edoc

The macrolide toxin mycolactone promotes bim-dependent apoptosis in Buruli ulcer through inhibition of mTOR

Bieri, Raphael and Scherr, Nicole and Ruf, Marie-Thérèse and Dangy, Jean-Pierre and Gersbach, Philipp and Gehringer, Matthias and Altmann, Karl-Heinz and Pluschke, Gerd. (2017) The macrolide toxin mycolactone promotes bim-dependent apoptosis in Buruli ulcer through inhibition of mTOR. ACS chemical biology, 12 (5). pp. 1297-1307.

Full text not available from this repository.

Official URL: http://edoc.unibas.ch/55412/

Downloads: Statistics Overview

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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Molecular Immunology (Pluschke)
UniBasel Contributors:Bieri, Raphael and Scherr, Nicole and Ruf, Marie-Thérèse and Ruf, Marie-Thérèse and Pluschke, Gerd
Item Type:Article, refereed
Publisher:American Chemical Society
ISSN:1554-8929
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:14 Jun 2017 14:20
Deposited On:14 Jun 2017 14:20

Repository Staff Only: item control page