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  • Review Article
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Exploiting pathogenic Escherichia coli to model transmembrane receptor signalling

Nature Reviews Microbiology volume 4, pages 358–370 (2006)Cite this article

Key Points

  • Many pathogens deploy a sophisticated virulence effector repertoire to promote their colonization, entry, survival and dissemination within mammalian hosts. Many of these subversive effectors target the cellular actin cytoskeleton.

  • Upon adhesion to host intestinal cells, enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC, respectively) induce dramatic reorganization of the host-cell actin cytoskeleton to promote their intimate attachment, a phenotype associated with disease in humans and animals.

  • EPEC and EHEC uniquely deliver their own receptor termed translocated intimin receptor (Tir) into the target-cell plasma membrane to trigger actin-pedestal assembly, which is engaged by the bacterial surface protein intimin. This ligand–receptor mimicry provides a tractable experimental system to dissect eukaryotic transmembrane-receptor signalling.

  • We discuss how studies of intimin have provided important insights into the molecular basis of ligand–receptor interaction, and have also revealed how intimin binding induces Tir clustering to trigger intracellular actin polymerization.

  • The translocated EPEC receptor Tir is tyrosine-phosphorylated. We consider how EPEC Tir can be used to model host tyrosine-kinase signalling and adaptor-protein docking at cellular transmembrane receptors, including those controlling immunological-synapse and focal-adhesion formation.

  • The translocated EHEC O157:H7 receptor Tir is not tyrosine-phosphorylated. We discuss how it can be used to decipher tyrosine-kinase-independent signalling cascades at the plasma membrane.

  • We discuss the prospects for exploiting the adaptor-like EHEC O157:H7 effector EspFU to provide insights into the regulation of cellular nucleation-promoting factors such as neural Wiskott–Aldrich syndrome protein, and to probe for other factors that control Arp2/3-dependent actin assembly at the plasma membrane.

Abstract

Many microbial pathogens manipulate the actin cytoskeleton of eukaryotic target cells to promote their internalization, intracellular motility and dissemination. Enteropathogenic and enterohaemorrhagic Escherichia coli, which both cause severe diarrhoeal disease, can adhere to mammalian intestinal cells and induce reorganization of the actin cytoskeleton into 'pedestal-like' pseudopods beneath the extracellular bacteria. As pedestal assembly is triggered by E. coli virulence factors that mimic several host cell-signalling components, such as transmembrane receptors, their cognate ligands and cytoplasmic adaptor proteins, it can serve as a powerful model system to study eukaryotic transmembrane signalling. Here, we consider the impact of recent data on our understanding of both E. coli pathogenesis and cell biology, and the rich prospects for exploiting these bacterial factors as versatile tools to probe cellular signalling pathways.

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Figure 1: Protein composition of adhesion pedestals formed by enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC).
Figure 2: The structure of neural Wiskott–Aldrich syndrome protein (N-WASP) and WASP-interacting adaptor proteins.
Figure 3: Comparison of the cellular signalling cascades subverted by microbial pathogens to manipulate host actin polymerization.
Figure 4: Intimin-induced clustering of the translocated intimin receptor (Tir) in the host plasma membrane.
Figure 5: Comparison of the tyrosine-kinase recruitment and activation underlying signalling by cellular transmembrane receptors and pathogen virulence effectors.
Figure 6: Neural Wiskott–Aldrich syndrome protein (N-WASP) activation by enterohaemorrhagic Escherichia coli (EHEC), Shigella and mammalian transmembrane receptors.

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Acknowledgements

We thank N. Phillips, D. Tipper and E. Koronakis for discussions and critique of the manuscript, and M. Brady, N. Phillips, S. Snapper, R. DeVinney, T. Newsome and M. Way for discussion and communication of unpublished results. Our work is supported by a Wellcome Trust programme grant, a Medical Research Council project grant and Biotechnology and Biological Research Council Studentship to V.K., and a National Institutes of Health (NIH) grant to J.M.L. K.G.C. visited the Koronakis laboratory with support from a Human Frontier Science Program international fellowship.

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Author notes

  1. Kenneth G. Campellone

    Present address: Department of Molecular and Cell Biology, University of California, Berkeley, California, 94720-3200, USA

  2. Richard D. Hayward and Kenneth G. Campellone: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK

    Richard D. Hayward & Vassilis Koronakis

  2. Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, 01655, Massachusetts, USA

    John M. Leong & Kenneth G. Campellone

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Correspondence to John M. Leong or Vassilis Koronakis.

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DATABASES

Entrez Genome

vaccinia virus

Entrez Genome Project

O157:H7

Yersinia pseudotuberculosis

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Glossary

Microvilli

Small, finger-like projections found on the exposed surfaces of epithelial cells that maximize the surface area.

Macropinocytosis

A form of regulated, actin-dependent endocytosis that involves the formation of large endocytic vesicles after the closure of cell-surface membrane ruffles.

Filopodia

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

Lamellipodia

Flattened protrusions at the leading edge of a moving cell that are enriched with a branched network of actin filaments.

Tight junction

A seal between adjacent epithelial cells, just beneath the apical surface, that forms a semi-permeable diffusion barrier between individual cells.

Focal adhesions

Cellular structures that link the extracellular matrix on the outside of the cell to the actin cytoskeleton inside the cell through integrin receptors.

Pathogenicity island

A contiguous block of genes acquired by horizontal transfer in which at least a subset of the genes code for virulence factors.

C-type lectin

Calcium-dependent carbohydrate-binding protein.

Immunological synapse

A large junctional structure formed at the cell surface between a T cell and an antigen-presenting cell, also known as the supramolecular activation cluster. Important molecules that are involved in T-cell activation — including the T-cell receptor, numerous signal-transduction molecules and molecular adaptors — accumulate in an orderly manner at this site. Immunological synapses are now known to also form between other types of immune cells, for example, between dendritic cells and natural killer cells.

Immunoreceptor tyrosine-based activation motif

(ITAM). A sequence found in the cytoplasmic domains of the invariant chains of various cell-surface immune receptors, such as the T-cell receptor. Following phosphorylation of their tyrosine residue, ITAMs function as docking sites for Src-homology-2-domain-containing tyrosine kinases and adaptor molecules, thereby facilitating intracellular-signalling cascades.

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Hayward, R., Leong, J., Koronakis, V. et al. Exploiting pathogenic Escherichia coli to model transmembrane receptor signalling. Nat Rev Microbiol 4, 358–370 (2006). https://doi.org/10.1038/nrmicro1391

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