Inter-kingdom Signaling by the Legionella Quorum Sensing Molecule LAI-1 Modulates Cell Migration through an IQGAP1-Cdc42-ARHGEF9-Dependent Pathway.
Sylvia Simon, Ursula Schell, Natalie Heuer, Dominik Hager, Michael F Albers, Jan Matthias, Felix Fahrnbauer, Dirk Trauner, Ludwig Eichinger, Christian Hedberg, Hubert Hilbi
Author Information
Sylvia Simon: Max von Pettenkofer Institute, Ludwig-Maximilians University, Munich, Germany.
Ursula Schell: Max von Pettenkofer Institute, Ludwig-Maximilians University, Munich, Germany.
Natalie Heuer: Institute of Biochemistry I, University of Cologne, Cologne, Germany.
Dominik Hager: Department of Chemistry, Ludwig-Maximilians University, Munich, Germany.
Michael F Albers: Department of Chemistry and Umeå Center for Microbial Research, Umeå University, Umeå, Sweden.
Jan Matthias: Institute of Biochemistry I, University of Cologne, Cologne, Germany.
Felix Fahrnbauer: Department of Chemistry, Ludwig-Maximilians University, Munich, Germany.
Dirk Trauner: Department of Chemistry, Ludwig-Maximilians University, Munich, Germany.
Ludwig Eichinger: Institute of Biochemistry I, University of Cologne, Cologne, Germany.
Christian Hedberg: Department of Chemistry and Umeå Center for Microbial Research, Umeå University, Umeå, Sweden.
Hubert Hilbi: Max von Pettenkofer Institute, Ludwig-Maximilians University, Munich, Germany.
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.
