title: Contractile actin cables induced by Bacillus anthracis lethal toxin depend on the histone acetylation machinery.
abstract: It remains a challenge to decode the molecular basis of the long-term actin cytoskeleton rearrangements that are governed by the reprogramming of gene expression. Bacillus anthracis lethal toxin (LT) inhibits mitogen-activated protein kinase (MAPK) signaling, thereby modulating gene expression, with major consequences for actin cytoskeleton organization and the loss of endothelial barrier function. Using a laser ablation approach, we characterized the contractile and tensile mechanical properties of LT-induced stress fibers. These actin cables resist pulling forces that are transmitted at cell-matrix interfaces and at cell-cell discontinuous adherens junctions. We report that treating the cells with trichostatin A (TSA), a broad range inhibitor of histone deacetylases (HDACs), or with MS-275, which targets HDAC1, 2 and 3, induces stress fibers. LT decreased the cellular levels of HDAC1, 2 and 3 and reduced the global HDAC activity in the nucleus. Both the LT and TSA treatments induced Rnd3 expression, which is required for the LT-mediated induction of actin stress fibers. Furthermore, we reveal that treating the LT-intoxicated cells with garcinol, an inhibitor of histone acetyl-transferases (HATs), disrupts the stress fibers and limits the monolayer barrier dysfunctions. These data demonstrate the importance of modulating the flux of protein acetylation in order to control actin cytoskeleton organization and the endothelial cell monolayer barrier.
authors.affiliation: Microbial Toxins in Host-Pathogen Interactions, Equipe Labellisée La Ligue Contre Le Cancer, INSERM, U1065, Centre Méditerranéen De Médecine Moléculaire (C3M), 151 Route St Antoine de Ginestière, BP 2 3194, 06204 Nice Cedex, France.|UFR Médecine, IFR50, Faculté De Médecine, Université De Nice-Sophia Antipolis, Nice, France.|Biologie Des Bactéries Intracellulaires, Institut Pasteur, Paris, France.|UMR 3525, CNRS, Paris, France.
authors.forename: Monica
authors.initials: M
authors.lastname: Rolando
authors.affiliation: Microbial Toxins in Host-Pathogen Interactions, Equipe Labellisée La Ligue Contre Le Cancer, INSERM, U1065, Centre Méditerranéen De Médecine Moléculaire (C3M), 151 Route St Antoine de Ginestière, BP 2 3194, 06204 Nice Cedex, France.|UFR Médecine, IFR50, Faculté De Médecine, Université De Nice-Sophia Antipolis, Nice, France.|Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Stefani
authors.affiliation: Microbial Toxins in Host-Pathogen Interactions, Equipe Labellisée La Ligue Contre Le Cancer, INSERM, U1065, Centre Méditerranéen De Médecine Moléculaire (C3M), 151 Route St Antoine de Ginestière, BP 2 3194, 06204 Nice Cedex, France.|UFR Médecine, IFR50, Faculté De Médecine, Université De Nice-Sophia Antipolis, Nice, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Doye
authors.affiliation: Microbial Toxins in Host-Pathogen Interactions, Equipe Labellisée La Ligue Contre Le Cancer, INSERM, U1065, Centre Méditerranéen De Médecine Moléculaire (C3M), 151 Route St Antoine de Ginestière, BP 2 3194, 06204 Nice Cedex, France.|UFR Médecine, IFR50, Faculté De Médecine, Université De Nice-Sophia Antipolis, Nice, France.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Acosta
authors.affiliation: Microbial Toxins in Host-Pathogen Interactions, Equipe Labellisée La Ligue Contre Le Cancer, INSERM, U1065, Centre Méditerranéen De Médecine Moléculaire (C3M), 151 Route St Antoine de Ginestière, BP 2 3194, 06204 Nice Cedex, France.|UFR Médecine, IFR50, Faculté De Médecine, Université De Nice-Sophia Antipolis, Nice, France.
authors.forename: Orane
authors.initials: O
authors.lastname: Visvikis
authors.affiliation: Institut Curie-Centre de Recherche, Membrane and Cell Functions Group; CNRS UMR 168, Physico-Chimie Curie, Université Pierre et Marie Curie, 26 Rue d'ulm, Paris Cedex 05, 75248, France.
authors.forename: Hannah G
authors.initials: HG
authors.lastname: Yevick
authors.affiliation: Biologie Des Bactéries Intracellulaires, Institut Pasteur, Paris, France.|UMR 3525, CNRS, Paris, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Buchrieser
authors.affiliation: Microbial Toxins in Host-Pathogen Interactions, Equipe Labellisée La Ligue Contre Le Cancer, INSERM, U1065, Centre Méditerranéen De Médecine Moléculaire (C3M), 151 Route St Antoine de Ginestière, BP 2 3194, 06204 Nice Cedex, France.|UFR Médecine, IFR50, Faculté De Médecine, Université De Nice-Sophia Antipolis, Nice, France.
authors.forename: Amel
authors.initials: A
authors.lastname: Mettouchi
authors.affiliation: Institut Curie-Centre de Recherche, Membrane and Cell Functions Group; CNRS UMR 168, Physico-Chimie Curie, Université Pierre et Marie Curie, 26 Rue d'ulm, Paris Cedex 05, 75248, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Bassereau
authors.affiliation: Microbial Toxins in Host-Pathogen Interactions, Equipe Labellisée La Ligue Contre Le Cancer, INSERM, U1065, Centre Méditerranéen De Médecine Moléculaire (C3M), 151 Route St Antoine de Ginestière, BP 2 3194, 06204 Nice Cedex, France.|UFR Médecine, IFR50, Faculté De Médecine, Université De Nice-Sophia Antipolis, Nice, France.
authors.forename: Emmanuel
authors.identifier: http://orcid.org/0000-0001-9080-7761
authors.initials: E
authors.lastname: Lemichez
mesh_terms: D000107:Acetylation; D000199:Actins / Q000737:chemistry*; D022005:Adherens Junctions; D000942:Antigens, Bacterial / Q000737:chemistry*; D001408:Bacillus anthracis / Q000737:chemistry*; D001427:Bacterial Toxins / Q000737:chemistry*; D002450:Cell Communication; D002467:Cell Nucleus / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D005786:Gene Expression Regulation; D006657:Histones / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D008027:Light; D008856:Microscopy, Fluorescence; D022502:Stress Fibers / Q000737:chemistry*; D013718:Tensile Strength
chemical_list: D000199:Actins; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D006657:Histones; D006877:Hydroxamic Acids; C030325:anthrax toxin; C012589:trichostatin A
keywords: Bacillus anthracis toxin; HAT; HDAC; actin cytoskeleton; gene expression; vascular permeability