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16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors

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16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, Page 1 of 2

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Abstract:

Pathogenic bacteria of humans and plants have coopted conjugation systems to export virulence factors to eukaryotic host cells. Although this is a functionally diverse family, there are some unifying themes: (i) exporters are assembled at least in part from subunits of DNA conjugation systems, and (ii) the known substrates recognized by these transporters are large macromolecules such as nucleoprotein particles, scaffolding proteins, guanine nucleotide exchange factors, or multisubunit toxins. The type IV secretion family is composed of toxin exporters used by several bacterial human pathogens. , the causative agent of whooping cough, uses the Ptl transporter to export the AB type pertussis toxin across the bacterial envelope. The growing list of pathogens that utilize type IV secretion system (TFSS) for delivery of effector molecules into the host cell environment, comprising species like , , , , and , is under continuous revision. The existence of a subset of VirB homologues in the and systems underscores the functional importance of these types of proteins in macromolecular export. The T-DNA-processing reaction resembles the conjugative DNA-processing reaction, resulting in formation of the T-strand/ VirD2/VirE2 nucleoprotein particle or T complex. Perhaps the most compelling evidence that conjugation machines recognize proteins as translocationcompetent substrates is that VirE2 SSB can be exported to plant cells independently of the T-strand/VirD2 complex. The evolution of a family of secretion systems from ancestral DNA conjugation machines raises many interesting questions and exciting new research directions.

Citation: Christie P, Covacci A. 2004. 16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, p 393-408. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch16

Key Concept Ranking

Type IV Secretion Systems
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Type III Secretion System
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Bacterial Proteins
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Figures

Image of Figure 16.1
Figure 16.1

Model of the infection process. Specific classes of phenolic and sugar molecules released from wounded plant cells induce the Vir regulon, resulting in the interkingdom transfer of the oncogenic T complex to plant nuclei.

Citation: Christie P, Covacci A. 2004. 16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, p 393-408. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch16
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Image of Figure 16.2
Figure 16.2

Alignment of genes encoding related components of the type IV transport systems. Of the 11 VirB proteins, those encoded by through are essential for T-complex transport to plant cells (T-DNA). The broad-host-range plasmids and the narrow-host-range (NHR) plasmids code for Tra proteins related to most or all of the VirB genes. Type IV transporters found in bacterial pathogens of humans export toxins or other protein effectors to human cells show regions that are highly conserved among species. Schematic representation of Dot/Icm region and R64 plasmid.

Citation: Christie P, Covacci A. 2004. 16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, p 393-408. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch16
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Image of Figure 16.3
Figure 16.3

Early steps in a proposed assembly pathway for the T-complex transporter. VirB proteins, including VirB7 and VirB9, are exported across the cytoplasmic membrane via the general secretory pathway. Lsp, signal peptidase II, processes the prelipoproteins. The VirB7 lipoprotein (fatty acid modification denoted by lollipop stick) assembles as homodimers and heterodimers with VirB9, possibly facilitated by VirB6. The VirB6-VirB7-VirB9 protein subcomplex is a proposed nucleation center for recruitment and stabilization of other VirB proteins, leading to assembly of the proposed gated channel-T pilus shown on the right.

Citation: Christie P, Covacci A. 2004. 16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, p 393-408. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch16
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Image of Figure 16.4
Figure 16.4

Schematic prototype model for a type IV secretion injectisome. Schematic illustration of the structure of the organelle featuring an inner core of fibrotic structures surrounded by a membranous sheet containing the VirB10 (HP0527) protein and the protruding basal complex of the VirB7-B9 homologues. After the formation of a nucleation center, the transglycosilase VirB1 lyses the petidoglycan layer, facilitating the growth of the pilus structure formed by the assembly of aggregates of the VirB2 cyclic monomers. Immunoreactive CagA is represented as black bodies.

Citation: Christie P, Covacci A. 2004. 16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, p 393-408. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch16
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Image of Figure 16.5
Figure 16.5

Suggested model for CagA action. Translocated CagA associates with cell membrane and is tyrosine phosphorylated by members of c-Src family (c-Src and c-Lyn) at the level of the EPIYA motifs (I). The presence of phosphate residues favors the recruitment of the cytoplasmic form of the phosphatase SHP-2 (II) and the transition from a closed into an open structure (III). Cell elongation depends on the number of CagA-phosphorylated sites and on the formation of a complex with the phosphatase (IV).

