Serveur d'exploration sur les relations entre la France et l'Australie

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Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy

Identifieur interne : 000B96 ( Pmc/Checkpoint ); précédent : 000B95; suivant : 000B97

Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy

Auteurs : Monica Rolando [France] ; Pedro Escoll [France] ; Tamara Nora [France] ; Joëlle Botti [France] ; Valérie Boitez [France] ; Carmen Bedia [France] ; Craig Daniels [Canada] ; Gilu Abraham [Australie] ; Peter J. Stogios [Canada] ; Tatiana Skarina [Canada] ; Charlotte Christophe [France] ; Delphine Dervins-Ravault [France] ; Christel Cazalet [France] ; Hubert Hilbi [Suisse] ; Thusitha W. T. Rupasinghe [Australie] ; Dedreia Tull [Australie] ; Malcolm J. Mcconville [Australie] ; Sze Ying Ong [Australie] ; Elizabeth L. Hartland [Australie] ; Patrice Codogno [France] ; Thierry Levade [France] ; Thomas Naderer [Australie] ; Alexei Savchenko [Canada] ; Carmen Buchrieser [France]

Source :

RBID : PMC:4763766

Abstract

Significance

Legionella pneumophila is the causative agent of Legionnaires’ disease. It translocates a large repertoire of effectors into the host cell through a specialized secretion system to subvert cellular defenses. A key characteristic of this pathogen is that the majority of its effectors are encoded by eukaryotic-like genes acquired through horizontal gene transfer. We determined the crystal structure of one of these effectors, sphingosine-1 phosphate lyase (LpSpl), and show that it has high similarity with its eukaryotic homologue. We demonstrate that LpSpl possesses lyase activity and that it disrupts sphingolipid metabolism in the host cells. LpSpl plays a critical and previously unknown role in decreasing autophagy and is a unique virulence factor facilitating intracellular replication of L. pneumophila.


Url:
DOI: 10.1073/pnas.1522067113
PubMed: 26831115
PubMed Central: 4763766


Affiliations:


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PMC:4763766

Le document en format XML

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<italic>Legionella pneumophila</italic>
S1P-lyase targets host sphingolipid metabolism and restrains autophagy</title>
<author>
<name sortKey="Rolando, Monica" sort="Rolando, Monica" uniqKey="Rolando M" first="Monica" last="Rolando">Monica Rolando</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1">
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<institution>CNRS</institution>
UMR 3525, 75724 Paris,
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;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Escoll, Pedro" sort="Escoll, Pedro" uniqKey="Escoll P" first="Pedro" last="Escoll">Pedro Escoll</name>
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<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<institution>CNRS</institution>
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<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Nora, Tamara" sort="Nora, Tamara" uniqKey="Nora T" first="Tamara" last="Nora">Tamara Nora</name>
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<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
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;</nlm:aff>
<country xml:lang="fr">France</country>
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<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Botti, Joelle" sort="Botti, Joelle" uniqKey="Botti J" first="Joëlle" last="Botti">Joëlle Botti</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<institution>Institut Necker Enfants-Malades</institution>
, INSERM U1151-CNRS UMR 8253, 75993 Paris,
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;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<affiliation wicri:level="1">
<nlm:aff id="aff4">
<institution>Université Paris Descartes-Sorbonne Paris Cité</institution>
, 75993 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Boitez, Valerie" sort="Boitez, Valerie" uniqKey="Boitez V" first="Valérie" last="Boitez">Valérie Boitez</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<institution>Institut Necker Enfants-Malades</institution>
, INSERM U1151-CNRS UMR 8253, 75993 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<institution>Université Paris Descartes-Sorbonne Paris Cité</institution>
, 75993 Paris,
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;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Bedia, Carmen" sort="Bedia, Carmen" uniqKey="Bedia C" first="Carmen" last="Bedia">Carmen Bedia</name>
<affiliation wicri:level="1">
<nlm:aff id="aff5">INSERM UMR1037,
<institution>Centre de Recherches en Cancérologie de Toulouse</institution>
, 31432 Toulouse,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Daniels, Craig" sort="Daniels, Craig" uniqKey="Daniels C" first="Craig" last="Daniels">Craig Daniels</name>
