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

Identifieur interne : 001B45 ( PubMed/Checkpoint ); précédent : 001B44; suivant : 001B46

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 :

Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2016.

RBID : pubmed:26831115

Descripteurs français

KwdFr :
- Aldehyde-lyases (), Aldehyde-lyases (métabolisme), Animaux, Autophagie, Conformation des protéines, Cristallographie aux rayons X, Domaine catalytique, Legionella pneumophila (enzymologie), Maladie des légionnaires (immunologie), Souris, Sphingolipides (métabolisme).
MESH :
- enzymologie : Legionella pneumophila.
- immunologie : Maladie des légionnaires.
- métabolisme : Aldehyde-lyases, Sphingolipides.
- Aldehyde-lyases, Animaux, Autophagie, Conformation des protéines, Cristallographie aux rayons X, Domaine catalytique, Souris.

English descriptors

KwdEn :
- Aldehyde-Lyases (chemistry), Aldehyde-Lyases (metabolism), Animals, Autophagy, Catalytic Domain, Crystallography, X-Ray, Legionella pneumophila (enzymology), Legionnaires' Disease (immunology), Mice, Protein Conformation, Sphingolipids (metabolism).
MESH :
- chemical , chemistry : Aldehyde-Lyases.
- chemical , metabolism : Aldehyde-Lyases, Sphingolipids.
- enzymology : Legionella pneumophila.
- immunology : Legionnaires' Disease.
- Animals, Autophagy, Catalytic Domain, Crystallography, X-Ray, Mice, Protein Conformation.

Abstract

Autophagy is an essential component of innate immunity, enabling the detection and elimination of intracellular pathogens. Legionella pneumophila, 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 L. pneumophila translocates the effector protein sphingosine-1 phosphate lyase (LpSpl) to target the host sphingosine biosynthesis and to curtail autophagy. Our structural characterization of LpSpl and its comparison with human SPL reveals high structural conservation, thus supporting prior phylogenetic analysis. We show that LpSpl possesses S1P lyase activity that was abrogated by mutation of the catalytic site residues. L. pneumophila triggers the reduction of several sphingolipids critical for macrophage function in an LpSpl-dependent and -independent manner. LpSpl activity alone was sufficient to prevent an increase in sphingosine levels in infected host cells and to inhibit autophagy during macrophage infection. LpSpl 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.

DOI: 10.1073/pnas.1522067113
PubMed: 26831115

Affiliations:

