Equipe 6

Team 6: Emmanuel Lemichez
MICROBIAL TOXINS IN HOST PATHOGEN INTERACTIONS

Previous activities
Bacterial protein AB toxins confer upon pathogenic bacteria individual specific virulence properties leading to distinctive pathophysiological effects. Protein toxins, such as neurotoxins and those targeting Rho GTPases have also proven being extremely useful tools to study cell biology processes and cell signaling pathways of broad importance and implicated in a large number of human diseases, such as mental disorders and cancer. Our team investigates the cellular mode of action of microbial toxins mainly through the study of CNF1 of uropathogenic Escherichia coli, EDIN exotoxins of Staphylococcus aureus and the anthrax toxin of Bacillus anthracis. These pathogens are responsible for high cost and/or severe infections. One of the main topics of our work is to define the functions of these toxins during the course of the infection in relation to their cytotoxicity. Noteworthy, our studies are focused on a group of toxins targeting host MAPK kinases, Rho GTPases and cAMP flux, which are master regulators of host cell homeostasis notably actin cytoskeleton and consequently endothelium barrier function. We have shown that the targeting of these host regulators of the actin cytoskeleton allows bacteria to invade their host and overwhelm host defenses. These last years we have 1) discovered a new cellular mechanism of formation of transcellular tunnels in endothelial cells induced by EDIN of S. aureus and adenylate cyclase toxins, such as the edema toxin of B. anthracis. 2) We have further deciphered the mode of action of the lethal factor, component of the anthrax toxin, on the endothelium by determining its major role in hijacking host transcription to induce actin cable formation strikingly in absence of direct activation of RhoA. 3) The third aspect corresponds to the follow up of our initial discovery of a cellular mode of regulation of Rho proteins by the ubiquitin and proteasome system. Most importantly, this allowed us to establish recently that the E3 ubiquitin-ligase activity of HACE1, a major tumor suppressor, targets activated Rac1 for degradation.
Major Publications
2015 Diabate M, Munro P, Garcia E, Jacquel A, Michel G, Obba S, Goncalves D, Luci C, Marchetti S, Demon D, Degos C, Bechah Y, Mege JL, Lamkanfi M, Auberger P, Gorvel JP, Stuart LM, Landraud L, Lemichez E, Boyer L. Escherichia coli α-Hemolysin counteracts the anti-virulence innate immune response triggered by the Rho GTPase activating toxin CNF1 during bacteremia. PLoS Path. 2015 in press. 2014 Hepatopulmonary syndrome associated with visceral leishmaniasis. Martis N, Pomares C, Jeandel PY, Lazure T, Marty P, Rosenthal E. Hepatopulmonary syndrome associated with visceral leishmaniasis. Immunol Res. 2015 61(1-2):169-71. Vassallo M, Moranne O, Ambrosetti D, Jeandel PY, Pomares C, Cassuto E, Boscagli A, Giraud G, Montagne N, Dentone C, Demacina I, Villaggio B, Secondo G, Ferrea G, Passeron C, Saudes L, Kaphan R, Marty P, Rosenthal E. Visceral leishmaniasis due to Leishmania infantum with renal involvement in HIV-infected patients. BMC Infect Dis. 2014 14(1):561. Abnave P, Mottola G, Gimenez G, Boucherit N, Trouplin V, Torre C, Conti F, Ben Amara A, Lepolard C, Djian B, Hamaoui D, Mettouchi A, Kumar A, Pagnotta S, Bonatti S, Lepidi H, Salvetti A, Abi-Rached L, Lemichez E, Mege JL, Ghigo E. Screening in planarians identifies MORN2 as a key component in LC3-associated phagocytosis and resistance to bacterial infection. Cell Host Microbe. 