title: The enteropathogenic E. coli effector EspH promotes actin pedestal formation and elongation via WASP-interacting protein (WIP).
abstract: Enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC) are diarrheagenic pathogens that colonize the gut mucosa via attaching-and-effacing lesion formation. EPEC and EHEC utilize a type III secretion system (T3SS) to translocate effector proteins that subvert host cell signalling to sustain colonization and multiplication. EspH, a T3SS effector that modulates actin dynamics, was implicated in the elongation of the EHEC actin pedestals. In this study we found that EspH is necessary for both efficient pedestal formation and pedestal elongation during EPEC infection. We report that EspH induces actin polymerization at the bacterial attachment sites independently of the Tir tyrosine residues Y474 and Y454, which are implicated in binding Nck and IRSp53/ITRKS respectively. Moreover, EspH promotes recruitment of neural Wiskott-Aldrich syndrome protein (N-WASP) and the Arp2/3 complex to the bacterial attachment site, in a mechanism involving the C-terminus of Tir and the WH1 domain of N-WASP. Dominant negative of WASP-interacting protein (WIP), which binds the N-WASP WH1 domain, diminished EspH-mediated actin polymerization. This study implicates WIP in EPEC-mediated actin polymerization and pedestal elongation and represents the first instance whereby N-WASP is efficiently recruited to the EPEC attachment sites independently of the Tir:Nck and Tir:IRTKS/IRSp53 pathways. Our study reveals the intricacies of Tir and EspH-mediated actin signalling pathways that comprise of distinct, convergent and synergistic signalling cascades.
authors.affiliation: Centre for Molecular Microbiology and Infection, Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, UK.
authors.forename: Alexander R C
authors.initials: AR
authors.lastname: Wong
authors.forename: Benoit
authors.initials: B
authors.lastname: Raymond
authors.forename: James W
authors.initials: JW
authors.lastname: Collins
authors.forename: Valerie F
authors.initials: VF
authors.lastname: Crepin
authors.forename: Gad
authors.initials: G
authors.lastname: Frankel
mesh_terms: D000199:Actins / Q000378:metabolism*; D058947:Bacterial Secretion Systems; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004705:Endocytosis; D054308:Enteropathogenic Escherichia coli / Q000472:pathogenicity*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008954:Models, Biological; D021381:Protein Transport
chemical_list: D000199:Actins; D058947:Bacterial Secretion Systems; D003598:Cytoskeletal Proteins; D029968:Escherichia coli Proteins; C472832:EspH protein, E coli; D047908:Intracellular Signaling Peptides and Proteins; C109903:WIPF1 protein, human