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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
1 Immunobiologie de l'Infection - Immunobiology of Infection
2 BIOCELLY - Biologie Cellulaire des Lymphocytes
3 Laboratoire d'Enzymologie et Biochimie Structurales
4 CSBC - Cambridge Systems Biology Centre & Department of Biochemistry
5 Department of Biochemistry
6 CITECH - Imagopole
7 Unibas - University of Basel
8 UIBC - Interactions Bactéries-Cellules
9 Trafic membranaire et Pathogénèse
10 Dynamiques des Réponses Immunes
11 Histopathologie humaine et Modèles animaux
12 UVSQ Santé - Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil
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.
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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⟩

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