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1. An RNA-Binding Protein Secreted by a Bacterial Pathogen Modulates RIG-I Signaling

Author

Alessandro Pagliuso, Bruno Dupuy, Christophe Bécavin, Mikael Koutero, Alice Lebreton, Frédéric Tangy, Andréa Dessen, Marie-Anne Nahori, Valérie Najburg, Fabrizia Stavru, Eric Allemand, To Nam Tham, Pascale Cossart, Anastassia V. Komarova, Christian Muchardt, Stevens Robertin, Sergey Bessonov, Quentin Bertrand, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulation épigénétique - Epigenetic regulation, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Génomique virale et vaccination, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Brazilian National Laboratory for Biosciences (LNBio), Centro Nacional de Pesquisa em Energia e materiais, Centra Nacional de Pesquisa-Centra Nacional de Pesquisa, Institut National de la Recherche Agronomique (INRA), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Platform access was supported by FRISBI (ANR-10-INBS-05-02) and GRAL, a project of the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003). The IBS acknowledges integration into the Interdisciplinary Research Institute of Grenoble (IRIG, CEA). We are grateful to R.Y. Sanchez David and R. Viber for technical support. Work in A.L.’s team was supported by Inserm ATIP-Avenir and Mairie de Paris (Programme Émergences—Recherche médicale). This work was supported by grants from the European Research Council (ERC) advanced grant BacCellEpi (670823) and the Fondation Le Roch to P.C., We thank all members of the Cossart laboratory for helpful discussions. We thank Dr. B. Kallipolitis for providing the anti-Listeria Hfq antibody and Dr. E. Hajnsdorf for the anti-E.coli Hfq. We acknowledge the platforms of the Grenoble Instruct-ERIC Center (ISBG, UMS 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology (PSB)., ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), European Project: 670823,H2020,ERC-2014-ADG,BacCellEpi(2015), Stavru, Fabrizia, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Bacterial, cellular and epigenetic factors that control enteropathogenicity - BacCellEpi - - H20202015-10-01 - 2018-09-30 - 670823 - VALID, Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-10-INBS-05-01/10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR: 17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris, Laboratoire d’innovation : vaccins – Innovation lab : vaccines, Institut Pasteur [Paris], Biologie Evolutive de la Cellule Microbienne - Evolutionary Biology of the Microbial Cell, Génétique des Interactions Macromoléculaires, and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris

Subjects
[SDV]Life Sciences [q-bio], Virulence, RNA-binding protein, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, medicine.disease_cause, Microbiology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Mice, 03 medical and health sciences, 0302 clinical medicine, Bacterial Proteins, Listeria monocytogenes, Virology, Extracellular, medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Humans, Pathogen, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, 030304 developmental biology, 0303 health sciences, Innate immune system, Host Microbial Interactions, RIG-I, RNA-Binding Proteins, food and beverages, Interferon-beta, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Immunity, Innate, extracellular RNA, 3. Good health, Cell biology, RNA, Bacterial, HEK293 Cells, DEAD Box Protein 58, Parasitology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 030217 neurology & neurosurgery, bacteriophage A118, type I IFN, Signal Transduction, Extracellular RNA
Abstract

International audience; RNA-binding proteins (RBPs) perform key cellular activities by controlling the function of bound RNAs. The widely held assumption that RBPs are strictly intracellular has been challenged by the discovery of secreted RBPs. However, extracellular RBPs have been described in eukaryotes, while secreted bacterial RBPs have not been reported. Here, we show that the bacterial pathogen Listeria monocytogenes secretes a small RBP that we named Zea. We show that Zea binds a subset of L. monocytogenes RNAs, causing their accumulation in the extracellular medium. Furthermore, during L. monocytogenes infection, Zea binds RIG-I, the non-self-RNA innate immunity sensor, potentiating interferon-β production. Mouse infection studies reveal that Zea affects L. monocytogenes virulence. Together, our results unveil that bacterial RNAs can be present extracellularly in association with RBPs, acting as “social RNAs” to trigger a host response during infection.