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<nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,
<institution>University of Toronto</institution>
, Toronto,
<country>Canada</country>
M5S 3E5;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Abraham, Gilu" sort="Abraham, Gilu" uniqKey="Abraham G" first="Gilu" last="Abraham">Gilu Abraham</name>
<affiliation wicri:level="1">
<nlm:aff id="aff7">Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute,
<institution>Monash University</institution>
, Clayton, VIC 3800,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Stogios, Peter J" sort="Stogios, Peter J" uniqKey="Stogios P" first="Peter J." last="Stogios">Peter J. Stogios</name>
<affiliation wicri:level="1">
<nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,
<institution>University of Toronto</institution>
, Toronto,
<country>Canada</country>
M5S 3E5;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Skarina, Tatiana" sort="Skarina, Tatiana" uniqKey="Skarina T" first="Tatiana" last="Skarina">Tatiana Skarina</name>
<affiliation wicri:level="1">
<nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,
<institution>University of Toronto</institution>
, Toronto,
<country>Canada</country>
M5S 3E5;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Christophe, Charlotte" sort="Christophe, Charlotte" uniqKey="Christophe C" first="Charlotte" last="Christophe">Charlotte Christophe</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Dervins Ravault, Delphine" sort="Dervins Ravault, Delphine" uniqKey="Dervins Ravault D" first="Delphine" last="Dervins-Ravault">Delphine Dervins-Ravault</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Cazalet, Christel" sort="Cazalet, Christel" uniqKey="Cazalet C" first="Christel" last="Cazalet">Christel Cazalet</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hilbi, Hubert" sort="Hilbi, Hubert" uniqKey="Hilbi H" first="Hubert" last="Hilbi">Hubert Hilbi</name>
<affiliation wicri:level="1">
<nlm:aff id="aff8">Institute of Medical Microbiology,
<institution>University of Zürich</institution>
,
<country>8006, Zurich, Switzerland</country>
;</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda</wicri:regionArea>
<wicri:noRegion>Bethesda</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Rupasinghe, Thusitha W T" sort="Rupasinghe, Thusitha W T" uniqKey="Rupasinghe T" first="Thusitha W. T." last="Rupasinghe">Thusitha W. T. Rupasinghe</name>
<affiliation wicri:level="1">
<nlm:aff id="aff9">Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute,
<institution>The University of Melbourne</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Tull, Dedreia" sort="Tull, Dedreia" uniqKey="Tull D" first="Dedreia" last="Tull">Dedreia Tull</name>
<affiliation wicri:level="1">
<nlm:aff id="aff9">Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute,
<institution>The University of Melbourne</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mcconville, Malcolm J" sort="Mcconville, Malcolm J" uniqKey="Mcconville M" first="Malcolm J." last="Mcconville">Malcolm J. Mcconville</name>
<affiliation wicri:level="1">
<nlm:aff id="aff9">Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute,
<institution>The University of Melbourne</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff10">Department of Biochemistry and Molecular Biology,
<institution>The University of Melbourne</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Ong, Sze Ying" sort="Ong, Sze Ying" uniqKey="Ong S" first="Sze Ying" last="Ong">Sze Ying Ong</name>
<affiliation wicri:level="1">
<nlm:aff id="aff11">Department of Microbiology and Immunology,
<institution>University of Melbourne at the Peter Doherty Institute for Infection and Immunity</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hartland, Elizabeth L" sort="Hartland, Elizabeth L" uniqKey="Hartland E" first="Elizabeth L." last="Hartland">Elizabeth L. Hartland</name>
<affiliation wicri:level="1">
<nlm:aff id="aff11">Department of Microbiology and Immunology,
<institution>University of Melbourne at the Peter Doherty Institute for Infection and Immunity</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Codogno, Patrice" sort="Codogno, Patrice" uniqKey="Codogno P" first="Patrice" last="Codogno">Patrice Codogno</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<institution>Institut Necker Enfants-Malades</institution>
, INSERM U1151-CNRS UMR 8253, 75993 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff4">
<institution>Université Paris Descartes-Sorbonne Paris Cité</institution>
, 75993 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Levade, Thierry" sort="Levade, Thierry" uniqKey="Levade T" first="Thierry" last="Levade">Thierry Levade</name>
<affiliation wicri:level="1">
<nlm:aff id="aff5">INSERM UMR1037,
<institution>Centre de Recherches en Cancérologie de Toulouse</institution>
, 31432 Toulouse,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Naderer, Thomas" sort="Naderer, Thomas" uniqKey="Naderer T" first="Thomas" last="Naderer">Thomas Naderer</name>
<affiliation wicri:level="1">
<nlm:aff id="aff7">Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute,
<institution>Monash University</institution>
, Clayton, VIC 3800,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Savchenko, Alexei" sort="Savchenko, Alexei" uniqKey="Savchenko A" first="Alexei" last="Savchenko">Alexei Savchenko</name>
<affiliation wicri:level="1">
<nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,
<institution>University of Toronto</institution>
, Toronto,
<country>Canada</country>
M5S 3E5;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Buchrieser, Carmen" sort="Buchrieser, Carmen" uniqKey="Buchrieser C" first="Carmen" last="Buchrieser">Carmen Buchrieser</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<title xml:lang="en" level="a" type="main">
<italic>Legionella pneumophila</italic>
S1P-lyase targets host sphingolipid metabolism and restrains autophagy</title>
<author>
<name sortKey="Rolando, Monica" sort="Rolando, Monica" uniqKey="Rolando M" first="Monica" last="Rolando">Monica Rolando</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Escoll, Pedro" sort="Escoll, Pedro" uniqKey="Escoll P" first="Pedro" last="Escoll">Pedro Escoll</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Nora, Tamara" sort="Nora, Tamara" uniqKey="Nora T" first="Tamara" last="Nora">Tamara Nora</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Botti, Joelle" sort="Botti, Joelle" uniqKey="Botti J" first="Joëlle" last="Botti">Joëlle Botti</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<institution>Institut Necker Enfants-Malades</institution>
, INSERM U1151-CNRS UMR 8253, 75993 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff4">
<institution>Université Paris Descartes-Sorbonne Paris Cité</institution>
, 75993 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Boitez, Valerie" sort="Boitez, Valerie" uniqKey="Boitez V" first="Valérie" last="Boitez">Valérie Boitez</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<institution>Institut Necker Enfants-Malades</institution>
, INSERM U1151-CNRS UMR 8253, 75993 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff4">
<institution>Université Paris Descartes-Sorbonne Paris Cité</institution>
, 75993 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Bedia, Carmen" sort="Bedia, Carmen" uniqKey="Bedia C" first="Carmen" last="Bedia">Carmen Bedia</name>
<affiliation wicri:level="1">
<nlm:aff id="aff5">INSERM UMR1037,
<institution>Centre de Recherches en Cancérologie de Toulouse</institution>
, 31432 Toulouse,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Daniels, Craig" sort="Daniels, Craig" uniqKey="Daniels C" first="Craig" last="Daniels">Craig Daniels</name>
<affiliation wicri:level="1">
<nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,
<institution>University of Toronto</institution>
, Toronto,
<country>Canada</country>
M5S 3E5;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Abraham, Gilu" sort="Abraham, Gilu" uniqKey="Abraham G" first="Gilu" last="Abraham">Gilu Abraham</name>
<affiliation wicri:level="1">
<nlm:aff id="aff7">Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute,
<institution>Monash University</institution>
, Clayton, VIC 3800,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Stogios, Peter J" sort="Stogios, Peter J" uniqKey="Stogios P" first="Peter J." last="Stogios">Peter J. Stogios</name>
<affiliation wicri:level="1">
<nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,
<institution>University of Toronto</institution>
, Toronto,
<country>Canada</country>
M5S 3E5;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Skarina, Tatiana" sort="Skarina, Tatiana" uniqKey="Skarina T" first="Tatiana" last="Skarina">Tatiana Skarina</name>
<affiliation wicri:level="1">
<nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,
<institution>University of Toronto</institution>
, Toronto,
<country>Canada</country>
M5S 3E5;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Christophe, Charlotte" sort="Christophe, Charlotte" uniqKey="Christophe C" first="Charlotte" last="Christophe">Charlotte Christophe</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Dervins Ravault, Delphine" sort="Dervins Ravault, Delphine" uniqKey="Dervins Ravault D" first="Delphine" last="Dervins-Ravault">Delphine Dervins-Ravault</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Cazalet, Christel" sort="Cazalet, Christel" uniqKey="Cazalet C" first="Christel" last="Cazalet">Christel Cazalet</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hilbi, Hubert" sort="Hilbi, Hubert" uniqKey="Hilbi H" first="Hubert" last="Hilbi">Hubert Hilbi</name>
<affiliation wicri:level="1">
<nlm:aff id="aff8">Institute of Medical Microbiology,
<institution>University of Zürich</institution>
,
<country>8006, Zurich, Switzerland</country>
;</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda</wicri:regionArea>
<wicri:noRegion>Bethesda</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Rupasinghe, Thusitha W T" sort="Rupasinghe, Thusitha W T" uniqKey="Rupasinghe T" first="Thusitha W. T." last="Rupasinghe">Thusitha W. T. Rupasinghe</name>
<affiliation wicri:level="1">
<nlm:aff id="aff9">Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute,
<institution>The University of Melbourne</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Tull, Dedreia" sort="Tull, Dedreia" uniqKey="Tull D" first="Dedreia" last="Tull">Dedreia Tull</name>
<affiliation wicri:level="1">
<nlm:aff id="aff9">Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute,
<institution>The University of Melbourne</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mcconville, Malcolm J" sort="Mcconville, Malcolm J" uniqKey="Mcconville M" first="Malcolm J." last="Mcconville">Malcolm J. Mcconville</name>
<affiliation wicri:level="1">
<nlm:aff id="aff9">Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute,
<institution>The University of Melbourne</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff10">Department of Biochemistry and Molecular Biology,
<institution>The University of Melbourne</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Ong, Sze Ying" sort="Ong, Sze Ying" uniqKey="Ong S" first="Sze Ying" last="Ong">Sze Ying Ong</name>
<affiliation wicri:level="1">
<nlm:aff id="aff11">Department of Microbiology and Immunology,
<institution>University of Melbourne at the Peter Doherty Institute for Infection and Immunity</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hartland, Elizabeth L" sort="Hartland, Elizabeth L" uniqKey="Hartland E" first="Elizabeth L." last="Hartland">Elizabeth L. Hartland</name>
<affiliation wicri:level="1">
<nlm:aff id="aff11">Department of Microbiology and Immunology,
<institution>University of Melbourne at the Peter Doherty Institute for Infection and Immunity</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Codogno, Patrice" sort="Codogno, Patrice" uniqKey="Codogno P" first="Patrice" last="Codogno">Patrice Codogno</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">
<institution>Institut Necker Enfants-Malades</institution>
, INSERM U1151-CNRS UMR 8253, 75993 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff4">
<institution>Université Paris Descartes-Sorbonne Paris Cité</institution>
, 75993 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Levade, Thierry" sort="Levade, Thierry" uniqKey="Levade T" first="Thierry" last="Levade">Thierry Levade</name>
<affiliation wicri:level="1">
<nlm:aff id="aff5">INSERM UMR1037,
<institution>Centre de Recherches en Cancérologie de Toulouse</institution>
, 31432 Toulouse,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Naderer, Thomas" sort="Naderer, Thomas" uniqKey="Naderer T" first="Thomas" last="Naderer">Thomas Naderer</name>
<affiliation wicri:level="1">
<nlm:aff id="aff7">Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute,
<institution>Monash University</institution>
, Clayton, VIC 3800,
<country>Australia</country>
;</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Savchenko, Alexei" sort="Savchenko, Alexei" uniqKey="Savchenko A" first="Alexei" last="Savchenko">Alexei Savchenko</name>
<affiliation wicri:level="1">
<nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,
<institution>University of Toronto</institution>
, Toronto,
<country>Canada</country>
M5S 3E5;</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Buchrieser, Carmen" sort="Buchrieser, Carmen" uniqKey="Buchrieser C" first="Carmen" last="Buchrieser">Carmen Buchrieser</name>
<affiliation wicri:level="1">
<nlm:aff id="aff1">Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="aff2">
<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Proceedings of the National Academy of Sciences of the United States of America</title>
<idno type="ISSN">0027-8424</idno>
<idno type="eISSN">1091-6490</idno>
<imprint>
<date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<title>Significance</title>
<p>
<italic>Legionella pneumophila</italic>
is the causative agent of Legionnaires’ disease. It translocates a large repertoire of effectors into the host cell through a specialized secretion system to subvert cellular defenses. A key characteristic of this pathogen is that the majority of its effectors are encoded by eukaryotic-like genes acquired through horizontal gene transfer. We determined the crystal structure of one of these effectors, sphingosine-1 phosphate lyase (
<italic>Lp</italic>
Spl), and show that it has high similarity with its eukaryotic homologue. We demonstrate that
<italic>Lp</italic>
Spl possesses lyase activity and that it disrupts sphingolipid metabolism in the host cells.
<italic>Lp</italic>
Spl plays a critical and previously unknown role in decreasing autophagy and is a unique virulence factor facilitating intracellular replication of
<italic>L. pneumophila</italic>
.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article">
<pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id>
<journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id>
<journal-id journal-id-type="hwp">pnas</journal-id>
<journal-id journal-id-type="pmc">pnas</journal-id>
<journal-id journal-id-type="publisher-id">PNAS</journal-id>
<journal-title-group>
<journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title>
</journal-title-group>
<issn pub-type="ppub">0027-8424</issn>
<issn pub-type="epub">1091-6490</issn>
<publisher>
<publisher-name>National Academy of Sciences</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">26831115</article-id>
<article-id pub-id-type="pmc">4763766</article-id>
<article-id pub-id-type="publisher-id">201522067</article-id>
<article-id pub-id-type="doi">10.1073/pnas.1522067113</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Biological Sciences</subject>
<subj-group>
<subject>Microbiology</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>
<italic>Legionella pneumophila</italic>
S1P-lyase targets host sphingolipid metabolism and restrains autophagy</article-title>
<alt-title alt-title-type="short">
<italic>Legionella</italic>
modulates the host’s sphingolipids</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Rolando</surname>
<given-names>Monica</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>b</sup>
</xref>
<xref ref-type="author-notes" rid="fn1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Escoll</surname>
<given-names>Pedro</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>b</sup>
</xref>
<xref ref-type="author-notes" rid="fn1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Nora</surname>
<given-names>Tamara</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Botti</surname>
<given-names>Joëlle</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>c</sup>
</xref>
<xref ref-type="aff" rid="aff4">
<sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Boitez</surname>
<given-names>Valérie</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>c</sup>
</xref>
<xref ref-type="aff" rid="aff4">
<sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0003-4584-5843</contrib-id>
<name>
<surname>Bedia</surname>
<given-names>Carmen</given-names>
</name>
<xref ref-type="aff" rid="aff5">
<sup>e</sup>
</xref>
<xref ref-type="author-notes" rid="fn2">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Daniels</surname>
<given-names>Craig</given-names>
</name>
<xref ref-type="aff" rid="aff6">
<sup>f</sup>
</xref>
<xref ref-type="author-notes" rid="fn3">
<sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Abraham</surname>
<given-names>Gilu</given-names>
</name>
<xref ref-type="aff" rid="aff7">
<sup>g</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Stogios</surname>
<given-names>Peter J.</given-names>
</name>
<xref ref-type="aff" rid="aff6">
<sup>f</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Skarina</surname>
<given-names>Tatiana</given-names>
</name>
<xref ref-type="aff" rid="aff6">
<sup>f</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Christophe</surname>
<given-names>Charlotte</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Dervins-Ravault</surname>
<given-names>Delphine</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Cazalet</surname>
<given-names>Christel</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hilbi</surname>
<given-names>Hubert</given-names>
</name>
<xref ref-type="aff" rid="aff8">
<sup>h</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Rupasinghe</surname>
<given-names>Thusitha W. T.</given-names>
</name>
<xref ref-type="aff" rid="aff9">
<sup>i</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Tull</surname>
<given-names>Dedreia</given-names>
</name>
<xref ref-type="aff" rid="aff9">
<sup>i</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>McConville</surname>
<given-names>Malcolm J.</given-names>
</name>
<xref ref-type="aff" rid="aff9">
<sup>i</sup>
</xref>
<xref ref-type="aff" rid="aff10">
<sup>j</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ong</surname>
<given-names>Sze Ying</given-names>
</name>
<xref ref-type="aff" rid="aff11">
<sup>k</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Hartland</surname>
<given-names>Elizabeth L.</given-names>
</name>
<xref ref-type="aff" rid="aff11">
<sup>k</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Codogno</surname>
<given-names>Patrice</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>c</sup>
</xref>
<xref ref-type="aff" rid="aff4">
<sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Levade</surname>
<given-names>Thierry</given-names>
</name>
<xref ref-type="aff" rid="aff5">
<sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Naderer</surname>
<given-names>Thomas</given-names>
</name>
<xref ref-type="aff" rid="aff7">
<sup>g</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Savchenko</surname>
<given-names>Alexei</given-names>
</name>
<xref ref-type="aff" rid="aff6">
<sup>f</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Buchrieser</surname>
<given-names>Carmen</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>b</sup>
</xref>
<xref ref-type="corresp" rid="cor1">
<sup>4</sup>
</xref>
</contrib>
<aff id="aff1">
<sup>a</sup>
Institut Pasteur,
<institution>Biologie des Bactéries Intracellulaires</institution>
, 75724 Paris,
<country>France</country>
;</aff>
<aff id="aff2">
<sup>b</sup>
<institution>CNRS</institution>
