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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en"><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><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Escoll, Pedro" sort="Escoll, Pedro" uniqKey="Escoll P" first="Pedro" last="Escoll">Pedro Escoll</name><affiliation><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Nora, Tamara" sort="Nora, Tamara" uniqKey="Nora T" first="Tamara" last="Nora">Tamara Nora</name><affiliation><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Botti, Joelle" sort="Botti, Joelle" uniqKey="Botti J" first="Joëlle" last="Botti">Joëlle Botti</name><affiliation><nlm:aff id="aff3"><institution>Institut Necker Enfants-Malades</institution>, INSERM U1151-CNRS UMR 8253, 75993 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Université Paris Descartes-Sorbonne Paris Cité</institution>, 75993 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Boitez, Valerie" sort="Boitez, Valerie" uniqKey="Boitez V" first="Valérie" last="Boitez">Valérie Boitez</name><affiliation><nlm:aff id="aff3"><institution>Institut Necker Enfants-Malades</institution>, INSERM U1151-CNRS UMR 8253, 75993 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Université Paris Descartes-Sorbonne Paris Cité</institution>, 75993 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Bedia, Carmen" sort="Bedia, Carmen" uniqKey="Bedia C" first="Carmen" last="Bedia">Carmen Bedia</name><affiliation><nlm:aff id="aff5">INSERM UMR1037,<institution>Centre de Recherches en Cancérologie de Toulouse</institution>, 31432 Toulouse,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Daniels, Craig" sort="Daniels, Craig" uniqKey="Daniels C" first="Craig" last="Daniels">Craig Daniels</name><affiliation><nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,<institution>University of Toronto</institution>, Toronto,<country>Canada</country> M5S 3E5;</nlm:aff></affiliation></author><author><name sortKey="Abraham, Gilu" sort="Abraham, Gilu" uniqKey="Abraham G" first="Gilu" last="Abraham">Gilu Abraham</name><affiliation><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></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><nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,<institution>University of Toronto</institution>, Toronto,<country>Canada</country> M5S 3E5;</nlm:aff></affiliation></author><author><name sortKey="Skarina, Tatiana" sort="Skarina, Tatiana" uniqKey="Skarina T" first="Tatiana" last="Skarina">Tatiana Skarina</name><affiliation><nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,<institution>University of Toronto</institution>, Toronto,<country>Canada</country> M5S 3E5;</nlm:aff></affiliation></author><author><name sortKey="Christophe, Charlotte" sort="Christophe, Charlotte" uniqKey="Christophe C" first="Charlotte" last="Christophe">Charlotte Christophe</name><affiliation><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></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><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Cazalet, Christel" sort="Cazalet, Christel" uniqKey="Cazalet C" first="Christel" last="Cazalet">Christel Cazalet</name><affiliation><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Hilbi, Hubert" sort="Hilbi, Hubert" uniqKey="Hilbi H" first="Hubert" last="Hilbi">Hubert Hilbi</name><affiliation><nlm:aff id="aff8">Institute of Medical Microbiology,<institution>University of Zürich</institution>,<country>8006, Zurich, Switzerland</country>;</nlm:aff></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><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></affiliation></author><author><name sortKey="Tull, Dedreia" sort="Tull, Dedreia" uniqKey="Tull D" first="Dedreia" last="Tull">Dedreia Tull</name><affiliation><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></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><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></affiliation><affiliation><nlm:aff id="aff10">Department of Biochemistry and Molecular Biology,<institution>The University of Melbourne</institution>, Melbourne, VIC 3010,<country>Australia</country>;</nlm:aff></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><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></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><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></affiliation></author><author><name sortKey="Codogno, Patrice" sort="Codogno, Patrice" uniqKey="Codogno P" first="Patrice" last="Codogno">Patrice Codogno</name><affiliation><nlm:aff id="aff3"><institution>Institut Necker Enfants-Malades</institution>, INSERM U1151-CNRS UMR 8253, 75993 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Université Paris Descartes-Sorbonne Paris Cité</institution>, 75993 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Levade, Thierry" sort="Levade, Thierry" uniqKey="Levade T" first="Thierry" last="Levade">Thierry Levade</name><affiliation><nlm:aff id="aff5">INSERM UMR1037,<institution>Centre de Recherches en Cancérologie de Toulouse</institution>, 31432 Toulouse,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Naderer, Thomas" sort="Naderer, Thomas" uniqKey="Naderer T" first="Thomas" last="Naderer">Thomas Naderer</name><affiliation><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></affiliation></author><author><name sortKey="Savchenko, Alexei" sort="Savchenko, Alexei" uniqKey="Savchenko A" first="Alexei" last="Savchenko">Alexei Savchenko</name><affiliation><nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,<institution>University of Toronto</institution>, Toronto,<country>Canada</country> M5S 3E5;</nlm:aff></affiliation></author><author><name sortKey="Buchrieser, Carmen" sort="Buchrieser, Carmen" uniqKey="Buchrieser C" first="Carmen" last="Buchrieser">Carmen Buchrieser</name><affiliation><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26831115</idno><idno type="pmc">4763766</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763766</idno><idno type="RBID">PMC:4763766</idno><idno