Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation
Laure Guenin-Macé, … , Marie-France Carlier, Caroline Demangel
Laure Guenin-Macé, … , Marie-France Carlier, Caroline Demangel
Published March 15, 2013
Citation Information: J Clin Invest. 2013;123(4):1501-1512. https://doi.org/10.1172/JCI66576.
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Research Article Infectious disease

Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation

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.

Authors

Laure Guenin-Macé, Romain Veyron-Churlet, Maria-Isabel Thoulouze, Guillaume Romet-Lemonne, Hui Hong, Peter F. Leadlay, Anne Danckaert, Marie-Thérèse Ruf, Serge Mostowy, Chiara Zurzolo, Philippe Bousso, Fabrice Chrétien, Marie-France Carlier, Caroline Demangel

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Figure 7

Remodeling of the skin epidermis after mycolactone administration.

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Remodeling of the skin epidermis after mycolactone administration. (A) H...
(A) H&E-stained sections of ear skin 24, 30, 48, 54, and 78 hours after intradermal injection of vehicle control or 7 nmol (5 μg) mycolactone. (B) Higher-magnification images of control and 78-hour mycolactone sections, showing thinning of all epidermal layers and loss of stratum granulosum. (C) Evolution of epidermal width at the site of injection of mycolactone or vehicle control. Data are mean ± SEM from 10 measurements per mouse in 3 mice. ***P < 0.001, Kruskal Wallis with Dunn post-test. (D and E) E-cadherin staining (D) and H&E staining and mean width (E) of the ear epidermis 78 hours after intradermal injection of 7 nmol mycolactone, 14 nmol wiskostatin, or both compared with vehicle control injection. Shown are representative images from 3 mice per group. Data are mean ± SEM from 10 measurements per mouse in 3 mice. ***P < 0.001, Kruskal Wallis with Dunn post-test. Scale bars: 20 μm (A, D, and E); 10 μm (B).