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Le document en format XML

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<author><name sortKey="Dervins Ravault, Delphine" sort="Dervins Ravault, Delphine" uniqKey="Dervins Ravault D" first="Delphine" last="Dervins-Ravault">Delphine Dervins-Ravault</name>
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<author><name sortKey="Ong, Sze Ying" sort="Ong, Sze Ying" uniqKey="Ong S" first="Sze Ying" last="Ong">Sze Ying Ong</name>
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<author><name sortKey="Hartland, Elizabeth L" sort="Hartland, Elizabeth L" uniqKey="Hartland E" first="Elizabeth L" last="Hartland">Elizabeth L. Hartland</name>
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<author><name sortKey="Levade, Thierry" sort="Levade, Thierry" uniqKey="Levade T" first="Thierry" last="Levade">Thierry Levade</name>
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<author><name sortKey="Escoll, Pedro" sort="Escoll, Pedro" uniqKey="Escoll P" first="Pedro" last="Escoll">Pedro Escoll</name>
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<wicri:regionArea>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris</wicri:regionArea>
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<author><name sortKey="Botti, Joelle" sort="Botti, Joelle" uniqKey="Botti J" first="Joëlle" last="Botti">Joëlle Botti</name>
<affiliation wicri:level="3"><nlm:affiliation>Institut Necker Enfants-Malades, INSERM U1151-CNRS UMR 8253, 75993 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris, France;</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut Necker Enfants-Malades, INSERM U1151-CNRS UMR 8253, 75993 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Boitez, Valerie" sort="Boitez, Valerie" uniqKey="Boitez V" first="Valérie" last="Boitez">Valérie Boitez</name>
<affiliation wicri:level="3"><nlm:affiliation>Institut Necker Enfants-Malades, INSERM U1151-CNRS UMR 8253, 75993 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris, France;</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut Necker Enfants-Malades, INSERM U1151-CNRS UMR 8253, 75993 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris</wicri:regionArea>
<placeName><region type="region" nuts="2">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
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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="3"><nlm:affiliation>INSERM UMR1037, Centre de Recherches en Cancérologie de Toulouse, 31432 Toulouse, France;</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>INSERM UMR1037, Centre de Recherches en Cancérologie de Toulouse, 31432 Toulouse</wicri:regionArea>
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<settlement type="city">Toulouse</settlement>
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<author><name sortKey="Daniels, Craig" sort="Daniels, Craig" uniqKey="Daniels C" first="Craig" last="Daniels">Craig Daniels</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada M5S 3E5;</nlm:affiliation>
<country>Canada</country>
<wicri:regionArea>Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</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:affiliation>Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia;</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800</wicri:regionArea>
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</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="4"><nlm:affiliation>Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada M5S 3E5;</nlm:affiliation>
<country>Canada</country>
<wicri:regionArea>Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
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<author><name sortKey="Skarina, Tatiana" sort="Skarina, Tatiana" uniqKey="Skarina T" first="Tatiana" last="Skarina">Tatiana Skarina</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada M5S 3E5;</nlm:affiliation>
<country>Canada</country>
<wicri:regionArea>Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</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:affiliation>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris, France;</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris</wicri:regionArea>
<wicri:noRegion>75724 Paris</wicri:noRegion>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</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:affiliation>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris, France;</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris</wicri:regionArea>
<wicri:noRegion>75724 Paris</wicri:noRegion>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</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:affiliation>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris, France;</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris</wicri:regionArea>
<wicri:noRegion>75724 Paris</wicri:noRegion>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Hilbi, Hubert" sort="Hilbi, Hubert" uniqKey="Hilbi H" first="Hubert" last="Hilbi">Hubert Hilbi</name>
<affiliation wicri:level="4"><nlm:affiliation>Institute of Medical Microbiology, University of Zürich, 8006, Zurich, Switzerland;</nlm:affiliation>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Institute of Medical Microbiology, University of Zürich, 8006, Zurich</wicri:regionArea>
<orgName type="university">Université de Zurich</orgName>
<placeName><settlement type="city">Zurich</settlement>
<region nuts="3" type="region">Canton de Zurich</region>
</placeName>
</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="4"><nlm:affiliation>Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia;</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Tull, Dedreia" sort="Tull, Dedreia" uniqKey="Tull D" first="Dedreia" last="Tull">Dedreia Tull</name>