2014 Sep Pomares C, MartyP, Delaunay P. Isolated itching of the genitals. Am J Trop Med Hyg. 2014 Apr;90(4):589-90. Jeddi F, Mary C, Aoun K, Harrat Z, Bouratbine A, Faraut F, Benikhlef R, Pomares C, Pratlong F,Marty P, Piarroux R. Heterogeneity of molecular resistance patterns in antimony-resistant field isolates of Leishmania species from the western Mediterranean area. Antimicrob Agents Chemother. 2014 58(8):4866-74. 2013 Effector-triggered versus pattern-triggered immunity: how animals sense pathogens. Stuart LM, Paquette N, Boyer L. Nat Rev Immunol. 2013 Mar;13(3):199-206. General aspects and recent advances on bacterial protein toxins. Lemichez E, Barbieri JT. Cold Spring Harb Perspect Med. 2013 Feb 1;3(2). Transcellular tunnel dynamics: Control of cellular dewetting by actomyosin contractility and I-BAR proteins. Lemichez E, Gonzalez-Rodriguez D, Bassereau P, Brochard-Wyart F. Biol Cell. 2013 Mar;105(3):109-17. Severity of Escherichia coli bacteraemia is independent of the intrinsic virulence of the strains assessed in a mouse model. Landraud L, Jauréguy F, Frapy E, Guigon G, Gouriou S, Carbonnelle E, Clermont O, Denamur E, Picard B, Lemichez E, Brisse S, Nassif X. Clin Microbiol Infect. 2013 Jan;19(1):85-90. 2012 The role of extracellular matrix in vascular branching morphogenesis. Mettouchi A. Cell Adh Migr. 2012 Nov-Dec;6(6):528-34. Impaired stimulation of p38α-MAPK/Vps41-HOPS by LPS from pathogenic Coxiella burnetii prevents trafficking to microbicidal phagolysosomes. Barry AO, Boucherit N, Mottola G, Vadovic P, Trouplin V, Soubeyran P, Capo C, Bonatti S, Nebreda A, Toman R, Lemichez E, Mege JL, Ghigo E. Cell Host Microbe. 2012 Dec 13;12(6):751-63. Bacterial effectors: learning on the fly. Boyer L, Paquette N, Silverman N, Stuart LM. Adv Exp Med Biol. 2012;710:29-36. Distribution of edin in Staphylococcus aureus isolated from diabetic foot ulcers. Messad N, Landraud L, Canivet B, Lina G, Richard JL, Sotto A, Lavigne JP, Lemichez E; the French Study Group on the Diabetic Foot. Clin Microbiol Infect. 2012 Oct 24. Role of N-terminal His6-Tags in binding and efficient translocation of polypeptides into cells using anthrax protective antigen (PA). Beitzinger C, Stefani C, Kronhardt A, Rolando M, Flatau G, Lemichez E, Benz R. PLoS One. 2012;7(10):e46964. Cellular dewetting: opening of macroapertures in endothelial cells. Gonzalez-Rodriguez D, Maddugoda MP, Stefani C, Janel S, Lafont F, Cuvelier D, Lemichez E, Brochard-Wyart F. Phys Rev Lett. 2012 May 25;108(21):218105. Ubiquitylation of active Rac1 by the E3 ubiquitin-ligase HACE1. Mettouchi A, Lemichez E. Small GTPases. 2012 Apr-Jun;3(2):102-6. Confluence switch signaling regulates ECM composition and the plasmin proteolytic cascade in keratinocytes. Botta A, Delteil F, Mettouchi A, Vieira A, Estrach S, Négroni L, Stefani C, Lemichez E, Meneguzzi G, Gagnoux-Palacios L. J Cell Sci. 2012 Sep 15;125(Pt 18):4241-52. Autophagy is required for CSF-1-induced macrophagic differentiation and acquisition of phagocytic functions. Jacquel A, Obba S, Boyer L, Dufies M, Robert G, Gounon P, Lemichez E, Luciano F, Solary E, Auberger P. Blood. 2012 May 10;119(19):4527-31. Modification of Salmonella Typhimurium motility by the probiotic yeast strain Saccharomyces boulardii. Pontier-Bres R, Prodon F, Munro P, Rampal P, Lemichez E, Peyron JF, Czerucka D. PLoS One. 2012;7(3):e33796. Distinguishing colonization from infection with Staphylococcus aureus in diabetic foot ulcers with miniaturized oligonucleotide arrays: a French multicenter study. Sotto A, Richard JL, Messad N, Molinari N, Jourdan N, Schuldiner S, Sultan A, Carrière C, Canivet B, Landraud L, Lina G, Lavigne JP; French Study Group on the Diabetic Foot. Diabetes Care. 2012 Mar;35(3):617-23. [The tumor suppressor HACE1 targets Rac1 to ubiquitin-mediated proteasomal degradation]. Gacon G, Mettouchi A, Lemichez E. Med Sci (Paris). 