Published
2019
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2. An RNA-binding protein secreted byListeria monocytogenesactivates RIG-I signaling

Author

Mikael Koutero, Valérie Najburg, Christophe Bécavin, Bruno Dupuy, To Nam Tham, Alessandro Pagliuso, Stevens Robertin, Pascale Cossart, Fabrizia Stavru, Alice Lebreton, Eric Allemand, Quentin Bertrand, Marie-Anne Nahori, Anastassia V. Komarova, Christian Muchard, and Andréa Dessen

Subjects
0303 health sciences, Innate immune system, 030306 microbiology, RIG-I, fungi, food and beverages, RNA-binding protein, Biology, medicine.disease_cause, 3. Good health, Cell biology, 03 medical and health sciences, Crosstalk (biology), Listeria monocytogenes, Extracellular, medicine, Extracellular ribonucleoprotein complex, Intracellular, 030304 developmental biology
Abstract

SummaryRecent studies have reported on the presence of bacterial RNA within or outside extracellular membrane vesicles, possibly as ribonucleoprotein complexes. Proteins that bind and stabilize bacterial RNAs in the extracellular environment have not been reported. Here, we show that the bacterial pathogenListeria monocytogenessecretes a small RNA binding protein that we named Zea. We show that Zea binds and stabilizes a subset ofL. monocytogenesRNAs causing their accumulation in the extracellular medium. Furthermore, Zea binds RIG-I, the vertebrate non-self-RNA innate immunity sensor and potentiates RIG-I-signaling leading to interferon β production. By performingin vivoinfection, we finally show that Zea modulatesL. monocytogenesvirulence. Together, this study reveals that bacterial extracellular RNAs and RNA binding proteins can affect the host-pathogen crosstalk.

Published
2019
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3. Lmo1656 is a secreted virulence factor of Listeria monocytogenes that interacts with the sorting nexin 6–BAR complex

Author

Pascale Cossart, Alessandro Pagliuso, Lilliana Radoshevich, Daryl J. V. David, Marie-Anne Nahori, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported in part by the Institut Pasteur, INSERM (Unité 604), Institut National de la Recherche Agronomique (INRA Unité Sous Contrat 2020), Université Paris Diderot, grants from Région Île-de-France, Fondation Le Roch Les Mousquetaires, and European Research Council Advanced Grant 670823 BacCellEpi (to P. C.)., We thank E. Gouin for help with antibody generation and crucial lab maintenance and Dr. O. Dussurget for fruitful discussion. We thank Dr. P. Cullen and B. Simonetti from the University of Bristol, UK for generously providing GFP-SNX plasmids., European Project: 670823,H2020,ERC-2014-ADG,BacCellEpi(2015), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), David, Daryl Jason, Pagliuso, Alessandro, Cossart, Pascale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), vicente, marie-therese, and Bacterial, cellular and epigenetic factors that control enteropathogenicity - BacCellEpi - - H20202015-10-01 - 2018-09-30 - 670823 - VALID

Subjects
0301 basic medicine, infection, host-pathogen interaction, virulence factor, sorting nexin (SNX), bacterial pathogenesis, Listeria monocytogenes, Lmo1656, sorting nexin 6, Host–pathogen interaction, 030106 microbiology, Virulence, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, medicine.disease_cause, Biochemistry, Microbiology, 03 medical and health sciences, medicine, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Pathogen, Intracellular parasite, Cell Biology, biology.organism_classification, 3. Good health, Sorting nexin, 030104 developmental biology, Sorting nexin 6, Listeria
Abstract

