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  • Review Article
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The type III secretion system of Pseudomonas aeruginosa: infection by injection

Key Points

  • The Pseudomonas aeruginosa type III secretion system consists of five functional parts: proteins that constitute the secretion machine itself, proteins that translocate the secreted proteins into host cells, proteins that regulate the secretion process, proteins that bind the secreted proteins to facilitate the secretion process, called chaperone proteins, and proteins that are actually injected into host cells, called effector proteins.

  • Only four effector proteins are known to be secreted by the P. aeruginosa type III secretion system: ExoS, ExoT, ExoU and ExoY.

  • ExoS is a bifunctional toxin with GTPase-activating and ADP ribosyl transferase activities. These activities lead to the disruption of the actin cytoskeleton and apoptosis-like cell death.

  • ExoT is 76% identical to ExoS and also has both GTPase-activating and ADP ribosyl transferase activities; however, the ADP ribosyl transferase activity of ExoT is directed against different substrates from that of ExoS. These activities lead to the disruption of the actin cytoskeleton and apoptosis-like cell death.

  • ExoU has phospholipase A2 activity that results in the rapid lysis of many mammalian cell types.

  • ExoY is an adenylyl cyclase. Its role in pathogenesis is unclear.

Abstract

The Gram-negative bacterium Pseudomonas aeruginosa uses a complex type III secretion apparatus to inject effector proteins into host cells. The configuration of this secretion machinery, the activities of the proteins that are injected by it and the consequences of this process for infection are now being elucidated. This Review summarizes our current knowledge of P. aeruginosa type III secretion, including the secretion and translocation machinery, the regulation of this machinery, and the associated chaperones and effector proteins. The features of this interesting secretion system have important implications for the pathogenesis of P. aeruginosa infections and for other type III secretion systems.

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Figure 1: An overview of Pseudomonas aeruginosa type III secretion.
Figure 2: The modular domains of ExoS, ExoT, ExoU and ExoY.
Figure 3: Localization of ExoS and ExoU following injection into mammalian cells.
Figure 4: The role of type III effector proteins in the pathogenesis of acute pneumonia.

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Acknowledgements

I apologize to colleagues whose work has been omitted owing to lack of space and limitations on the allowed number of citations. I thank N. Cianciotto, M. Diaz, H. Howell, V. Kung and J. Veesenmeyer for reviewing the manuscript and for discussions. This work was supported by the National Institutes of Health (K02 AI065615, R01 AI075191 and R01 AI053674).

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Alan R. Hauser is a consultant for Microbiotix Corp., which is developing inhibitors of Pseudomonas aeruginosa type III secretion, and a collaborator on a National Institutes of Health Small Business Innovation Research grant submitted by Microbiotix Corp.

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DATABASES

Entrez Genome

Aeromonas salmonicida

Bacillus anthracis

Bordetella pertussis

Desulfovibrio vulgaris

Escherichia coli

Photorhabdus luminescens

Pseudomonas aeruginosa

Salmonella enterica

Shigella flexneri

Vibrio parahaemolyticus

Yersinia enterocolitica

OMIM

cystic fibrosis

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Glossary

Inflammasome

A multiprotein cytoplasmic complex that mediates the activation of caspase 1 in order to promote the maturation of the interleukins IL-1β and IL-18. This activation may also lead to a form of cell death termed 'pryoptosis'. The inflammasome itself may be activated by NOD-like receptors in response to intracellular microbial triggers.

Flagellin

The protein monomer that forms the hollow filament of the bacterial flagellum.

AraC/XylS family

A large family of transcriptional activators that are defined by a 100-amino acid region of sequence similarity. These proteins regulate diverse bacterial functions, including catabolism, stress responses and virulence.

Adenylyl cyclase

An enzyme that catalyses the conversion of ATP to cAMP and pyrophosphate.

cAMP receptor protein

A regulatory protein that, in the presence of cAMP, binds tightly to a specific DNA sequence in the promoters of a subset of bacterial genes, modulating their transcription. Also known as catabolite gene activator protein (CAP).

Two-component signal transduction system

A system that is commonly used by bacteria to couple environmental stimuli to response mechanisms. They consist of sensor and response regulator components that are linked by phosphorelays.

GTPase-activating protein

A member of a family of regulatory proteins that stimulate the intrinsic GTPase activity of small signalling G proteins, which results in their inactivation.

ADP ribosyl transferase activity

The enzymatic activity that covalently transfers an ADP–ribose group from NAD+ to a substrate protein, usually altering the activity of the substrate.

E3 ubiquitin ligase

An enzyme that covalently attaches ubiquitin to lysines in substrate proteins. Single or multiple ubiquitin molecules may be attached to a single lysine and may target the substrate protein for degradation or for an alteration of cellular location or function.

Lysophospholipid

Any phospholipid that is missing one of its two acyl chains.

Cu2+, Zn2+-superoxide dismutase

A superoxide dismutase that binds Cu2+ and Zn2+ ions and converts harmful free superoxide radicals into molecular oxygen and hydrogen peroxide.

Arachidonic acid

A fatty acid that is freed from certain phospholipids by the catalytic activity of phospholipase A2 enzymes and is an important inflammatory intermediate that is converted into eicosanoids.

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Hauser, A. The type III secretion system of Pseudomonas aeruginosa: infection by injection. Nat Rev Microbiol 7, 654–665 (2009). https://doi.org/10.1038/nrmicro2199

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