Key Points
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'Type III secretion' (TTS) is a mechanism by which Gram-negative bacteria that are either extracellular or localized in a phagosome communicate with eukaryotic cells by injecting bacterial proteins across cellular membranes into the cytosol of these cells.
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The Ysc injectisome of Yersinia is an organelle that spans the peptidoglycan layer and the two bacterial membranes, and is topped by a needle-like structure that protrudes outside the bacterium. The plasmid-encoded Ysc–Yop TTS system allows extracellular Yersinia docked at the surface of cells of the immune system to deliver Yop 'effectors' into the cytosol of these cells. Yops are recognized specifically by the Ysc injectisome by a signal that is located in the first few residues/codons of the protein/gene.
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Several Yops need the assistance of specialized chaperones to be secreted by the injectisome, and secretion is triggered by intimate contact with a eukaryotic target cell. Translocation of the effector Yops across the eukaryotic cell membrane requires other Yops (YopB, YopD and LcrV), known as 'translocator' Yops, and these translocators form pores in the membrane of the target cells.
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The effector Yops YopH, YopE, YopT and YpkA/YopO paralyse phagocytes. YopH is a tyrosine phosphatase that dephosphorylates focal adhesion complexes and a complex that comprises Fyb and SKAP-HOM. YopE is a GTPase-activating protein (GAP) for the Rho family of GTPases. YopT is a protease that cleaves the carboxyl terminus of members of the same Rho GTPase family, which detaches them from their prenyl membrane anchor. YopO/YpkA is a serine/threonine kinase that is activated by actin.
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The effector Yops YopP and YopH block the pro-inflammatory response of infected cells. YopP is a protease, possibly a SUMO-protease, that blocks the nuclear factor-κB and mitogen-activated protein kinase pathways and hence the release of pro-inflammatory cytokines and adhesion molecules. YopH blocks the activation of the phosphatidylinositol 3-kinase pathway, which prevents lymphocyte proliferation and macrophage recruitment.
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YopM is a protein with leucine-rich repeats that migrates to the nucleus. Although it is an important virulence factor, its target(s) and role(s) are unknown.
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LcrV is an important Yop protein that has many functions — for example, as a regulator, a translocator and an extracellular anti-inflammatory agent.
Abstract
'Type III secretion' — the mechanism by which some pathogenic bacteria inject proteins straight into the cytosol of eukaryotic cells to 'anaesthetize' or 'enslave' them — was discovered in 1994. Important progress has been made in this area during the past few years: the bacterial organelles responsible for this secretion — called 'injectisomes' — have been visualized, the structures of some of the bacterial protein 'effectors' have been determined, and considerable progress has been made in understanding the intracellular action of the effectors. Type III secretion is key to the pathogenesis of bacteria from the Yersinia genus.
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Acknowledgements
I am grateful to all the members of my group for continuous crucial and challenging discussions. I thank L. Journet for supplying Figure 1b, P. Troisfontaines for assistance in preparing Box 1 and M. Feldmann for assistance in preparing the Box 5 figure. I apologize to my collegues whose excellent work could not be cited because of the lack of space. My laboratory in Brussels was supported by the Belgian Fonds National de la Recherche Scientifique Médicale, the Direction Générale de la Recherche Scientifique-Communauté Française de Belgique, and by two European Union TMR networks. In Basel, my laboratory is supported by the Swiss National Science Foundation.
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Movie 1 | Phagocytosis of wild-type Yersinia enterocolitica E40 by macrophages transfected with green fluorescent protein–actin.
The multiplicity of infection is 50. On the left, fluorescence microscopy shows the dynamics of actin underneath the bacteria. On the right, the dynamics of actin underneath the bacteria are shown by phase-contrast microscopy. 120 frames were recorded at a speed of one frame every 5 seconds. Two frames are played per second, so one minute of movie represents 10 minutes of real time. You can see that every phagocytic event or attempt involves the formation of a phagocytic 'cup', which is made of fluorescent actin. It is difficult to see from the movie whether every 'cup' engulfs a bacterium or whether some phagocytosis attempts abort. These videos illustrate the speed of phagocytosis and hence the speed of the antiphagocytic response of Yersinia. Note that the actin punctuation develops during the infection, owing to Yop action. This is the work of N. Grosdent and G.R.C., University of Louvain, Belgium, in collaboration with A. Sechi and J. Wehland, Gesellschaft für Biotechnologische Forschung, Braunschweig, Germany.
Movie 2 | Phagocytosis of yscN Yersinia enterocolitica (type III secretion deficient) by macrophages transfected with green fluorescent protein–actin.
