title: The Macrolide Toxin Mycolactone Promotes Bim-Dependent Apoptosis in Buruli Ulcer through Inhibition of mTOR.
abstract: Mycolactone, the macrolide exotoxin produced by Mycobacterium ulcerans, is central to the pathogenesis of the chronic necrotizing skin disease Buruli ulcer (BU). Here we show that mycolactone acts as an inhibitor of the mechanistic Target of Rapamycin (mTOR) signaling pathway by interfering with the assembly of the two distinct mTOR protein complexes mTORC1 and mTORC2, which regulate different cellular processes. Inhibition of the assembly of the rictor containing mTORC2 complex by mycolactone prevents phosphorylation of the serine/threonine protein kinase Akt. The associated inactivation of Akt leads to the dephosphorylation and activation of the Akt-targeted transcription factor FoxO3. Subsequent up-regulation of the FoxO3 target gene BCL2L11 (Bim) increases expression of the pro-apoptotic regulator Bim, driving mycolactone treated mammalian cells into apoptosis. The central role of Bim-dependent apoptosis in BU pathogenesis deduced from our experiments with cultured mammalian cells was further verified in an experimental M. ulcerans infection model. As predicted by the model, M. ulcerans infected Bim knockout mice did not develop necrotic BU lesions with large clusters of extracellular bacteria, but were able to contain the mycobacterial multiplication. Our findings provide a new coherent and comprehensive concept of BU pathogenesis.
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.|University of Basel , Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bieri
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.|University of Basel , Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Scherr
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.|University of Basel , Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Ruf
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.|University of Basel , Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Jean-Pierre
authors.identifier: 0000-0001-7368-195X
authors.initials: JP
authors.lastname: Dangy
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zürich , Vladimir-Prelog-Weg 1-5/10, 8093 Zürich, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Gersbach
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zürich , Vladimir-Prelog-Weg 1-5/10, 8093 Zürich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gehringer
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zürich , Vladimir-Prelog-Weg 1-5/10, 8093 Zürich, Switzerland.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.|University of Basel , Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Gerd
authors.identifier: 0000-0003-1957-2925
authors.initials: G
authors.lastname: Pluschke
mesh_terms: D000818:Animals; D017209:Apoptosis; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054312:Buruli Ulcer / Q000382:microbiology / Q000473:pathology*; D002478:Cells, Cultured; D055786:Gene Knockout Techniques; D018942:Macrolides / Q000494:pharmacology* / Q000633:toxicity; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000187:drug effects; D019911:Mycobacterium ulcerans / Q000737:chemistry / Q000472:pathogenicity; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects
chemical_list: D000072224:Bcl-2-Like Protein 11; D018942:Macrolides; D046912:Multiprotein Complexes; C117218:mycolactone; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases