Exploiting pathogenic escherichia coli to model transmembrane receptor signalling

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. Access through your institution Buy or subscribe This is a preview of subscription content,

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EFFACEMENT INDUCED BY ENTEROHEMORRHAGIC _ESCHERICHIA COLI_ Article Open access 04 January 2021 THE PATHOGEN-ENCODED SIGNALLING RECEPTOR TIR EXPLOITS HOST-LIKE INTRINSIC DISORDER FOR

INFECTION Article Open access 13 February 2024 MICROSCALE COMMUNICATION BETWEEN BACTERIAL PATHOGENS AND THE HOST EPITHELIUM Article Open access 29 September 2021 REFERENCES * Cossart, P.

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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. AUTHOR INFORMATION Author

notes * Kenneth G. Campellone Present address: Department of Molecular and Cell Biology, University of California, Berkeley, California, 94720-3200, USA * Richard D. Hayward and Kenneth G.

Campellone: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK Richard D.

Hayward & Vassilis Koronakis * 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 Authors * Richard D. Hayward View author publications You can also search for this author inPubMed Google Scholar * John M. Leong View author

publications You can also search for this author inPubMed Google Scholar * Vassilis Koronakis View author publications You can also search for this author inPubMed Google Scholar * Kenneth

G. Campellone View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to John M. Leong or Vassilis Koronakis. ETHICS

DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED LINKS RELATED LINKS DATABASES ENTREZ GENOME vaccinia virus ENTREZ GENOME PROJECT O157:H7

_Yersinia pseudotuberculosis_ FURTHER INFORMATION Vassils Koronakis' homepage John M. Leong's homepage 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. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Published: 03 April 2006 * Issue Date: May 2006 * DOI: https://doi.org/10.1038/nrmicro1391 SHARE THIS

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