UMR 3525, 75724 Paris,
<country>France</country>
;</aff>
<aff id="aff3">
<sup>c</sup>
<institution>Institut Necker Enfants-Malades</institution>
, INSERM U1151-CNRS UMR 8253, 75993 Paris,
<country>France</country>
;</aff>
<aff id="aff4">
<sup>d</sup>
<institution>Université Paris Descartes-Sorbonne Paris Cité</institution>
, 75993 Paris,
<country>France</country>
;</aff>
<aff id="aff5">
<sup>e</sup>
INSERM UMR1037,
<institution>Centre de Recherches en Cancérologie de Toulouse</institution>
, 31432 Toulouse,
<country>France</country>
;</aff>
<aff id="aff6">
<sup>f</sup>
Department of Chemical Engineering and Applied Chemistry,
<institution>University of Toronto</institution>
, Toronto,
<country>Canada</country>
M5S 3E5;</aff>
<aff id="aff7">
<sup>g</sup>
Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute,
<institution>Monash University</institution>
, Clayton, VIC 3800,
<country>Australia</country>
;</aff>
<aff id="aff8">
<sup>h</sup>
Institute of Medical Microbiology,
<institution>University of Zürich</institution>
,
<country>8006, Zurich, Switzerland</country>
;</aff>
<aff id="aff9">
<sup>i</sup>
Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute,
<institution>The University of Melbourne</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
;</aff>
<aff id="aff10">
<sup>j</sup>
Department of Biochemistry and Molecular Biology,
<institution>The University of Melbourne</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
;</aff>
<aff id="aff11">
<sup>k</sup>
Department of Microbiology and Immunology,
<institution>University of Melbourne at the Peter Doherty Institute for Infection and Immunity</institution>
, Melbourne, VIC 3010,
<country>Australia</country>
</aff>
</contrib-group>
<author-notes>
<corresp id="cor1">
<sup>4</sup>
To whom correspondence should be addressed. Email:
<email>cbuch@pasteur.fr</email>
.</corresp>
<fn fn-type="edited-by">
<p>Edited by Ralph R. Isberg, Howard Hughes Medical Institute/Tufts University School of Medicine, Boston, MA, and approved December 30, 2015 (received for review November 10, 2015)</p>
</fn>
<fn fn-type="con">
<p>Author contributions: E.L.H., P.C., T. Naderer, A.S., and C. Buchrieser designed research; M.R., P.E., T. Nora, J.B., V.B., C. Bedia, C.D., G.A., P.J.S., T.S., C. Christophe, D.D.-R., C. Cazalet, T.W.T.R., D.T., M.J.M., and S.Y.O. performed research; M.R., P.E., T. Nora, P.J.S., H.H., E.L.H., P.C., T.L., T. Naderer, A.S., and C. Buchrieser analyzed data; and M.R., P.E., P.J.S., A.S., and C. Buchrieser wrote the paper.</p>
</fn>
<fn fn-type="present-address" id="fn2">
<p>
<sup>2</sup>
Present address: Institute of Environmental Assessment and Water Research (IDAEA-CSIC), 08034 Barcelona, Spain.</p>
</fn>
<fn fn-type="present-address" id="fn3">
<p>
<sup>3</sup>
Present address: Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8.</p>
</fn>
<fn fn-type="equal" id="fn1">
<p>
<sup>1</sup>
M.R. and P.E. contributed equally to this work.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub">
<day>16</day>
<month>2</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="epub">
<day>1</day>
<month>2</month>
<year>2016</year>
</pub-date>
<volume>113</volume>
<issue>7</issue>
<fpage>1901</fpage>
<lpage>1906</lpage>
<permissions></permissions>
<self-uri xlink:title="pdf" xlink:href="pnas.201522067.pdf"></self-uri>
<abstract abstract-type="executive-summary">
<title>Significance</title>
<p>
<italic>Legionella pneumophila</italic>
is the causative agent of Legionnaires’ disease. It translocates a large repertoire of effectors into the host cell through a specialized secretion system to subvert cellular defenses. A key characteristic of this pathogen is that the majority of its effectors are encoded by eukaryotic-like genes acquired through horizontal gene transfer. We determined the crystal structure of one of these effectors, sphingosine-1 phosphate lyase (
<italic>Lp</italic>
Spl), and show that it has high similarity with its eukaryotic homologue. We demonstrate that
<italic>Lp</italic>
Spl possesses lyase activity and that it disrupts sphingolipid metabolism in the host cells.
<italic>Lp</italic>
Spl plays a critical and previously unknown role in decreasing autophagy and is a unique virulence factor facilitating intracellular replication of
<italic>L. pneumophila</italic>
.</p>
</abstract>
<abstract>
<p>Autophagy is an essential component of innate immunity, enabling the detection and elimination of intracellular pathogens.
<italic>Legionella pneumophila</italic>
, an intracellular pathogen that can cause a severe pneumonia in humans, is able to modulate autophagy through the action of effector proteins that are translocated into the host cell by the pathogen’s Dot/Icm type IV secretion system. Many of these effectors share structural and sequence similarity with eukaryotic proteins. Indeed, phylogenetic analyses have indicated their acquisition by horizontal gene transfer from a eukaryotic host. Here we report that
<italic>L. pneumophila</italic>
translocates the effector protein sphingosine-1 phosphate lyase (
<italic>Lp</italic>
Spl) to target the host sphingosine biosynthesis and to curtail autophagy. Our structural characterization of
<italic>Lp</italic>
Spl and its comparison with human SPL reveals high structural conservation, thus supporting prior phylogenetic analysis. We show that
<italic>Lp</italic>
Spl possesses S1P lyase activity that was abrogated by mutation of the catalytic site residues.
<italic>L. pneumophila</italic>
triggers the reduction of several sphingolipids critical for macrophage function in an
<italic>Lp</italic>
Spl-dependent and -independent manner.
