A distinctive feature of the human pathogen Mycobacterium ulcerans is the production of mycolactone. This original polyketide-derived macrolide is essential for bacterial virulence and sufficient to induce ulcerative lesions in the skin that are marked by an extensive tissue necrosis. In vitro, mycolactone diffuses passively into the cytoplasm of skin cell lines to induce retraction, detachment and eventually cell death by anoikis. We found that mycolactone operates by stimulating the activity of the Wiskott-Aldrich syndrome protein N-WASP.
WAVE 1-3, WASP and N-WASP constitute a family of scaffold proteins transducing a variety of signals into dynamic remodeling of the actin cytoskeleton, via interaction of their C-terminal verprolin-cofilin-acidic (VCA) domain with the Arp2/3 actin-nucleating complex. We showed that mycolactone-induced stimulation of N-WASP in epithelial cells caused defects in cell-cell and cell-matrix adhesion, and directional migration. Consistently in vivo, injection of mycolactone into the ears of mice altered the junctional organization and stratification of keratinocytes, leading to thinning of the epidermis. This process was reduced by co-administration of the N-WASP inhibitor wiskostatin, demonstrating the contribution of N-WASP in mycolactone-mediated ulceration of the skin. On-going investigations aim at determining if mycolactone-mediated activation of N-WASP play a role in the analgesia that is associated with Buruli ulcers.