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Bacterial cytotoxins: targeting eukaryotic switches

  • Review Article
  • Published:

From Nature Reviews Microbiology

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Key Points

  • The Rho GTPases are frequently targeted by many different bacterial cytotoxins. Although it might seem surprising that a divergent array of toxins that have different modes of action and come from a range of bacterial species target the same effector, the Rho GTPases have been identified as eukaryotic master 'molecular switches' in many signal transduction pathways and, crucially, in regulation of the actin cytoskeleton.

  • Rho GTPases have many regulatory roles in host–pathogen interactions and host defence, including maintaining epithelial barriers, leukocyte migration, phagocytosis, T cell–APC (antigen presenting cell) interaction, and nuclear factor κB (NF-κB) regulation.

  • The GTPase cycle is the key to regulating the activity of the Rho GTPases. Bacterial cytotoxins can affect all the phases of the GTPase cycle.

  • The irreversible inhibition of Rho GTPases by cytotoxins is achieved through covalent modification by glucosylation (for example, by the clostridial glucosylating cytotoxins), ADP-ribosylation (the C3-like exoenzymes) or proteolytic cleavage (Yersinia enterocolitica YopT).

  • Reversible inhibition is achieved by bacterial effectors with a GTPase-activating protein-like activity (for example Yersinia spp. YopE, Salmonella SptP and Pseudomonas aeruginosa ExoS and ExoT).

  • GTPases can also be activated by deamidation and transglutamination by Escherichia coli and Yersinia pseudotuberculosis cytotoxic necrotizing factors and Bordetella spp. dermotoxic necrotizing toxin, respectively.

  • Additionally, some toxins are able to modify actin directly, including the family of binary actin-ADP-ribosylating toxins, the actin ADP-ribosyltransferase SpvB from Salmonella, and the actin crosslinking repeats-in-toxin cytotoxin from Vibrio cholerae.

Abstract

Many bacterial cytotoxins act on eukaryotic cells by targeting the regulators that are involved in controlling the cytoskeleton or by directly modifying actin, with members of the Rho GTPase family being particularly important targets. The actin cytoskeleton, and especially the GTPase 'molecular switches' that are involved in its control, have crucial functions in innate and adaptive immunity, and have pivotal roles in the biology of infection. In this review, we briefly discuss the role of the actin cytoskeleton and the Rho GTPases in host–pathogen interactions, and review the mode of actions of bacterial protein toxins that target these components.

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Figure 1: The GTPase cycle and the regulation of Rho proteins by GEFs, GAPs and GDI.
Figure 2: A simplified model of the tight junctions found in the epithelial barrier.
Figure 3: Schematic structures of Rho-inactivating toxins and Rho-activating toxins.
Figure 4: Consequences of the actions of bacterial cytotoxins on Rho GTPases.
Figure 5: The effects of Clostridium difficile toxins A and B on the intestine.

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Acknowledgements

J.T.B. is supported by grants from National Institutes of Health. K.A. is supported by the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Institut für Experimentelle und Klinische Pharmakologie und Toxikologie der Albert-Ludwigs-Universität, Otto-Krayer-Haus, Albert-Strasse 25, Freiburg, D-79104, Germany

    Klaus Aktories

  2. Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, 53226, Wisconsin, USA

    Joseph T. Barbieri

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DATABASES

Entrez

Bacillus cereus

Clostridium difficile

Escherichia coli K-12

Yersinia enterocolitica

Yersinia pseudotuberculosis

SwissProt

C. botulinum exoenzyme C3

Cdc42

CDT

C. difficile toxin A

C. difficile toxin B

Clostridium perfringens iota toxin

CNF1

CNF2

component C2I

component C2II

ExoS

ExoT

Rac1

RhoA

SptP

SpvB

YopT

Glossary

FOCAL CONTACTS

Regions of cell attachment to the extracellular matrix. Adhesion receptors and specific cytoskeletal proteins are clustered in these regions.

LAMELLIPODIA

Broad, flat protrusions at the leading edge of a moving cell that are enriched with a branched network of actin filaments. They are often associated with cell migration.

FOCAL COMPLEXES

Small dot-like adhesion structures that are present mainly at the edges of the lamellipodia.

FILOPODIA

Thin, transient actin protrusions that extend out from the cell surface and are formed by the elongation of bundled actin filaments.

TIGHT JUNCTIONS

Regions of apical adhesion between adjacent epithelial or endothelial cells. Tight junctions regulate paracellular flux, and contribute to the maintenance of cell polarity by stopping molecules from diffusing in the plane of the membrane.

ADHERENS JUNCTIONS

Epithelial cell–cell adhesion complexes associated with actin filaments that contain cadherins.

MAST CELL

A type of leukocyte with large secretory granules containing histamine and various protein mediators.

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Aktories, K., Barbieri, J. Bacterial cytotoxins: targeting eukaryotic switches. Nat Rev Microbiol 3, 397–410 (2005). https://doi.org/10.1038/nrmicro1150

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