Back
The Macrolide Toxin Mycolactone Promotes Bim-Dependent Apoptosis in Buruli Ulcer through Inhibition of mTOR.
Journal article

The Macrolide Toxin Mycolactone Promotes Bim-Dependent Apoptosis in Buruli Ulcer through Inhibition of mTOR.

  • Bieri R Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.
  • Scherr N Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.
  • Ruf MT Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.
  • Dangy JP Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.
  • Gersbach P 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.
  • Gehringer M 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.
  • Altmann KH 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.
  • Pluschke G Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.
Show more…
  • 2017-03-16
Published in:
  • ACS chemical biology. - 2017
Animals
Apoptosis
Bcl-2-Like Protein 11
Buruli Ulcer
Cells, Cultured
Gene Knockout Techniques
Macrolides
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Mice
Multiprotein Complexes
Mycobacterium ulcerans
TOR Serine-Threonine Kinases
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.rero.ch/global/documents/101332
Statistics
Document views: 28 File downloads: