Screening for eukaryotic motifs in Legionella pneumophila reveals Smh1 as bacterial deacetylase of host histones
Stefanie M. Herbel,
Lambert Moyon,
Marvin Christ,
Eslam M. Elsayed,
Brian E. Caffrey,
Silke Malmsheimer,
Iwan Grin,
Kerstin Hoffmann,
Kristin Surmann,
Sascha Blankenburg,
Anna Lena Jung,
Christina E. Herkt,
Marco Borsò,
Beyza Bozdag,
Axel Imhof,
Anke Becker,
Samuel Wagner,
Gert Bange,
Uwe Völker,
Wilhelm Bertrams,
Annalisa Marsico,
Bernd Schmeck
Affiliations
Stefanie M. Herbel
Institute for Lung Research, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Philipps-University Marburg, Marburg, Germany
Lambert Moyon
Computational Health Center, Helmholtz Zentrum München, Neuherberg, Germany
Marvin Christ
Department of Chemistry, Philipps-University Marburg, Marburg, Germany
Eslam M. Elsayed
Center for Synthetic Microbiology (SYNMIKRO), Philipps-University Marburg, Marburg, Germany
Brian E. Caffrey
Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany
Silke Malmsheimer
Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Tübingen, Germany
Iwan Grin
Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Tübingen, Germany
Kerstin Hoffmann
Institute for Lung Research, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Philipps-University Marburg, Marburg, Germany
Kristin Surmann
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
Sascha Blankenburg
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
Anna Lena Jung
Institute for Lung Research, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Philipps-University Marburg, Marburg, Germany
Christina E. Herkt
Institute for Lung Research, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Philipps-University Marburg, Marburg, Germany
Marco Borsò
Zentrallabor für Proteinanalytik, BioMedical Center, Faculty of Medicine, Ludwig-Maximilians-University of Munich, Planegg-Martinsried
Beyza Bozdag
Zentrallabor für Proteinanalytik, BioMedical Center, Faculty of Medicine, Ludwig-Maximilians-University of Munich, Planegg-Martinsried
Axel Imhof
Zentrallabor für Proteinanalytik, BioMedical Center, Faculty of Medicine, Ludwig-Maximilians-University of Munich, Planegg-Martinsried
Anke Becker
Center for Synthetic Microbiology (SYNMIKRO), Philipps-University Marburg, Marburg, Germany
Samuel Wagner
Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Tübingen, Germany
Gert Bange
Department of Chemistry, Philipps-University Marburg, Marburg, Germany
Uwe Völker
Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
Wilhelm Bertrams
Institute for Lung Research, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Philipps-University Marburg, Marburg, Germany
Annalisa Marsico
Computational Health Center, Helmholtz Zentrum München, Neuherberg, Germany
Bernd Schmeck
Institute for Lung Research, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Philipps-University Marburg, Marburg, Germany
Legionella pneumophila (L.p.) is a bacterial pathogen which is a common causative agent of pneumonia. In humans, it infects alveolar macrophages and transfers hundreds of virulence factors that interfere with cellular signalling pathways and the transcriptomic landscape to sustain its own replication. By this interaction, it has acquired eukaryote-like protein motifs by gene transfer events that partake in the pathogenicity of Legionella. In a computational screening approach for eukaryotic motifs in the transcriptome of Legionella, we identified the L.p. strain Corby protein ABQ55614 as putative histone-deacetylase and named it “suppressing modifier of histones 1” (Smh1). During infection, Smh1 is translocated from the Legionella vacuole into the host cytosol. When expressed in human macrophage THP-1 cells, Smh1 was localized predominantly in the nucleus, leading to broad histone H3 and H4 deacetylation, blunted expression of a large number of genes (e.g. IL-1β and IL-8), and fostered intracellular bacterial replication. L.p. with a Smh1 knockdown grew normally in media but showed a slight growth defect inside the host cell. Furthermore, Smh1 showed a very potent histone deacetylation activity in vitro, e.g. at H3K14, that could be inhibited by targeted mutation of the putative catalytic center inferred by analogy with eukaryotic HDAC8, and with the deacetylase inhibitor trichostatin A. In summary, Smh1 displays functional homology with class I/II type HDACs. We identified Smh1 as a new Legionella virulence factor with a eukaryote-like histone-deacetylase activity that moderates host gene expression and might pave the way for further histone modifications.IMPORTANCELegionella pneumophila (L.p.) is a prominent bacterial pathogen, which is a common causative agent of pneumonia. In order to survive inside the host cell, the human macrophage, it profoundly interacts with host cell processes to advance its own replication. In this study, we identify a bacterial factor, Smh1, with yet unknown function as a host histone deacetylase. The activity of this factor in the host cell leads to attenuated gene expression and increased intracellular bacterial replication.