Citation: Christie P, Covacci A. 2004. 16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, p 393-408. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch16
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Image of Figure 16.6
Figure 16.6

A revised model based on the different behavior of nonpolarized AGS cells and polarized MDCK cells. The absence of junction formation is typical of AGS cells. CagA translocation induces ectopic synthesis of the ZO-1 and Jam proteins that are associated with the early stage of junctional assembly. Transfection with the N-terminal fragment of CagA is associated with elongation phenotytpe resulting from the phosphorylation activity. During monolayer formation of individual MDCK cells and assembly of junctional components, a single transfectant for the C-terminal portion of CagA exhibits dominant negative interference with the core complex of the apical junctional complex (AJC) and lacks of junctional activity. The cell is characterized by increased motility condensation activity for ZO-1 and Jam, and recruitment of SHP-2 at the level of junction In the absence of the AJC controls, the cell protrusions look for inhibitory contacts and the cell is marked by stratified growth

Citation: Christie P, Covacci A. 2004. 16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, p 393-408. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch16
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Image of Figure 16.7
Figure 16.7

Schematic summary of effects depending on CagA translocation. Grb-2 interactions trigger signal transduction pathways. Tyosine phosphorylation is responsible for the elongating effect and disruption of the AJC by ZO-1 and Jam recruitment and SHP-2 delocalization alters terminal differentiation processes.

Citation: Christie P, Covacci A. 2004. 16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, p 393-408. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch16
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Image of Figure 16.8
Figure 16.8

As with the type III systems, type IV systems are present in bacteria with different pathogenic behaviors. attachment to the eukaryotic cell surface is mediated by cell skeleton remodeling. and likely establish contact with eukaryotic host cells via a pilus structure prior to intracellular delivery of effector molecules. secretes toxin via the Ptl system. Intracellular microorganisms, like and , confined in vacuoles, cross talk with the cytoplasmic compartment with a Ptl-like system, presumably deprived of piliated protrusions.

Citation: Christie P, Covacci A. 2004. 16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, p 393-408. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch16
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References

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1. Amieva, M. R.,, R. Vogelmann,, A. Covacci,, L. S. Tompkins,, W. J. Nelson,, and S. Falkow. 2003. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300:14301434.
2. Cascales, E.,, and P. J. Christie. 2003. The versatile bacterial Type IV secretion systems. Nat. Rev. Microbiol. 1:137149.
3. Covacci, A.,, J. L. Telford,, G. Del Giudice,, J. Parsonnet,, and R. Rappuoli. 1999. Helicobacter pylori virulence and genetic geography. Science 284:13281333.
4. Ding, Z.,, K. Atmakuri,, and P. J. Christie. 2003. The outs and ins of bacterial type IV secretion substrates. Trends Microbiol. 11:527535.
5. Hatakeyama, M. 2003. Helicobacter pylori CagA: a potential bacterial oncoprotein that functionally mimics the mammalian Gab family of adaptor proteins. Microb. Infect. 5:143150.
6. Higashi, H.,, R. Tsutsumi,, S. Muto,, T. Sugiyama,, T. Azuma,, M. Asaka,, and M. Hatakeyama. 2002. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295:683686.
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8. Montecucco, C.,, and R. Rappuoli. 2001. Living dangerously: how Helicobacter pylori survives in the human stomach. Nat. Rev. Mol. Cell Biol. 2:457466.
9. Nagai, H.,, and C. R. Roy. 2003. Show me the substrates: modulation of host cell function by type IV secretion systems. Cell Microbiol. 5:373383.
10. Rohde, M.,, J. Puls,, R. Buhrdorf,, W. Fischer,, and R. Haas. 2003. A novel sheathed surface organelle of the Helicobacter pylori cag type IV secretion system. Mol. Microbiol. 49:219234.
11. Schaeper, U.,, N. H. Gehring,, K. P. Fuchs,, M. Sachs,, B. Kempkes,, and W. Birchmeier. 2000. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. J. Cell Biol. 149:14191432.
12. Stein, M.,, F. Bagnoli,, R. Halenbeck,, R. Rappuoli,, W. J. Fantl,, and A. Covacci. 2002. c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol. Microbiol. 43:971980.

Tables

Generic image for table
Table 16.1

Biological effects mediated by type IV secretion systems in various bacterial pathogens

Citation: Christie P, Covacci A. 2004. 16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, p 393-408. In Cossart P, Boquet P, Normark S, Rappuoli R (ed), Cellular Microbiology, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817633.ch16

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