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J. Biol. Chem., Vol. 283, Issue 26, 18113-18123, June 27, 2008

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The Legionella Autoinducer Synthase LqsA Produces an -Hydroxyketone Signaling Molecule^*

Thomas Spirig, André Tiaden, Patrick Kiefer, Carmen Buchrieser, Julia A. Vorholt, and Hubert Hilbi¹

From the Institute of Microbiology, ETH Zürich, 8093 Zürich, Switzerland and Unité de Biologie des Bactéries Intracellulaires and CNRS URA 2171, Institute Pasteur, 75724 Paris, France

The opportunistic pathogen Legionella pneumophila replicates in human lung macrophages and in free-living amoebae. To accommodate the transfer between host cells, L. pneumophila switches from a replicative to a transmissive phase. L. pneumophila harbors a gene cluster homologous to the Vibrio cholerae cqsAS quorum sensing system, encoding a putative autoinducer synthase (lqsA) and a sensor kinase (lqsS), which flank a response regulator (lqsR). LqsR is an element of the L. pneumophila virulence regulatory network, which promotes pathogen-host cell interactions and inhibits entry into the replicative growth phase. Here, we show that lqsA functionally complements a V. cholerae cqsA autoinducer synthase deletion mutant and, upon expression in L. pneumophila or Escherichia coli, produces the diffusible signaling molecule LAI-1 (Legionella autoinducer-1). LAI-1 is distinct from CAI-1 (Cholerae autoinducer-1) and was identified as 3-hydroxypentadecan-4-one using liquid chromatography coupled to high resolution tandem mass spectrometry. The activity of both LqsA and CqsA was abolished upon mutation of a conserved lysine, and covalent binding of the cofactor pyridoxal 5'-phosphate to this lysine was confirmed by mass spectrometry. Thus, LqsA and CqsA belong to a family of pyridoxal 5'-phosphate-dependent autoinducer synthases, which produce the -hydroxyketone signaling molecules LAI-1 and CAI-1.

Received for publication, March 10, 2008 , and in revised form, April 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant AI044212 (to C. B.). This work was also supported by grants from the Swiss National Science Foundation (631-065952; PP00A-112592), the ETH Zürich (TH 17/02-3), the Commission for Technology and Innovation (6629.2 BTS-LS), and the Swiss Federal Agency for Energy (to H. H.), and by funding from the Agence Française de Sécurité Sanitaire de l'Environment et du Travail (ARCL-2005-002) (to C. B.). The group of H. H. participates in the NEMO (Non-mammalian Experimental Models for the Study of Bacterial Infections) Network supported by the Swiss 3R foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Tables S1 and S2.

¹ To whom correspondence should be addressed: Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland. Tel.: 41-44-632-4782; Fax: 41-44-632-1137; E-mail: hilbi{at}micro.biol.ethz.ch.

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