<affiliation wicri:level="4"><nlm:affiliation>Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia;</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</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="4"><nlm:affiliation>Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia; Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, VIC 3010, Australia;</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia; Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, VIC 3010</wicri:regionArea>
<orgName type="university">Université de Melbourne</orgName>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
</placeName>
</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:affiliation>Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3010, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3010</wicri:regionArea>
<wicri:noRegion>VIC 3010</wicri:noRegion>
</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:affiliation>Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3010, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3010</wicri:regionArea>
<wicri:noRegion>VIC 3010</wicri:noRegion>
</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:affiliation>Institut Necker Enfants-Malades, INSERM U1151-CNRS UMR 8253, 75993 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris, France;</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Institut Necker Enfants-Malades, INSERM U1151-CNRS UMR 8253, 75993 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris</wicri:regionArea>
<wicri:noRegion>75993 Paris</wicri:noRegion>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</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:affiliation>INSERM UMR1037, Centre de Recherches en Cancérologie de Toulouse, 31432 Toulouse, France;</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>INSERM UMR1037, Centre de Recherches en Cancérologie de Toulouse, 31432 Toulouse</wicri:regionArea>
<wicri:noRegion>31432 Toulouse</wicri:noRegion>
<placeName><settlement type="city">Toulouse</settlement>
<region type="region" nuts="2">Occitanie (région administrative)</region>
<region type="old region" nuts="2">Midi-Pyrénées</region>
</placeName>
</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:affiliation>Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia;</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800</wicri:regionArea>
<wicri:noRegion>VIC 3800</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Savchenko, Alexei" sort="Savchenko, Alexei" uniqKey="Savchenko A" first="Alexei" last="Savchenko">Alexei Savchenko</name>
<affiliation wicri:level="4"><nlm:affiliation>Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada M5S 3E5;</nlm:affiliation>
<country>Canada</country>
<wicri:regionArea>Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto</wicri:regionArea>
<orgName type="university">Université de Toronto</orgName>
<placeName><settlement type="city">Toronto</settlement>
<region type="state">Ontario</region>
</placeName>
</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:affiliation>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris, France; cbuch@pasteur.fr.</nlm:affiliation>
<country wicri:rule="url">France</country>
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<wicri:noRegion>75724 Paris</wicri:noRegion>
<placeName><settlement type="city">Paris</settlement>
<region type="région" nuts="2">Île-de-France</region>
</placeName>
</affiliation>
</author>
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<series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title>
<idno type="eISSN">1091-6490</idno>
<imprint><date when="2016" type="published">2016</date>
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<term>Aldehyde-Lyases (metabolism)</term>
<term>Animals</term>
<term>Autophagy</term>
<term>Catalytic Domain</term>
<term>Crystallography, X-Ray</term>
<term>Legionella pneumophila (enzymology)</term>
<term>Legionnaires' Disease (immunology)</term>
<term>Mice</term>
<term>Protein Conformation</term>
<term>Sphingolipids (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Aldehyde-lyases ()</term>
<term>Aldehyde-lyases (métabolisme)</term>
<term>Animaux</term>
<term>Autophagie</term>
<term>Conformation des protéines</term>
<term>Cristallographie aux rayons X</term>
<term>Domaine catalytique</term>
<term>Legionella pneumophila (enzymologie)</term>
<term>Maladie des légionnaires (immunologie)</term>
<term>Souris</term>
<term>Sphingolipides (métabolisme)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Aldehyde-Lyases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Aldehyde-Lyases</term>
<term>Sphingolipids</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Legionella pneumophila</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Legionella pneumophila</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Maladie des légionnaires</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Legionnaires' Disease</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Aldehyde-lyases</term>
<term>Sphingolipides</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Autophagy</term>
<term>Catalytic Domain</term>
<term>Crystallography, X-Ray</term>
<term>Mice</term>
<term>Protein Conformation</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Aldehyde-lyases</term>
<term>Animaux</term>
<term>Autophagie</term>
<term>Conformation des protéines</term>
<term>Cristallographie aux rayons X</term>
<term>Domaine catalytique</term>
<term>Souris</term>