International audience; Listeria monocytogenes (Lm) is a facultative intracellular bacterial pathogen and the causative agent of listeriosis, a rare but fatal disease. During infection, Lm can traverse several physiological barriers; it can cross the intestine and placenta barrier and, in immunocompromised individuals, the blood– brain barrier. With the recent plethora of sequenced genomes available for Lm, it is clear that the complete repertoire of genes used by Lm to interact with its host remains to be fully explored. Recently, we focused on secreted Lm proteins because they are likely to interact with host cell components. Here, we investigated a putatively secreted protein of Lm, Lmo1656, that is present in most sequenced strains of Lm but absent in the nonpathogenic species Listeria innocua. lmo1656 gene is predicted to encode a small, positively charged protein. We show that Lmo1656 is secreted by Lm. Furthermore, deletion of the lmo1656 gene (lmo1656) attenuates virulence in mice infected orally but not intravenously, suggesting that Lmo1656 plays a role during oral listeriosis. We identified sorting nexin 6 (SNX6), an endosomal sorting component and BAR domain– containing protein, as a host cell interactor of Lmol656. SNX6 colocal-izes with WT Lm during the early steps of infection. This colocalization depends on Lmo1656, and RNAi of SNX6 impairs infection in infected tissue culture cells, suggesting that SNX6 is utilized by Lm during infection. Our results reveal that Lmo1656 is a novel secreted virulence factor of Lm that facilitates recruitment of a specific member of the sorting nexin family in the mam-malian host. The foodborne pathogen Listeria monocytogenes (Lm) 5 can cross several physiological barriers and infect multiple cell types. The pathogenic potential of Lm relies on the ability of this bacterium to cross multiple physiological barriers as well as its ability to enter and replicate within a wide variety of host cell types (for recent reviews, see Refs. 1 and 2). Upon binding to host cell surface receptors, Lm induces its internalization into both professional phagocytes and nonphagocytic cells (for a recent review, see Ref. 2). From there, Lm escapes into the cyto-sol by rupturing its vacuole. Lm is able to evade host cell immune responses (for a recent review, see Ref. 3) and subvert the host cell actin cytoskeleton to drive intra-and intercellular motility (for recent reviews, see Refs. 4 –6). Secreted and surface-exposed Lm proteins can encounter host components and serve as virulence factors. For example, the secreted pore-forming toxin listeriolysin O (LLO) is one of the most well-characterized and potent virulence factors of Lm (for a review, see Ref. 7). Secretion of LLO occurs prior to Lm entry into the host cell. It inserts into the host plasma membrane and makes large pores. The resulting ion flux drives a diverse array of responses within the cell from global deSUMOylation (8) to mitochondrial fragmentation (9). Upon entry, Lm can escape into the host cytosol by lysing the phagosomal membrane through the combined actions of secreted LLO and phospholipases A and B (PlcA and PlcB) (10 –12). Recent work has uncovered novel secreted Lm virulence factors and their binding partners in the host cell. The secreted protein Listeria nuclear targeted protein A (LntA) targets the host epigenetic regulator BAHD1, altering host cell transcription (13). The small secreted protein internalin C (InlC) sequesters Tuba, a Cdc42 guanine exchange factor, to induce relaxation of membrane cortical tension, thereby facilitating increased bacterial cell-to-cell spread (14, 15). InlC also directly binds to host IB kinase , interfering with host innate immunity (16). The recent plethora of genomics data and the rise of bioin-formatics pipelines have enabled the rapid comparison of mul

Published
2018
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4. A 14-3-3γ dimer-based scaffold bridges CtBP1-S/BARS to PI(4)KIIIβ to regulate post-Golgi carrier formation

Author

Renato Gaibisso, Stefania Spanò, Daniela Corda, Alessandro Pagliuso, Carmen Valente, Alberto Luini, Fabio Formiggini, Daniele Piccini, Gabriele Turacchio, Stefania Mariggiò, Giuseppe Di Tullio, Antonino Colanzi, Michele Santoro, and Roman S. Polishchuk

Subjects
Fission, Golgi Apparatus, GTPase, DNA-binding protein, 03 medical and health sciences, symbols.namesake, Chlorocebus aethiops, Animals, Humans, Phosphorylation, Protein Kinase C, Protein kinase C, 030304 developmental biology, 0303 health sciences, Budding, Chemistry, 030302 biochemistry & molecular biology, Signal transducing adaptor protein, Cell Biology, Golgi apparatus, Rats, Cell biology, DNA-Binding Proteins, Alcohol Oxidoreductases, Phosphotransferases (Alcohol Group Acceptor), 14-3-3 Proteins, p21-Activated Kinases, COS Cells, symbols, Carrier Proteins, Dimerization
Abstract

Large pleiomorphic carriers leave the Golgi complex for the plasma membrane by en bloc extrusion of specialized tubular domains, which then undergo fission. Several components of the underlying molecular machinery have been identified, including those involved in the budding/initiation of tubular carrier precursors (for example, the phosphoinositide kinase PI(4)KIIIβ, the GTPase ARF, and FAPP2), and in the fission of these precursors (for example, PKD, CtBP1-S/BARS). However, how these proteins interact to bring about carrier formation is poorly understood. Here, we describe a protein complex that mediates carrier formation and contains budding and fission molecules, as well as other molecules, such as the adaptor protein 14-3-3γ. Specifically, we show that 14-3-3γ dimers bridge CtBP1-S/BARS with PI(4)KIIIβ, and that the resulting complex is stabilized by phosphorylation by PKD and PAK. Disrupting the association of these proteins inhibits the fission of elongating carrier precursors, indicating that this complex couples the carrier budding and fission processes.

Published
2012
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5. Golgi membrane fission requires the CtBP1-S/BARS-induced activation of lysophosphatidic acid acyltransferase δ

Author

Lucia Laura Giordano, Alberto Luini, Carmen Valente, Guiling Li, Angela Filograna, Gabriele Turacchio, Vincenzo Manuel Marzullo, Luigi Mandrich, Roman S. Polishchuk, Daniela Corda, Alessandro Pagliuso, Diego Circolo, Mikhail A. Zhukovsky, and Fabio Formiggini

Subjects
0301 basic medicine, Science, General Physics and Astronomy, Golgi Apparatus, Phosphatidic Acids, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, symbols.namesake, chemistry.chemical_compound, Membrane fission, Transferases, Lysophosphatidic acid, Humans, Protein kinase C, Protein Kinase C, Cytokinesis, Golgi membrane, Multidisciplinary, General Chemistry, Phosphatidic acid, Intracellular Membranes, Golgi apparatus, Membrane traffic, Cell biology, DNA-Binding Proteins, Alcohol Oxidoreductases, Phosphotransferases (Alcohol Group Acceptor), 030104 developmental biology, chemistry, 14-3-3 Proteins, p21-Activated Kinases, Acyltransferase, symbols, Lysophospholipids, Acyltransferases, HeLa Cells
Abstract

Membrane fission is an essential cellular process by which continuous membranes split into separate parts. We have previously identified CtBP1-S/BARS (BARS) as a key component of a protein complex that is required for fission of several endomembranes, including basolateral post-Golgi transport carriers. Assembly of this complex occurs at the Golgi apparatus, where BARS binds to the phosphoinositide kinase PI4KIIIβ through a 14-3-3γ dimer, as well as to ARF and the PKD and PAK kinases. We now report that, when incorporated into this complex, BARS binds to and activates a trans-Golgi lysophosphatidic acid (LPA) acyltransferase type δ (LPAATδ) that converts LPA into phosphatidic acid (PA); and that this reaction is essential for fission of the carriers. LPA and PA have unique biophysical properties, and their interconversion might facilitate the fission process either directly or indirectly (via recruitment of proteins that bind to PA, including BARS itself)., CtBP1-S/BARS is required for fission of endomembrane compartments including the Golgi. Here the authors show that CtBP1-S/BARS activates a trans-Golgi lysophosphatidic acid acyltransferase that catalyses the production of phosphatidic acid and is required for fission of the post-Golgi carrier membrane.

