title: 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.affiliation: Institut Pasteur, Unité d'Immunobiologie de l'Infection, Paris, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Guenin-Macé
authors.forename: Romain
authors.initials: R
authors.lastname: Veyron-Churlet
authors.forename: Maria-Isabel
authors.initials: MI
authors.lastname: Thoulouze
authors.forename: Guillaume
authors.initials: G
authors.lastname: Romet-Lemonne
authors.forename: Hui
authors.initials: H
authors.lastname: Hong
authors.forename: Peter F
authors.initials: PF
authors.lastname: Leadlay
authors.forename: Anne
authors.initials: A
authors.lastname: Danckaert
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Ruf
authors.forename: Serge
authors.initials: S
authors.lastname: Mostowy
authors.forename: Chiara
authors.initials: C
authors.lastname: Zurzolo
authors.forename: Philippe
authors.initials: P
authors.lastname: Bousso
authors.forename: Fabrice
authors.initials: F
authors.lastname: Chrétien
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Carlier
authors.forename: Caroline
authors.initials: C
authors.lastname: Demangel
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D054312:Buruli Ulcer / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology; D002448:Cell Adhesion; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D019911:Mycobacterium ulcerans; D011412:Propanolamines / Q000494:pharmacology; D055503:Protein Multimerization; D021381:Protein Transport; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000037:antagonists & inhibitors / Q000378:metabolism; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D001427:Bacterial Toxins; D002227:Carbazoles; D018942:Macrolides; D011412:Propanolamines; C495771:WASL protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; C117218:mycolactone; C489942:wiskostatin
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