title: The Chlamydia effector TarP mimics the mammalian leucine-aspartic acid motif of paxillin to subvert the focal adhesion kinase during invasion.
abstract: Host cell signal transduction pathways are often targets of bacterial pathogens, especially during the process of invasion when robust actin remodeling is required. We demonstrate that the host cell focal adhesion kinase (FAK) was necessary for the invasion by the obligate intracellular pathogen Chlamydia caviae. Bacterial adhesion triggered the transient recruitment of FAK to the plasma membrane to mediate a Cdc42- and Arp2/3-dependent actin assembly. FAK recruitment was via binding to a domain within the virulence factor TarP that mimicked the LD2 motif of the FAK binding partner paxillin. Importantly, bacterial two-hybrid and quantitative imaging assays revealed a similar level of interaction between paxillin-LD2 and TarP-LD. The conserved leucine residues within the L(D/E)XLLXXL motif were essential to the recruitment of FAK, Cdc42, p34(Arc), and actin to the plasma membrane. In the absence of FAK, TarP-LD-mediated F-actin assembly was reduced, highlighting the functional relevance of this interaction. Together, the data indicate that a prokaryotic version of the paxillin LD2 domain targets the FAK signaling pathway, with TarP representing the first example of an LD-containing Type III virulence effector.
authors.affiliation: Centre for Molecular Microbiology and Infection, Imperial College, London SW7 2AZ, United Kingdom,; Bacteriology Section, Programme in Microbiology, Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom, and.
authors.forename: Tristan
authors.initials: T
authors.lastname: Thwaites
authors.affiliation: Centre for Molecular Microbiology and Infection, Imperial College, London SW7 2AZ, United Kingdom,; Bacteriology Section, Programme in Microbiology, Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom, and.
authors.forename: Ana T
authors.initials: AT
authors.lastname: Nogueira
authors.affiliation: Centre for Molecular Microbiology and Infection, Imperial College, London SW7 2AZ, United Kingdom.
authors.forename: Ivan
authors.initials: I
authors.lastname: Campeotto
authors.affiliation: Bacteriology Section, Programme in Microbiology, Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom, and.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Silva
authors.affiliation: Department of Oral Biology, University of Florida School of Dentistry, Gainesville, Florida 32610.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Grieshaber
authors.affiliation: Centre for Molecular Microbiology and Infection, Imperial College, London SW7 2AZ, United Kingdom,; Bacteriology Section, Programme in Microbiology, Institute of Medical Sciences, School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom, and. Electronic address: r.carabeo@abdn.ac.uk.
authors.forename: Rey A
authors.initials: RA
authors.lastname: Carabeo
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001422:Bacterial Adhesion; D001426:Bacterial Proteins / Q000737:chemistry / Q000502:physiology*; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology / Q000382:microbiology; D002692:Chlamydia trachomatis / Q000502:physiology*; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D051419:Paxillin / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D037521:Virulence Factors / Q000737:chemistry / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D001426:Bacterial Proteins; D051419:Paxillin; D037521:Virulence Factors; D051417:Focal Adhesion Kinase 1; D020764:cdc42 GTP-Binding Protein
keywords: Actin; Bacterial Pathogenesis; Cell Biology; Chlamydia; PTK2 Protein-tyrosine Kinase 2 (PTK2) (Focal Adhesion Kinase) (FAK); Signaling; Virulence Factor