Published
2015
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6. A role for septin 2 in Drp1‐mediated mitochondrial fission

Author

Anne Spang, To Nam Tham, Julia Stevens, Alessandro Pagliuso, Thibault Lagache, Pascale Cossart, Roger Persson, Jean-Christophe Olivo-Marin, Stephane Oddos, Audrey Salles, Fabrizia Stavru, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biozentrum, Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Bioaxial, Imagopole (CITECH), Institut Pasteur [Paris], We gratefully acknowledge the kind financial support of the Institut Pasteur (Paris), the France-BioImaging infrastructure network supported by the French National Research Agency (ANR-10–INSB–04, Investments for the future), and the Région Ile-de-France (program DIM-Malinf). TL is funded by a Bourse Roux fellowship from Institut Pasteur and the Labex IBEID. FS is a CNRS senior research fellow, and PC is a Senior International HHMI Scholar. Work in the EMBO reports Vol 17 |No 6 | 2016 ª 2016 The Authors EMBOreports Septin 2 in mitochondrial fission Alessandro Pagliuso et al 870 Published online: May 23, 2016 Spang Laboratory is funded by the University of Basel and Swiss National Science Foundation (CRSII 3_141956). The Cossart Laboratory is supported by Institut Pasteur, Inserm (U604), ANR (Grant 12-BSV3-0017-03Mitopatho), and ERC (Grant 670823BacCellEpi)., ANR-12-BSV3-0017,MITOPATHO,Rôle des mitochondries durant l'invasion des cellules par les bactéries Listeria et Shigella(2012), European Project: 670823,H2020,ERC-2014-ADG,BacCellEpi(2015), Cossart, Pascale, Stavru, Fabrizia, Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Analyse d'images biologiques - BioImage Analysis (AIQ), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], ANR: Mitopatho,12-BSV3-0017-03, vicente, marie-therese, BLANC - Rôle des mitochondries durant l'invasion des cellules par les bactéries Listeria et Shigella - - MITOPATHO2012 - ANR-12-BSV3-0017 - BLANC - VALID, and Bacterial, cellular and epigenetic factors that control enteropathogenicity - BacCellEpi - - H20202015-10-01 - 2018-09-30 - 670823 - VALID

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], MESH: Actomyosin, Mitochondrion, Septin, Biochemistry, GTP Phosphohydrolases, News & Views, MESH: Gene Silencing, Membrane & Intracellular Transport, Cytoskeleton, Caenorhabditis elegans, biology, MESH: Mitochondrial Proteins, Articles, Actomyosin, MESH: Caenorhabditis elegans Proteins, Biological Evolution, Mitochondria, Cell biology, [SDV] Life Sciences [q-bio], mitochondrial fusion, Gene Knockdown Techniques, Mitochondrial fission, biological phenomena, cell phenomena, and immunity, Microtubule-Associated Proteins, Dynamins, MESH: Septins, endocrine system, MESH: GTP Phosphohydrolases, Immunoprecipitation, MESH: Mitochondria, MESH: Biological Evolution, macromolecular substances, Drp1, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Mitochondrial Proteins, 03 medical and health sciences, mitochondrial dynamics, septin, Genetics, Humans, Gene Silencing, Caenorhabditis elegans Proteins, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, MESH: Humans, 030102 biochemistry & molecular biology, biology.organism_classification, MESH: Gene Knockdown Techniques, MESH: Mitochondrial Dynamics, MESH: Microtubule-Associated Proteins, 030104 developmental biology, MESH: HeLa Cells, DNAJA3, Septins, HeLa Cells
Abstract

International audience; Mitochondria are essential eukaryotic organelles often forming intricate networks. The overall network morphology is determined by mitochondrial fusion and fission. Among the multiple mechanisms that appear to regulate mitochondrial fission, the ER and actin have recently been shown to play an important role by mediating mitochondrial constriction and promoting the action of a key fission factor, the dynamin-like protein Drp1. Here, we report that the cytoskeletal component septin 2 is involved in Drp1-dependent mitochondrial fission in mammalian cells. Septin 2 localizes to a subset of mitochondrial constrictions and directly binds Drp1, as shown by immunoprecipitation of the endogenous proteins and by pulldown assays with recombinant proteins. Depletion of septin 2 reduces Drp1 recruitment to mitochondria and results in hyperfused mitochondria and delayed FCCP-induced fission. Strikingly, septin depletion also affects mitochondrial morphology in Caenorhabditis elegans, strongly suggesting that the role of septins in mitochondrial dynamics is evolutionarily conserved.

