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

Guenin-Macé, Laure and Veyron-Churlet, Romain and Thoulouze, Maria-Isabel and Romet-Lemonne, Guillaume and Hong, Hui and Leadlay, Peter F. and Danckaert, Anne and Ruf, Marie-Thérèse and Mostowy, Serge and Zurzolo, Chiara and Bousso, Philippe and Chrétien, Fabrice and Carlier, Marie-France and Demangel, Caroline. (2013) Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation. Journal of Clinical Investigation, Vol. 123, H. 4. pp. 1501-1512.

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Official URL: http://edoc.unibas.ch/dok/A6124562

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Molecular Immunology (Pluschke)
UniBasel Contributors:Ruf, Marie-Thérèse
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Society for Clinical Investigation
ISSN:0021-9738
e-ISSN:1558-8238
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:13 Oct 2017 08:20
Deposited On:16 Aug 2013 07:32

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