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16 Bacterial Type IV Secretion Systems: DNA Conjugation Machines Adapted for Export of Virulence Factors, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555817633/9781555813024_Chap16-1.gif /docserver/preview/fulltext/10.1128/9781555817633/9781555813024_Chap16-2.gifAbstract:
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. Bordetella pertussis, 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 Brucella, Actinobacillus, Ehrlichia, Wolbachia, and Xilella, is under continuous revision. The existence of a subset of VirB homologues in the Helicobacter pylori cag and Legionella pneumophila icm/dot systems underscores the functional importance of these types of proteins in macromolecular export. The Agrobacterium tumefaciens 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.
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Model of the Agrobacterium 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.
Model of the Agrobacterium 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.
Alignment of genes encoding related components of the type IV transport systems. (A) Of the 11 VirB proteins, those encoded by virB2 through virB11 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. (B) Schematic representation of Legionella pneumophila Dot/Icm region and R64 plasmid.
Alignment of genes encoding related components of the type IV transport systems. (A) Of the 11 VirB proteins, those encoded by virB2 through virB11 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. (B) Schematic representation of Legionella pneumophila Dot/Icm region and R64 plasmid.
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.
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.
Schematic prototype model for a type IV secretion injectisome. (A) Schematic illustration of the structure of the cag 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. (B) 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.
Schematic prototype model for a type IV secretion injectisome. (A) Schematic illustration of the structure of the cag 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. (B) 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.
Suggested model for CagA action. Translocated CagA associates with cell membrane (A) and is tyrosine phosphorylated (B) 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).
Suggested model for CagA action. Translocated CagA associates with cell membrane (A) and is tyrosine phosphorylated (B) 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).
A revised model based on the different behavior of nonpolarized AGS cells and polarized MDCK cells. (A to D) 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. (A′ to D′) 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 (B′) condensation activity for ZO-1 and Jam, and recruitment of SHP-2 at the level of junction (C′). In the absence of the AJC controls, the cell protrusions look for inhibitory contacts and the cell is marked by stratified growth (D′).
A revised model based on the different behavior of nonpolarized AGS cells and polarized MDCK cells. (A to D) 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. (A′ to D′) 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 (B′) condensation activity for ZO-1 and Jam, and recruitment of SHP-2 at the level of junction (C′). In the absence of the AJC controls, the cell protrusions look for inhibitory contacts and the cell is marked by stratified growth (D′).
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.
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.
As with the type III systems, type IV systems are present in bacteria with different pathogenic behaviors. Helicobacter attachment to the eukaryotic cell surface is mediated by cell skeleton remodeling. Agrobacterium and Helicobacter likely establish contact with eukaryotic host cells via a pilus structure prior to intracellular delivery of effector molecules. Bordetella secretes toxin via the Ptl system. Intracellular microorganisms, like Legionella and Rickettsia, confined in vacuoles, cross talk with the cytoplasmic compartment with a Ptl-like system, presumably deprived of piliated protrusions.
As with the type III systems, type IV systems are present in bacteria with different pathogenic behaviors. Helicobacter attachment to the eukaryotic cell surface is mediated by cell skeleton remodeling. Agrobacterium and Helicobacter likely establish contact with eukaryotic host cells via a pilus structure prior to intracellular delivery of effector molecules. Bordetella secretes toxin via the Ptl system. Intracellular microorganisms, like Legionella and Rickettsia, confined in vacuoles, cross talk with the cytoplasmic compartment with a Ptl-like system, presumably deprived of piliated protrusions.
Biological effects mediated by type IV secretion systems in various bacterial pathogens
Biological effects mediated by type IV secretion systems in various bacterial pathogens