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7. Listeria monocytogenesexploits the MICOS complex subunit Mic10 to promote mitochondrial fragmentation and cellular infection

Author

Mariette Matondo, Pascale Cossart, Filipe Carvalho, Fabrizia Stavru, Anna Spier, T. Chaze, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), This study was supported by grants to P.C. from the European Research Council (H2020-ERC-2014-409ADG 670823-BacCellEpi), the Agence Nationale de la Recherche (ANR) and the French Government’s 'Investissements d’Avenir' program Laboratoires d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (LabEx IBEID, ANR-10-LABX-62-IBEID). A.S. was supported by a BioSPC doctoral fellowship from the Université Paris Diderot. P.C. is a Senior International Research Scholar of the Howard Hughes Medical Institute. F.S. is a CNRS permanent researcher, We thank current and past lab members for helpful discussions, Francis Impens and Evy Timmerman (VIB Proteomics Core, University of Ghent, Belgium) for training and assistance with proteomic analyses, and Alessandro Pagliuso for critical reading of the manuscript, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 670823,H2020,ERC-2014-ADG,BacCellEpi(2015), Centre National de la Recherche Scientifique (CNRS)-Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris], ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Stavru, Fabrizia, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Bacterial, cellular and epigenetic factors that control enteropathogenicity - BacCellEpi - - H20202015-10-01 - 2018-09-30 - 670823 - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA)

Subjects
Mic10, MESH: HCT116 Cells, MESH: Mitochondria, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mitochondrion, Biology, MESH: Listeria monocytogenes, medicine.disease_cause, 03 medical and health sciences, proteomics, 0302 clinical medicine, Listeria monocytogenes, Organelle, MESH: Up-Regulation, medicine, Inner mitochondrial membrane, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, 030304 developmental biology, 0303 health sciences, MESH: Humans, MICOS complex, mitochondrial fission, MESH: Proteomics, Listeriolysin O, MESH: Mitochondrial Proteins, MESH: Mitochondrial Dynamics, Cell biology, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Mitochondrial fission, MESH: Membrane Proteins, 030217 neurology & neurosurgery, Intracellular
Abstract

Mitochondrial function adapts to cellular demands and is affected by the ability of the organelle to undergo fusion and fission in response to physiological and non-physiological cues. We previously showed that infection with the human bacterial pathogenListeria monocytogeneselicits transient mitochondrial fission and a drop in mitochondrial-dependent energy production through a mechanism requiring the bacterial pore-forming toxin listeriolysin O (LLO). Here, we performed quantitative mitochondrial proteomics to search for host factors involved inL. monocytogenes-induced mitochondrial fission. We found that Mic10, a critical component of the mitochondrial contact site and cristae organizing system (MICOS) complex, is significantly enriched in mitochondria isolated from cells infected with wild-type but not with LLO-deficientL. monocytogenes. Increased mitochondrial Mic10 levels did not correlate with upregulated transcription, suggesting a post-transcriptional regulation. We showed that Mic10 is necessary forL. monocytogenes-induced mitochondrial network fragmentation, and that it contributes toL. monocytogenescellular infection independently of MICOS proteins Mic13, Mic26 and Mic27. Together,L. monocytogenesinfection allowed us to uncover a role for Mic10 in mitochondrial fission.ImportancePathogenic bacteria can target host cell organelles to take control of key cellular processes and promote their intracellular survival, growth, and persistence. Mitochondria are essential, highly dynamic organelles with pivotal roles in a wide variety of cell functions. Mitochondrial dynamics and function are intimately linked. Our previous research showed thatListeria monocytogenesinfection impairs mitochondrial function and triggers fission of the mitochondrial network at an early infection stage, in a process that is independent of the main mitochondrial fission protein Drp1. Here, we analyzed how mitochondrial proteins change in response toL. monocytogenesinfection and found that infection raises the levels of Mic10, a mitochondrial inner membrane protein involved in formation of cristae. We show that Mic10 is important forL. monocytogenes-dependent mitochondrial fission and infection of host cells. Our findings thus offer new insight into the mechanisms used byL. monocytogenesto hijack mitochondria to optimize host infection.

Published
2019
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