 |
Journal articles
Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation.
Laure Guenin-Macé
1
Romain Veyron-Churlet
1
Maria-Isabel Thoulouze
2
Guillaume Romet ‐ Lemonne
3
Hui Hong
4
Peter F Leadlay
5
Anne Danckaert
6
Marie-Thérèse Ruf
7
Serge Mostowy
8
Chiara Zurzolo
9
Philippe Bousso
10
Fabrice Chrétien
11, 12
Marie-France Carlier
3
Caroline Demangel
Laure Guenin-Macé 1
Author IdHAL : lguenin ORCID : https://orcid.org/0000-0002-9791-5308
Romain Veyron-Churlet 1
Author IdHAL : romain-veyron-churlet ORCID : https://orcid.org/0000-0001-6902-5917
Maria-Isabel Thoulouze 2
Author
Guillaume Romet ‐ Lemonne 3
Author IdHAL : guillaume-romet-lemonne
Hui Hong 4
Author
Peter F Leadlay 5
Author
Anne Danckaert 6
Author IdHAL : anne-danckaert ORCID : https://orcid.org/0000-0001-8984-643X
Marie-Thérèse Ruf 7
Author
Serge Mostowy 8
Author
Chiara Zurzolo 9
Author IdHAL : chiara-zurzolo IdRef : https://www.idref.fr/11602075X ORCID : https://orcid.org/0000-0001-6048-6602
Philippe Bousso 10
Author IdHAL : philippe-bousso
Fabrice Chrétien 11, 12
Author
Marie-France Carlier 3
Author
Caroline Demangel
Author
1
Immunobiologie de l'Infection - Immunobiology of Infection (Département d'Immunologie, 25-28, rue du Docteur Roux, 75724 Paris Cedex 15 - France)
- Institut Pasteur [Paris] (25-28, rue du docteur Roux, 75724 Paris cedex 15 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1221 (101, rue de Tolbiac, 75013 Paris - France)
2
BIOCELLY - Biologie Cellulaire des Lymphocytes (25-28 rue du Docteur Roux F-75724 Paris Cedex 15 - France)
- Institut Pasteur [Paris] (25-28, rue du docteur Roux, 75724 Paris cedex 15 - France)
- CNRS - Centre National de la Recherche Scientifique : URA1961 (France)
3
Laboratoire d'Enzymologie et Biochimie Structurales (Cytoskeleton Dynamics and Motility, Laboratoire d'Enzymologie et Biochimie Structurales, Gif-sur-Yvette, France - France)
- CNRS - Centre National de la Recherche Scientifique : UPR3089 (France)
4
CSBC - Cambridge Systems Biology Centre & Department of Biochemistry (Sanger Building 80 Tennis Court Road Cambridge CB2 1GA - United Kingdom)
- CAM - University of Cambridge [UK] (The Old Schools, Trinity Lane, Cambridge CB2 1TN - United Kingdom)
5
Department of Biochemistry (United Kingdom)
- CAM - University of Cambridge [UK] (The Old Schools, Trinity Lane, Cambridge CB2 1TN - United Kingdom)
6
CITECH - Imagopole (Département Biologie cellulaire et Infection, 25-28 rue du Docteur Roux, F-75724 Paris Cedex 15 - France)
- Institut Pasteur [Paris] (25-28, rue du docteur Roux, 75724 Paris cedex 15 - France)
7
Unibas - University of Basel (Petersplatz 1, P. O. Box
4001 Basel - Switzerland)
8
UIBC - Interactions Bactéries-Cellules (Département Biologie cellulaire et infection, 25-28 rue du Docteur Roux, F-75724 Paris Cedex 15 - France)
- INRA - Institut National de la Recherche Agronomique : USC2020 (France)
- Institut Pasteur [Paris] (25-28, rue du docteur Roux, 75724 Paris cedex 15 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U604 (101, rue de Tolbiac, 75013 Paris - France)
9
Trafic membranaire et Pathogénèse (Département de Biologie cellulaire et Infection, 25-28, rue du docteur Roux, 75724 Paris Cedex 15 - France)
- Institut Pasteur [Paris] (25-28, rue du docteur Roux, 75724 Paris cedex 15 - France)
10
Dynamiques des Réponses Immunes (25-28 rue du Docteur Roux F-75724 Paris Cedex 15 - France)
- Institut Pasteur [Paris] (25-28, rue du docteur Roux, 75724 Paris cedex 15 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U668 (101, rue de Tolbiac, 75013 Paris - France)
11
Histopathologie humaine et Modèles animaux (Département Infection et Epidémiologie, 25-28 rue du Docteur Roux, F-75724 Paris Cedex 15 - France)
- Institut Pasteur [Paris] (25-28, rue du docteur Roux, 75724 Paris cedex 15 - France)
12
UVSQ Santé - Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (2 avenue de la Source de la Bièvre - 78180 Montigny-le-Bretonneux - France)
- UVSQ - Université de Versailles Saint-Quentin-en-Yvelines (55 avenue de Paris - 78035 Versailles cedex - France)
Abstract : Mycolactone is a diffusible lipid secreted by the human pathogen Mycobacterium ulcerans, which induces the formation of open skin lesions referred to as Buruli ulcers. Here, we show that mycolactone operates by hijacking the Wiskott-Aldrich syndrome protein (WASP) family of actin-nucleating factors. By disrupting WASP autoinhibition, mycolactone leads to uncontrolled activation of ARP2/3-mediated assembly of actin in the cytoplasm. In epithelial cells, mycolactone-induced stimulation of ARP2/3 concentrated in the perinuclear region, resulting in defective cell adhesion and directional migration. In vivo injection of mycolactone into mouse ears consistently altered the junctional organization and stratification of keratinocytes, leading to epidermal thinning, followed by rupture. This degradation process was efficiently suppressed by coadministration of the N-WASP inhibitor wiskostatin. These results elucidate the molecular basis of mycolactone activity and provide a mechanism for Buruli ulcer pathogenesis. Our findings should allow for the rationale design of competitive inhibitors of mycolactone binding to N-WASP, with anti-Buruli ulcer therapeutic potential.
Document type :
Journal articles
Domain :
Complete list of metadata
https://hal-pasteur.archives-ouvertes.fr/pasteur-00874628
Contributor : Olga Valty Connect in order to contact the contributor
Submitted on : Friday, October 18, 2013 - 3:42:07 PM
Last modification on : Friday, November 26, 2021 - 10:44:08 AM
Long-term archiving on: : Sunday, January 19, 2014 - 4:26:13 AM
Contributor : Olga Valty Connect in order to contact the contributor
Submitted on : Friday, October 18, 2013 - 3:42:07 PM
Last modification on : Friday, November 26, 2021 - 10:44:08 AM
Long-term archiving on: : Sunday, January 19, 2014 - 4:26:13 AM
File
JCI66576.pdf
Publisher files allowed on an open archive
Identifiers
- HAL Id : pasteur-00874628, version 1
- DOI : 10.1172/JCI66576
- PRODINRA : 481140
- PUBMED : 23549080
Citation
Laure Guenin-Macé, Romain Veyron-Churlet, Maria-Isabel Thoulouze, Guillaume Romet ‐ Lemonne, Hui Hong, et al.. Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation.. Journal of Clinical Investigation, American Society for Clinical Investigation, 2013, 123 (4), pp.1501-12. ⟨10.1172/JCI66576⟩. ⟨pasteur-00874628⟩
Metrics
Les métriques sont temporairement indisponibles