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  • whocc
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  • Assistant Professor
  • Associate Professor
  • Clinical Research Assistant
  • Full Professor
  • Graduate Student
  • Lab assistant
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  • Permanent Researcher
  • Pharmacist
  • PhD Student
  • Physician
  • Post-doc
  • Project Manager
  • Research Associate
  • Research Engineer
  • Retired scientist
  • Technician
  • Undergraduate Student
  • Veterinary
  • Visiting Scientist
  • Deputy Director of Center
  • Deputy Director of Department
  • Deputy Director of National Reference Center
  • Deputy Head of Facility
  • Director of Center
  • Director of Department
  • Director of Institute
  • Director of National Reference Center
  • Group Leader
  • Head of Facility
  • Head of Operations
  • Head of Structure
  • Honorary President of the Departement
  • Labex Coordinator
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Starting Date
01
Jul 2015
Status
Ongoing
Members
4
Structures
1
Publications
6

About

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.

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References