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  • Review Article
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Bacterial protein toxins that modify host regulatory GTPases

Nature Reviews Microbiology volume 9, pages 487–498 (2011)Cite this article

Subjects

Key Points

  • Many bacterial pathogens produce protein toxins and effectors that target host regulatory GTPases such as those belonging to the RHO family, which control the actin cytoskeleton. As a result, the pathogens weaken the epithelial and endothelial barriers and manipulate the host immune response, leading to bacterial invasion and dissemination in tissues.

  • Regulatory GTPases switch between an active, GTP-bound form that is attached to the cell membrane through an isoprenyl moiety, and an inactive, GDP-bound form in the cytosol. This GTPase cycle is controlled by various classes of host proteins such as guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs).

  • Various bacterial effectors can affect the activity of host GTPases by mimicking host regulators of the GTPase cycle through mechanisms that do not involve covalent modifications of the target proteins. For example, effectors of the SopE and WXXXE families act in a GEF-like manner, whereas YopE from Yersinia pseudotuberculosis is a GAP mimic.

  • Other bacterial proteins modulate the activity of regulatory GTPases by covalent modifications. Bacterial protein toxins of the C3 family inhibit the regulatory activity of RHO-family proteins by ADP-ribosylation of a specific amino acid residue, whereas the toxin complex (Tc) toxin TccC5 from Photorhabdus luminescens stimulates the activity of RHO-family proteins by ADP-ribosylating a different residue.

  • Various protein toxins from Clostridium spp. inactivate regulatory GTPases by addition of a glucose or an N-acetylglucosamine residue.

  • The adenylylation (also known as 'AMP-ylation') of RHO-family proteins by the toxins VopS and IbpA (immunoglobulin-binding protein A) from Vibrio parahemolyticus and Histophilus somni, respectively, leads to inhibition of downstream signalling of these host GTPases, whereas the same reaction on a different amino acid residue, catalysed by DrrA from Legionella pneumophila, leads to stimulation of RAB1A regulatory activity.

  • YopT from Yersinia spp. is a protease that cleaves RHO-family proteins directly upstream of the carboxy-terminal cysteine residue to which the isoprenyl moiety is attached. As a result, the RHO-family protein is released from the membrane and therefore inactivated.

  • RHO-family proteins can be persistently activated by deamidation and transglutamination catalysed by the cytotoxic necrotizing factors (Cnfs) of Escherichia coli and Y. pseudotuberculosis and the dermonecrotizing toxin (Dnt) of Bordetella spp. In addition, Pasteurella multocida toxin (Pmt) activates heterotrimeric guanine-nucleotide-binding (G) proteins, a family of multisubunit regulatory GTPases, by deamidation.

Abstract

Many bacterial pathogens produce protein toxins to outmanoeuvre the immune system of the host. Some of these proteins target regulatory GTPases such as those belonging to the RHO family, which control the actin cytoskeleton of the host cell. In this Review, I discuss a diversity of mechanisms that are used by bacterial effectors and toxins to modulate the activity of host GTPases, with a focus on covalent modifications such as ADP-ribosylation, glucosylation, adenylylation, proteolysis, deamidation and transglutamination.

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Figure 1: Regulation of the RHO-family GTPase cycle.
Figure 2: Bacterial effectors that modify RHO-family GTPases.
Figure 3: Photorhabdus luminescens toxins act on the cytoskeleton.
Figure 4: Structure of Escherichia coli cytotoxic necrotizing factor 1 and Pasturella multocida toxin.

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Acknowledgements

The work from the K.A. laboratory that is described in this article was financially supported by the German Research Foundation (DFG) and by the Centre for Biological Signalling Studies (BIOSS) at the University of Freiburg, Germany.

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    Klaus Aktories

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Glossary

GTPases

GTP-binding proteins that have GTP hydrolysis activity and act as molecular switches, dependent on the bound nucleotide (GDP-bound proteins are in the off state, and GTP-bound proteins are in the on state).