The multiplicity of infection is 50. 120 frames were recorded at a speed of one frame every 5 seconds. Two frames are played per second, so one minute of movie represents 10 minutes of real time. Every phagocytic event involves the formation of a phagocytic 'cup', which is made of fluorescent actin. Note the speed of phagocytosis. Most of the phagocytic events take place at one pole of this elongated cell. This is the work of N. Grosdent and G.R.C., University of Louvain, Belgium, in collaboration with A. Sechi and J. Wehland, Gesellschaft für Biotechnologische Forschung, Braunschweig, Germany.
Movie 3 | Destruction of the cytoskeleton of Rat-1 fibroblasts by Yersinia enterocolitica E40.
Rat-1 fibroblasts that are transiently transfected with green fluorescent protein–actin were infected with wild-type Y. enterocolitica E40 at a multiplicity of infection of 50. One frame was taken every minute, and one frame is played per second, so the movie sequence seen is 60 times faster than the real-time sequence of events. You can see the destruction of the cytoskeleton and the rounding of the fibroblasts. This is the work of N. Grosdent and G.R.C., University of Louvain, Belgium, in collaboration with A. Sechi and J. Wehland, Gesellschaft für Biotechnologische Forschung, Braunschweig, Germany.
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FURTHER INFORMATION
Glossary
- EXOTOXINS
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Bacterial protein toxins that are secreted by pathogenic bacteria and that contribute to infectious disease.
- MACROPHAGES
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Long-lived bone-marrow-derived cells that are central to the host defence against microbes. Their main functions are phagocytosis, antigen-presentation and the release of inflammatory cytokines.
- POLYMORPHONUCLEAR LEUKOCYTES
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Short-lived bone-marrow-derived cells with high motility and phagocytic capacities.
- INJECTISOME
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The organelle responsible for 'secretion' of virulence proteins by the 'type III secretion' mechanism.
- BASAL BODY
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The basal body of the flagellum is the part that is embedded in the cell surface and that is in the bacterial cytoplasm. It consists of a rod, a set of four thin rings (L, P, S and M), and a large ring (C) that contains the flagellin-export apparatus.
- PEPTIDOGLYCAN
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Peptidoglycan is the rigid, shape-determining complex polymer that forms the cell wall of bacteria. It is made of chains of heteropolysaccharides linked by tetrapeptides.
- FLAGELLUM
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The locomotive organelle of bacteria. It consists of a basal body and a long hollow filament that is rotated by a molecular motor.
- F0F1 PROTON TRANSLOCASE
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A large and complex enzyme in the mitochondrial inner membrane that catalyses the synthesis of ATP, which is driven by a flow of protons.
- PSYCHROPHILIC BACTERIA
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Bacteria that can grow at 4 °C.
- CHAPERONES
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Several families of proteins, known as molecular chaperones, that assist nascent proteins in their folding or prevent premature or illicit associations with other proteins, folded or partially folded. Some chaperones, such as those involved in type III secretion, are small (∼15 kDa) proteins without any ATP-binding site, whereas others, known as chaperonins, form large heteropolymeric cylinders and consume ATP.
- ADHESINS
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Bacterial proteins that promote adherence to host-cell membranes. Some are simply anchored in the bacterial membrane, whereas others are placed at the tips of pili.
- NECROSIS
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Death in response to cell or tissue damage, which ends in the release of the intracellular content and the onset of inflammation.
- STRESS FIBRES
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Long axial bundles of actin microfilaments that run along the entire length of the cell.
- PHOSPHOTYROSINE-BINDING (PTB) DOMAINS
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Domains that bind phosphotyrosine residues and allow signalling interactions.
- SH2 DOMAINS
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Src-homology 2 domains are PTB domains that bind to phosphotyrosine residues, such as those that are found in activated receptor- or cytoplasmic-tyrosine kinases, and are involved in signalling processes.
- RhoA, Rac AND Cdc42
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Monomeric GTPases that are involved in the control of actin polymerization/depolymerization.
- OPSONIZATION
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The process by which IgG or complement C3b molecules bind to and coat particles, which enhances the efficiency of phagocytosis.
- APOPTOSIS
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Programmed cell death governed by complex signalling pathways and marked by a well-defined sequence of morphological changes, resulting in small bodies that are phagocytosed by other cells.
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Cornelis, G. The Yersinia Ysc–Yop 'Type III' weaponry. Nat Rev Mol Cell Biol 3, 742–753 (2002). https://doi.org/10.1038/nrm932
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DOI: https://doi.org/10.1038/nrm932
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