4SS functions as a DNA release system; coregulation of a type IV pilusmediated DNA uptake system promotes gene flux and genetic diversity. doi:10.1128/9781555818524.ch18f8

Citation: Laverde-Gomez J, Sarkar M, Christie P. 2013. Regulation of Bacterial Type IV Secretion, p 335-362. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch18
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Figure 9

Posttranscriptional control of T4SS function. Intracellular factors can regulate the efficiency of timing of substrate translocation. Representative factors and their biological roles in modulating access of DNA or protein substrates with the T4CP receptor are listed. Target cell contact also regulates translocation. DNA transfer is inhibited by entry exclusion systems to prevent redundant transfer among equivalent donor cells. In F systems, a mating signal generated upon contact with a potential recipient cell activates the T4SS through an unknown mechanism. In , binding of a T4SS adhesin serves to activate both β-integrin receptors on the mammalian cell and the Cag T4SS on the bacterial cell to stimulate CagA translocation. doi:10.1128/9781555818524.ch18f9

Citation: Laverde-Gomez J, Sarkar M, Christie P. 2013. Regulation of Bacterial Type IV Secretion, p 335-362. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch18
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Table 1

Regulatory mechanisms controlling type IV secretion

Citation: Laverde-Gomez J, Sarkar M, Christie P. 2013. Regulation of Bacterial Type IV Secretion, p 335-362. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch18

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