type="doi">10.1073/pnas.1522067113</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000490</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000490</idno></publicationStmt><sourceDesc><biblStruct><analytic><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><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Escoll, Pedro" sort="Escoll, Pedro" uniqKey="Escoll P" first="Pedro" last="Escoll">Pedro Escoll</name><affiliation><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Nora, Tamara" sort="Nora, Tamara" uniqKey="Nora T" first="Tamara" last="Nora">Tamara Nora</name><affiliation><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Botti, Joelle" sort="Botti, Joelle" uniqKey="Botti J" first="Joëlle" last="Botti">Joëlle Botti</name><affiliation><nlm:aff id="aff3"><institution>Institut Necker Enfants-Malades</institution>, INSERM U1151-CNRS UMR 8253, 75993 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Université Paris Descartes-Sorbonne Paris Cité</institution>, 75993 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Boitez, Valerie" sort="Boitez, Valerie" uniqKey="Boitez V" first="Valérie" last="Boitez">Valérie Boitez</name><affiliation><nlm:aff id="aff3"><institution>Institut Necker Enfants-Malades</institution>, INSERM U1151-CNRS UMR 8253, 75993 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Université Paris Descartes-Sorbonne Paris Cité</institution>, 75993 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Bedia, Carmen" sort="Bedia, Carmen" uniqKey="Bedia C" first="Carmen" last="Bedia">Carmen Bedia</name><affiliation><nlm:aff id="aff5">INSERM UMR1037,<institution>Centre de Recherches en Cancérologie de Toulouse</institution>, 31432 Toulouse,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Daniels, Craig" sort="Daniels, Craig" uniqKey="Daniels C" first="Craig" last="Daniels">Craig Daniels</name><affiliation><nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,<institution>University of Toronto</institution>, Toronto,<country>Canada</country> M5S 3E5;</nlm:aff></affiliation></author><author><name sortKey="Abraham, Gilu" sort="Abraham, Gilu" uniqKey="Abraham G" first="Gilu" last="Abraham">Gilu Abraham</name><affiliation><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></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><nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,<institution>University of Toronto</institution>, Toronto,<country>Canada</country> M5S 3E5;</nlm:aff></affiliation></author><author><name sortKey="Skarina, Tatiana" sort="Skarina, Tatiana" uniqKey="Skarina T" first="Tatiana" last="Skarina">Tatiana Skarina</name><affiliation><nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,<institution>University of Toronto</institution>, Toronto,<country>Canada</country> M5S 3E5;</nlm:aff></affiliation></author><author><name sortKey="Christophe, Charlotte" sort="Christophe, Charlotte" uniqKey="Christophe C" first="Charlotte" last="Christophe">Charlotte Christophe</name><affiliation><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></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><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Cazalet, Christel" sort="Cazalet, Christel" uniqKey="Cazalet C" first="Christel" last="Cazalet">Christel Cazalet</name><affiliation><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Hilbi, Hubert" sort="Hilbi, Hubert" uniqKey="Hilbi H" first="Hubert" last="Hilbi">Hubert Hilbi</name><affiliation><nlm:aff id="aff8">Institute of Medical Microbiology,<institution>University of Zürich</institution>,<country>8006, Zurich, Switzerland</country>;</nlm:aff></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><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></affiliation></author><author><name sortKey="Tull, Dedreia" sort="Tull, Dedreia" uniqKey="Tull D" first="Dedreia" last="Tull">Dedreia Tull</name><affiliation><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></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><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></affiliation><affiliation><nlm:aff id="aff10">Department of Biochemistry and Molecular Biology,<institution>The University of Melbourne</institution>, Melbourne, VIC 3010,<country>Australia</country>;</nlm:aff></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><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></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><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></affiliation></author><author><name sortKey="Codogno, Patrice" sort="Codogno, Patrice" uniqKey="Codogno P" first="Patrice" last="Codogno">Patrice Codogno</name><affiliation><nlm:aff id="aff3"><institution>Institut Necker Enfants-Malades</institution>, INSERM U1151-CNRS UMR 8253, 75993 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><institution>Université Paris Descartes-Sorbonne Paris Cité</institution>, 75993 Paris,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Levade, Thierry" sort="Levade, Thierry" uniqKey="Levade T" first="Thierry" last="Levade">Thierry Levade</name><affiliation><nlm:aff id="aff5">INSERM UMR1037,<institution>Centre de Recherches en Cancérologie de Toulouse</institution>, 31432 Toulouse,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Naderer, Thomas" sort="Naderer, Thomas" uniqKey="Naderer T" first="Thomas" last="Naderer">Thomas Naderer</name><affiliation><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></affiliation></author><author><name sortKey="Savchenko, Alexei" sort="Savchenko, Alexei" uniqKey="Savchenko A" first="Alexei" last="Savchenko">Alexei Savchenko</name><affiliation><nlm:aff id="aff6">Department of Chemical Engineering and Applied Chemistry,<institution>University of Toronto</institution>, Toronto,<country>Canada</country> M5S 3E5;</nlm:aff></affiliation></author><author><name sortKey="Buchrieser, Carmen" sort="Buchrieser, Carmen" uniqKey="Buchrieser C" first="Carmen" last="Buchrieser">Carmen Buchrieser</name><affiliation><nlm:aff id="aff1">Institut Pasteur,<institution>Biologie des Bactéries Intracellulaires</institution>, 75724 Paris,<country>France</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>CNRS</institution> UMR 3525, 75724 Paris,<country>France</country>;</nlm:aff></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></record>Pour manipuler ce document sous Unix (Dilib)
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