Isoprenylated tail

The carboxy-terminal tail of the protein to which an isoprenyl moiety has been attached at the carboxy-terminal cysteine residue as a post-translational modification. Isoprenylation of many small GTPases, including RHO-family proteins, is essential for membrane binding. A C20 isoprenyl moiety (geranylgeranyl) is usually attached to RHO-family proteins.

RAB

A family of small GTPases that are involved in membrane and vesicle traffic.

ARF

(ADP-ribosylating factor). A family of small GTPases that are involved in membrane and vesicle traffic. These factors were initially recognized as cofactors for the ADP-ribosylation that is catalysed by the cholera toxin.

Switch I and II regions

Regions of GTP-binding proteins that change the conformation of these proteins between the GDP-bound (inactive) and GTP-bound (active) state. Accordingly, effectors recognize these regions in particular. In RHOA, the switch I region covers residues 27–42, and the switch II region, residues 59–73.

DBL

A family of typical guanine nucleotide exchange factors acting on the RHO-family GTPases.

RAS

A family of small GTPases that are involved in proliferation and differentiation. This term is also sometimes (but not here) used to refer to a protein superfamily of small GTPases that includes the RAS, RAB, ARF (ADP-ribosylating factor), RHO and RAN protein families, among others.

RALA

One of the RAL proteins, a group of GTP-binding proteins in the RAS family. RAL proteins are involved in proliferation, motility and protein sorting.

CRK

(CT10 regulator of kinase). A family of adaptor proteins that mediate the signalling involved in focal adhesion and the regulation of phagocytosis.

Stress fibres

Contractile bundles of polymerized actin that also contain myosin motor proteins. The formation of stress fibres is induced by activation of RHOA.

Pull-down assays

Precipitation experiments in which one protein or domain of interest is coupled to beads as a bait to pull down those proteins that interact with it. In the case of RHO-family proteins, their interactions can be studied by using the RHO-binding domains of their effectors as bait.

WNT signalling

A pathway that transfers a signal from membrane receptors to the nucleus and is involved in embryogenesis and tumour development.

Avirulence factors

Bacterial factors that induce a strong antimicrobial response in host plants, with the consequence that the plant is protected. The factors seem to be virulence factors under certain conditions.

Laminin receptor

A cell membrane protein that is the receptor for the extracellular matrix glycoprotein laminin and is involved in cell adhesion to the basement membrane.

Lamellipodia

Broad, membrane ruffling-like processes that contain actin and are induced by the activation of RAC proteins.

Filopodia

Thin, finger-like cell protrusions that contain actin and are induced by activation of the GTPase cell division cycle 42 (CDC42).

Mitotic catastrophe

Mitotic-linked cell death as a consequence of the inappropriate entry of cells into mitosis.

Polyubiquitylation

The attachment of several ∼8 kDa ubiquitin peptide molecules onto lysine residues of target proteins by a three-enzyme cascade. It is often the prerequisite for the proteasomal degradation of the target proteins.

Furin

A serine endoprotease that cleaves endogenous precursor proteins. Furin is also involved in the processing of anthrax toxin, Pseudomonas exotoxin A and envelope proteins of various viruses.

Dynamin

A large GTPase that is regulated by oligomerization and forms a collar-like structure around invaginations of membranes during the pinch-off process of vesicle formation.

Polyamines

Metabolites such as putrescine, spermine and spermidine that are derived from arginine and methionine. They seem to be involved in many cellular processes, such as proliferation and migration.

RHO kinases

Endogenous effectors of RHO-family proteins; RHO kinases are activated by the GTP-bound form of RHO-family GTPases and regulate smooth muscle contraction and many signalling processes that are related to the cytoskeleton.

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Aktories, K. Bacterial protein toxins that modify host regulatory GTPases. Nat Rev Microbiol 9, 487–498 (2011). https://doi.org/10.1038/nrmicro2592

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