<italic>Lp</italic>
Spl activity alone was sufficient to prevent an increase in sphingosine levels in infected host cells and to inhibit autophagy during macrophage infection.
<italic>Lp</italic>
Spl was required for efficient infection of A/J mice, highlighting an important virulence role for this effector. Thus, we have uncovered a previously unidentified mechanism used by intracellular pathogens to inhibit autophagy, namely the disruption of host sphingolipid biosynthesis.</p>
</abstract>
<kwd-group>
<kwd>
<italic>Legionella pneumophila</italic>
</kwd>
<kwd>sphingosine-1-phosphate lyase</kwd>
<kwd>autophagy</kwd>
<kwd>sphingolipids</kwd>
<kwd>virulence</kwd>
</kwd-group>
<funding-group>
<award-group id="gs1">
<funding-source id="sp1">Agence Nationale de la Recherche (L' Agence Nationale de la Recherche)
<named-content content-type="funder-id">501100001665</named-content>
</funding-source>
<award-id rid="sp1">ANR-10-LABX-62-IBEID</award-id>
</award-group>
<award-group id="gs2">
<funding-source id="sp2">Agence Nationale de la Recherche (L' Agence Nationale de la Recherche)
<named-content content-type="funder-id">501100001665</named-content>
</funding-source>
<award-id rid="sp2">ANR-13-IFEC-0003-02</award-id>
</award-group>
<award-group id="gs3">
<funding-source id="sp3">Fondation de la recherche medicale</funding-source>
<award-id rid="sp3">DEQ20120323697</award-id>
</award-group>
<award-group id="gs4">
<funding-source id="sp4">Swiss National Science Foundation (Schweizerische Nationalfonds)
<named-content content-type="funder-id">501100001711</named-content>
</funding-source>
<award-id rid="sp4">SNF</award-id>
<award-id rid="sp4">31003A_153200</award-id>
</award-group>
<award-group id="gs5">
<funding-source id="sp5">Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
<named-content content-type="funder-id">501100002347</named-content>
</funding-source>
<award-id rid="sp5">031A410A</award-id>
</award-group>
<award-group id="gs6">
<funding-source id="sp6">HHS | National Institutes of Health (NIH)
<named-content content-type="funder-id">100000002</named-content>
</funding-source>
<award-id rid="sp6">U54-GM074942</award-id>
</award-group>
<award-group id="gs7">
<funding-source id="sp7">HHS | National Institutes of Health (NIH)
<named-content content-type="funder-id">100000002</named-content>
</funding-source>
<award-id rid="sp7">U54-GM094585</award-id>
</award-group>
</funding-group>
<counts>
<page-count count="6"></page-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations>
<list>
<country>
<li>Australie</li>
<li>Canada</li>
<li>France</li>
<li>Suisse</li>
</country>
</list>
<tree>
<country name="France">
<noRegion>
<name sortKey="Rolando, Monica" sort="Rolando, Monica" uniqKey="Rolando M" first="Monica" last="Rolando">Monica Rolando</name>
</noRegion>
<name sortKey="Bedia, Carmen" sort="Bedia, Carmen" uniqKey="Bedia C" first="Carmen" last="Bedia">Carmen Bedia</name>
<name sortKey="Boitez, Valerie" sort="Boitez, Valerie" uniqKey="Boitez V" first="Valérie" last="Boitez">Valérie Boitez</name>
<name sortKey="Boitez, Valerie" sort="Boitez, Valerie" uniqKey="Boitez V" first="Valérie" last="Boitez">Valérie Boitez</name>
<name sortKey="Botti, Joelle" sort="Botti, Joelle" uniqKey="Botti J" first="Joëlle" last="Botti">Joëlle Botti</name>
<name sortKey="Botti, Joelle" sort="Botti, Joelle" uniqKey="Botti J" first="Joëlle" last="Botti">Joëlle Botti</name>
<name sortKey="Buchrieser, Carmen" sort="Buchrieser, Carmen" uniqKey="Buchrieser C" first="Carmen" last="Buchrieser">Carmen Buchrieser</name>
<name sortKey="Buchrieser, Carmen" sort="Buchrieser, Carmen" uniqKey="Buchrieser C" first="Carmen" last="Buchrieser">Carmen Buchrieser</name>
<name sortKey="Cazalet, Christel" sort="Cazalet, Christel" uniqKey="Cazalet C" first="Christel" last="Cazalet">Christel Cazalet</name>