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<front><div type="abstract" xml:lang="en">Autophagy is an essential component of innate immunity, enabling the detection and elimination of intracellular pathogens. Legionella pneumophila, 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 L. pneumophila translocates the effector protein sphingosine-1 phosphate lyase (LpSpl) to target the host sphingosine biosynthesis and to curtail autophagy. Our structural characterization of LpSpl and its comparison with human SPL reveals high structural conservation, thus supporting prior phylogenetic analysis. We show that LpSpl possesses S1P lyase activity that was abrogated by mutation of the catalytic site residues. L. pneumophila triggers the reduction of several sphingolipids critical for macrophage function in an LpSpl-dependent and -independent manner. LpSpl activity alone was sufficient to prevent an increase in sphingosine levels in infected host cells and to inhibit autophagy during macrophage infection. LpSpl 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.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26831115</PMID>
<DateCreated><Year>2016</Year>
<Month>02</Month>
<Day>17</Day>
</DateCreated>
<DateCompleted><Year>2016</Year>
<Month>07</Month>
<Day>22</Day>
</DateCompleted>
<DateRevised><Year>2017</Year>
<Month>11</Month>
<Day>16</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1091-6490</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>113</Volume>
<Issue>7</Issue>
<PubDate><Year>2016</Year>
<Month>Feb</Month>
<Day>16</Day>
</PubDate>
</JournalIssue>
<Title>Proceedings of the National Academy of Sciences of the United States of America</Title>
<ISOAbbreviation>Proc. Natl. Acad. Sci. U.S.A.</ISOAbbreviation>
</Journal>
<ArticleTitle>Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy.</ArticleTitle>
<Pagination><MedlinePgn>1901-6</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1073/pnas.1522067113</ELocationID>
<Abstract><AbstractText>Autophagy is an essential component of innate immunity, enabling the detection and elimination of intracellular pathogens. Legionella pneumophila, 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 L. pneumophila translocates the effector protein sphingosine-1 phosphate lyase (LpSpl) to target the host sphingosine biosynthesis and to curtail autophagy. Our structural characterization of LpSpl and its comparison with human SPL reveals high structural conservation, thus supporting prior phylogenetic analysis. We show that LpSpl possesses S1P lyase activity that was abrogated by mutation of the catalytic site residues. L. pneumophila triggers the reduction of several sphingolipids critical for macrophage function in an LpSpl-dependent and -independent manner. LpSpl activity alone was sufficient to prevent an increase in sphingosine levels in infected host cells and to inhibit autophagy during macrophage infection. LpSpl 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.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Rolando</LastName>
<ForeName>Monica</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris, France;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Escoll</LastName>
<ForeName>Pedro</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris, France;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Nora</LastName>
<ForeName>Tamara</ForeName>
<Initials>T</Initials>
<AffiliationInfo><Affiliation>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris, France;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Botti</LastName>
<ForeName>Joëlle</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Institut Necker Enfants-Malades, INSERM U1151-CNRS UMR 8253, 75993 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris, France;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Boitez</LastName>
<ForeName>Valérie</ForeName>
<Initials>V</Initials>
<AffiliationInfo><Affiliation>Institut Necker Enfants-Malades, INSERM U1151-CNRS UMR 8253, 75993 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris, France;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Bedia</LastName>
<ForeName>Carmen</ForeName>
<Initials>C</Initials>
<Identifier Source="ORCID">http://orcid.org/0000-0003-4584-5843</Identifier>
<AffiliationInfo><Affiliation>INSERM UMR1037, Centre de Recherches en Cancérologie de Toulouse, 31432 Toulouse, France;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Daniels</LastName>
<ForeName>Craig</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada M5S 3E5;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Abraham</LastName>
<ForeName>Gilu</ForeName>
<Initials>G</Initials>
<AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology and the Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Stogios</LastName>
<ForeName>Peter J</ForeName>
<Initials>PJ</Initials>
<AffiliationInfo><Affiliation>Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada M5S 3E5;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Skarina</LastName>
<ForeName>Tatiana</ForeName>
<Initials>T</Initials>
<AffiliationInfo><Affiliation>Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada M5S 3E5;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Christophe</LastName>
<ForeName>Charlotte</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>Institut Pasteur, Biologie des Bactéries Intracellulaires, 75724 Paris, France; CNRS UMR 3525, 75724 Paris, France;</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Dervins-Ravault</LastName>
<ForeName>Delphine</ForeName>
<Initials>D</Initials>
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<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="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>
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<country name="Suisse"><region name="Canton de Zurich"><name sortKey="Hilbi, Hubert" sort="Hilbi, Hubert" uniqKey="Hilbi H" first="Hubert" last="Hilbi">Hubert Hilbi</name>
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   |texte=   Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy.
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	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.

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

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