2012 Jan;28(1):39-41. Assessing ubiquitylation of Rho GTPases in mammalian cells. Doye A, Mettouchi A, Lemichez E. Methods Mol Biol. 2012;827:77-86. 2011 cAMP signaling by anthrax edema toxin induces transendothelial cell tunnels, which are resealed by MIM via Arp2/3-driven actin polymerization. Maddugoda MP, Stefani C, Gonzalez-Rodriguez D, Saarikangas J, Torrino S, Janel S, Munro P, Doye A, Prodon F, Aurrand-Lions M, Goossens PL, Lafont F, Bassereau P, Lappalainen P, Brochard F, Lemichez E. Cell Host Microbe. 2011 Nov 17;10(5):464-74. Pathogen-derived effectors trigger protective immunity via activation of the Rac2 enzyme and the IMD or Rip kinase signaling pathway. Boyer L, Magoc L, Dejardin S, Cappillino M, Paquette N, Hinault C, Charriere GM, Ip WK, Fracchia S, Hennessy E, Erturk-Hasdemir D, Reichhart JM, Silverman N, Lacy-Hulbert A, Stuart LM. Immunity. 2011 Oct 28;35(4):536-49. The E3 ubiquitin-ligase HACE1 catalyzes the ubiquitylation of active Rac1. Torrino S, Visvikis O, Doye A, Boyer L, Stefani C, Munro P, Bertoglio J, Gacon G, Mettouchi A, Lemichez E. Dev Cell. 2011 Nov 15;21(5):959-65. Luciferase-expressing Leishmania infantum allows the monitoring of amastigote population size, in vivo, ex vivo and in vitro. Michel G, Ferrua B, Lang T, Maddugoda MP, Munro P, Pomares C, Lemichez E, Marty P. PLoS Negl Trop Dis. 2011 Sep;5(9):e1323. Cross-reactivity of anthrax and C2 toxin: protective antigen promotes the uptake of botulinum C2I toxin into human endothelial cells. Kronhardt A, Rolando M, Beitzinger C, Stefani C, Leuber M, Flatau G, Popoff MR, Benz R, Lemichez E. PLoS One. 2011;6(8):e23133. Characterization of a cluster of oncogenic mutations in E6 of a human papillomavirus 83 variant isolated from a high-grade squamous intraepithelial lesion. Cannavo I, Benchetrit M, Loubatier C, Michel G, Lemichez E, Giordanengo V. J Gen Virol. 2011 Oct;92(Pt 10):2428-36. Laminin-binding integrins induce Dll4 expression and Notch signaling in endothelial cells. Estrach S, Cailleteau L, Franco CA, Gerhardt H, Stefani C, Lemichez E, Gagnoux-Palacios L, Meneguzzi G, Mettouchi A. Circ Res. 2011 Jul 8;109(2):172-82. Bacillus sphaericus binary toxin elicits host cell autophagy as a response to intoxication. Opota O, Gauthier NC, Doye A, Berry C, Gounon P, Lemichez E, Pauron D. PLoS One. 2011 Feb 14;6(2):e14682. High prevalence of edin-C encoding RhoA-targeting toxin in clinical isolates of Staphylococcus aureus. Munro P, Clément R, Lavigne JP, Pulcini C, Lemichez E, Landraud L. Eur J Clin Microbiol Infect Dis. 2011 Aug;30(8):965-72. Escherichia coli producing CNF1 toxin hijacks Tollip to trigger Rac1-dependent cell invasion. Visvikis O, Boyer L, Torrino S, Doye A, Lemonnier M, Lorès P, Rolando M, Flatau G, Mettouchi A, Bouvard D, Veiga E, Gacon G, Cossart P, Lemichez E. Traffic. 2011 May;12(5):579-90. 2010 Coxiella burnetii, the agent of Q fever, replicates within trophoblasts and induces a unique transcriptional response. Ben Amara A, Ghigo E, Le Priol Y, Lépolard C, Salcedo SP, Lemichez E, Bretelle F, Capo C, Mege JL. PLoS One. 2010 Dec 14;5(12):e15315. Alpha2beta1 integrin controls association of Rac with the membrane and triggers quiescence of endothelial cells. Cailleteau L, Estrach S, Thyss R, Boyer L, Doye A, Domange B, Johnsson N, Rubinstein E, Boucheix C, Ebrahimian T, Silvestre JS, Lemichez E, Meneguzzi G, Mettouchi A. J Cell Sci. 2010 Jul 15;123(Pt 14):2491-501. The Staphylococcus aureus epidermal cell differentiation inhibitor toxin promotes formation of infection foci in a mouse model of bacteremia. Munro P, Benchetrit M, Nahori MA, Stefani C, Clément R, Michiels JF, Landraud L, Dussurget O, Lemichez E. Infect Immun. 