Exploiting pathogenic Escherichia coli to model transmembrane receptor signalling

Abstract

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 EspF_U 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.