title: Mechanism of action of EPEC type III effector molecules.
abstract: Enteropathogenic E. coli (EPEC) is a prototypic member of the family of related 'attaching and effacing (A/E)' pathogens that induce diarrhoeal disease, especially to the young that can be fatal, of a wide range of mammalian species. Disease is correlated with the loss of absorptive gut epithelial microvilli and the reorganisation of host cytoskeletal proteins into pedestal-like structures beneath the adherent bacteria. These phenotypes are dependent on a pathogenicity island (LEE; Locus of Enterocyte Effacement) encoding a type III secretion system, secreted proteins, chaperone molecules, regulatory proteins and the bacterial outer membrane protein intimin. The type III secretion apparatus directs the transfer of specific proteins across the bacterial envelope, with a subset (EPEC secreted proteins - EspA, EspB and EspD) functioning to transfer effector proteins into host cells. These effector molecules subvert cellular processes that undoubtedly benefit the pathogen and contribute to disease. Three LEE-encoded EPEC effector molecules have so far been identified with one, Tir (Translocated intimin receptor), being transferred into host cells where it is modified by host kinases and becomes inserted into the plasma membrane to orchestrate cytoskeletal rearrangements linked to disease. This activity is dependent on its interaction with intimin and on tyrosine phosphorylation, with Tir-intimin interaction essential for virulence. A second effector Map, Mitochondrial-associated protein, is targeted to mitochondria where it has membrane-potential disrupting activity. The third, EspF disrupts intestinal barrier function and can induce host cell death by unknown mechanisms. Recent data relating to the mechanism by which Tir and Map function within host cells is discussed.
authors.affiliation: Department of Pathology and Microbiology, School of Medical Sciences, University Walk, Bristol, UK. B.Kenny@bristol.ac.uk
authors.forename: Brendan
authors.initials: B
authors.lastname: Kenny
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis; D019453:Escherichia coli O157 / Q000378:metabolism / Q000472:pathogenicity*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010750:Phosphoproteins; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine
chemical_list: D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; C087863:EaeB protein, E coli; D029968:Escherichia coli Proteins; C102051:EspA protein, E coli; C474481:EspD protein, E coli; C457340:LEE protein, E coli; C095564:Map protein, Staphylococcus aureus; D008565:Membrane Proteins; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; C109287:Tir protein, E coli; D014443:Tyrosine