title: Inter-kingdom Signaling by the Legionella Quorum Sensing Molecule LAI-1 Modulates Cell Migration through an IQGAP1-Cdc42-ARHGEF9-Dependent Pathway.
abstract: Small molecule signaling promotes the communication between bacteria as well as between bacteria and eukaryotes. The opportunistic pathogenic bacterium Legionella pneumophila employs LAI-1 (3-hydroxypentadecane-4-one) for bacterial cell-cell communication. LAI-1 is produced and detected by the Lqs (Legionella quorum sensing) system, which regulates a variety of processes including natural competence for DNA uptake and pathogen-host cell interactions. In this study, we analyze the role of LAI-1 in inter-kingdom signaling. L. pneumophila lacking the autoinducer synthase LqsA no longer impeded the migration of infected cells, and the defect was complemented by plasmid-borne lqsA. Synthetic LAI-1 dose-dependently inhibited cell migration, without affecting bacterial uptake or cytotoxicity. The forward migration index but not the velocity of LAI-1-treated cells was reduced, and the cell cytoskeleton appeared destabilized. LAI-1-dependent inhibition of cell migration involved the scaffold protein IQGAP1, the small GTPase Cdc42 as well as the Cdc42-specific guanine nucleotide exchange factor ARHGEF9, but not other modulators of Cdc42, or RhoA, Rac1 or Ran GTPase. Upon treatment with LAI-1, Cdc42 was inactivated and IQGAP1 redistributed to the cell cortex regardless of whether Cdc42 was present or not. Furthermore, LAI-1 reversed the inhibition of cell migration by L. pneumophila, suggesting that the compound and the bacteria antagonistically target host signaling pathway(s). Collectively, the results indicate that the L. pneumophila quorum sensing compound LAI-1 modulates migration of eukaryotic cells through a signaling pathway involving IQGAP1, Cdc42 and ARHGEF9.
authors.affiliation: Max von Pettenkofer Institute, Ludwig-Maximilians University, Munich, Germany.|Institute of Medical Microbiology, University of Zürich, Zürich, Switzerland.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Simon
authors.affiliation: Max von Pettenkofer Institute, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Schell
authors.affiliation: Institute of Biochemistry I, University of Cologne, Cologne, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Heuer
authors.affiliation: Department of Chemistry, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Hager
authors.affiliation: Department of Chemistry and Umeå Center for Microbial Research, Umeå University, Umeå, Sweden.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Albers
authors.affiliation: Institute of Biochemistry I, University of Cologne, Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Matthias
authors.affiliation: Department of Chemistry, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Fahrnbauer
authors.affiliation: Department of Chemistry, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Trauner
authors.affiliation: Institute of Biochemistry I, University of Cologne, Cologne, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Eichinger
authors.affiliation: Department of Chemistry and Umeå Center for Microbial Research, Umeå University, Umeå, Sweden.|Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Dortmund, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hedberg
authors.affiliation: Max von Pettenkofer Institute, Ludwig-Maximilians University, Munich, Germany.|Institute of Medical Microbiology, University of Zürich, Zürich, Switzerland.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hilbi
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D006790:Host-Parasite Interactions / Q000502:physiology*; D016952:Legionella pneumophila; D007877:Legionnaires' Disease / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D053038:Quorum Sensing / Q000502:physiology*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
chemical_list: C577410:ARHGEF9 protein, human; D001426:Bacterial Proteins; C101203:IQ motif containing GTPase activating protein 1; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; D020703:ras GTPase-Activating Proteins; C030654:N-(3-oxohexanoyl)-3-aminodihydro-2(3H)-furanone; D020764:cdc42 GTP-Binding Protein; D015107:4-Butyrolactone