<name sortKey="Cazalet, Christel" sort="Cazalet, Christel" uniqKey="Cazalet C" first="Christel" last="Cazalet">Christel Cazalet</name>
<name sortKey="Christophe, Charlotte" sort="Christophe, Charlotte" uniqKey="Christophe C" first="Charlotte" last="Christophe">Charlotte Christophe</name>
<name sortKey="Christophe, Charlotte" sort="Christophe, Charlotte" uniqKey="Christophe C" first="Charlotte" last="Christophe">Charlotte Christophe</name>
<name sortKey="Codogno, Patrice" sort="Codogno, Patrice" uniqKey="Codogno P" first="Patrice" last="Codogno">Patrice Codogno</name>
<name sortKey="Codogno, Patrice" sort="Codogno, Patrice" uniqKey="Codogno P" first="Patrice" last="Codogno">Patrice Codogno</name>
<name sortKey="Dervins Ravault, Delphine" sort="Dervins Ravault, Delphine" uniqKey="Dervins Ravault D" first="Delphine" last="Dervins-Ravault">Delphine Dervins-Ravault</name>
<name sortKey="Dervins Ravault, Delphine" sort="Dervins Ravault, Delphine" uniqKey="Dervins Ravault D" first="Delphine" last="Dervins-Ravault">Delphine Dervins-Ravault</name>
<name sortKey="Escoll, Pedro" sort="Escoll, Pedro" uniqKey="Escoll P" first="Pedro" last="Escoll">Pedro Escoll</name>
<name sortKey="Escoll, Pedro" sort="Escoll, Pedro" uniqKey="Escoll P" first="Pedro" last="Escoll">Pedro Escoll</name>
<name sortKey="Levade, Thierry" sort="Levade, Thierry" uniqKey="Levade T" first="Thierry" last="Levade">Thierry Levade</name>
<name sortKey="Nora, Tamara" sort="Nora, Tamara" uniqKey="Nora T" first="Tamara" last="Nora">Tamara Nora</name>
<name sortKey="Nora, Tamara" sort="Nora, Tamara" uniqKey="Nora T" first="Tamara" last="Nora">Tamara Nora</name>
<name sortKey="Rolando, Monica" sort="Rolando, Monica" uniqKey="Rolando M" first="Monica" last="Rolando">Monica Rolando</name>
</country>
<country name="Canada">
<noRegion>
<name sortKey="Daniels, Craig" sort="Daniels, Craig" uniqKey="Daniels C" first="Craig" last="Daniels">Craig Daniels</name>
</noRegion>
<name sortKey="Savchenko, Alexei" sort="Savchenko, Alexei" uniqKey="Savchenko A" first="Alexei" last="Savchenko">Alexei Savchenko</name>
<name sortKey="Skarina, Tatiana" sort="Skarina, Tatiana" uniqKey="Skarina T" first="Tatiana" last="Skarina">Tatiana Skarina</name>
<name sortKey="Stogios, Peter J" sort="Stogios, Peter J" uniqKey="Stogios P" first="Peter J." last="Stogios">Peter J. Stogios</name>
</country>
<country name="Australie">
<noRegion>
<name sortKey="Abraham, Gilu" sort="Abraham, Gilu" uniqKey="Abraham G" first="Gilu" last="Abraham">Gilu Abraham</name>
</noRegion>
<name sortKey="Hartland, Elizabeth L" sort="Hartland, Elizabeth L" uniqKey="Hartland E" first="Elizabeth L." last="Hartland">Elizabeth L. Hartland</name>
<name sortKey="Mcconville, Malcolm J" sort="Mcconville, Malcolm J" uniqKey="Mcconville M" first="Malcolm J." last="Mcconville">Malcolm J. Mcconville</name>
<name sortKey="Mcconville, Malcolm J" sort="Mcconville, Malcolm J" uniqKey="Mcconville M" first="Malcolm J." last="Mcconville">Malcolm J. Mcconville</name>
<name sortKey="Naderer, Thomas" sort="Naderer, Thomas" uniqKey="Naderer T" first="Thomas" last="Naderer">Thomas Naderer</name>
<name sortKey="Ong, Sze Ying" sort="Ong, Sze Ying" uniqKey="Ong S" first="Sze Ying" last="Ong">Sze Ying Ong</name>
<name sortKey="Rupasinghe, Thusitha W T" sort="Rupasinghe, Thusitha W T" uniqKey="Rupasinghe T" first="Thusitha W. T." last="Rupasinghe">Thusitha W. T. Rupasinghe</name>
<name sortKey="Tull, Dedreia" sort="Tull, Dedreia" uniqKey="Tull D" first="Dedreia" last="Tull">Dedreia Tull</name>
</country>
<country name="Suisse">
<noRegion>
<name sortKey="Hilbi, Hubert" sort="Hilbi, Hubert" uniqKey="Hilbi H" first="Hubert" last="Hilbi">Hubert Hilbi</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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