2010 Aug;78(8):3404-11. Direct modifications of Rho proteins: deconstructing GTPase regulation. Visvikis O, Maddugoda MP, Lemichez E. Biol Cell. 2010 Apr 6;102(7):377-89. The SWI/SNF protein BAF60b is ubiquitinated through a signalling process involving Rac GTPase and the RING finger protein Unkempt. Lorès P, Visvikis O, Luna R, Lemichez E, Gacon G. FEBS J. 2010 Mar;277(6):1453-64. Interaction of Saccharomyces boulardii with Salmonella enterica serovar Typhimurium protects mice and modifies T84 cell response to the infection. Martins FS, Dalmasso G, Arantes RM, Doye A, Lemichez E, Lagadec P, Imbert V, Peyron JF, Rampal P, Nicoli JR, Czerucka D. PLoS One. 2010 Jan 27;5(1):e8925. Transcriptome dysregulation by anthrax lethal toxin plays a key role in induction of human endothelial cell cytotoxicity. Rolando M, Stefani C, Flatau G, Auberger P, Mettouchi A, Mhlanga M, Rapp U, Galmiche A, Lemichez E. Cell Microbiol. 2010 Jul;12(7):891-905. Breaking the wall: targeting of the endothelium by pathogenic bacteria. Lemichez E, Lecuit M, Nassif X, Bourdoulous S. Nat Rev Microbiol. 2010 Feb;8(2):93-104. Injection of Staphylococcus aureus EDIN by the Bacillus anthracis protective antigen machinery induces vascular permeability. Rolando M, Munro P, Stefani C, Auberger P, Flatau G, Lemichez E. Infect Immun. 2009 Sep;77(9):3596-601. Oxytocin controls differentiation of human mesenchymal stem cells and reverses osteoporosis. Elabd C, Basillais A, Beaupied H, Breuil V, Wagner N, Scheideler M, Zaragosi LE, Massiéra F, Lemichez E, Trajanoski Z, Carle G, Euller-Ziegler L, Ailhaud G, Benhamou CL, Dani C, Amri EZ. Stem Cells. 2008 Sep;26(9):2399-407. Isoform-specific interaction of C-RAF with mitochondria. Galmiche A, Fueller J, Santel A, Krohne G, Wittig I, Doye A, Rolando M, Flatau G, Lemichez E, Rapp UR. J Biol Chem. 2008 May 23;283(21):14857-66. Activated Rac1, but not the tumorigenic variant Rac1b, is ubiquitinated on Lys 147 through a JNK-regulated process. Visvikis O, Lorès P, Boyer L, Chardin P, Lemichez E, Gacon G. FEBS J. 2008 Jan;275(2):386-96. The evolution of contact-dependent inhibition in non-growing populations of Escherichia coli. Lemonnier M, Levin BR, Romeo T, Garner K, Baquero MR, Mercante J, Lemichez E, Baquero F, Blázquez J. Proc Biol Sci. 2008 Jan 7;275(1630):3-10. Intranasal immunization with tetanus toxoid and CNF1 as a new mucosal adjuvant protects BALB/c mice against lethal challenge. Munro P, Flatau G, Lemichez E. Vaccine. 2007 Dec 17;25(52):8702-6. Rho GTPase-activating bacterial toxins: from bacterial virulence regulation to eukaryotic cell biology. Lemonnier M, Landraud L, Lemichez E. FEMS Microbiol Rev. 2007 Sep;31(5):515-34. [EDIN of S. aureus induces the formation of large transcellular tunnels in endothelial cells and increases vascular permeability]. Landraud L, Lemichez E. Med Sci (Paris). 2007 May;23(5):459-60. French. No abstract available. Specificity of immunomodulator secretion in urinary samples in response to infection by alpha-hemolysin and CNF1 bearing uropathogenic Escherichia coli. Real JM, Munro P, Buisson-Touati C, Lemichez E, Boquet P, Landraud L. Cytokine. 2007 Jan;37(1):22-5.

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