Molecular mechanisms of mycobacteria exit from their host cell
Cell Biology
Final Report Abstract
The Dictyostelium - M. marinum system is a biochemically and genetically tractable system that allows to dissect host-pathogen interactions. In this project we focussed on the mechanism, how mycobacteria exit their host cell, pathogen egress. In Dictyostelium it is known, that bacteria leave through an F-actin dense structure, termed the ejectosome. During egress, membranes have been observed to specifically associate at the intracellular, distal pole of the bacteria. In this study, we confirmed that the membranes have several characteristics of an early autophagosome. However, the origin of the membranes remains to be resolved. While it has been shown, that in absence of the distal autophagosome cell-to-cell transmission is decreased and cells appear leaky, the precise function of the structure and its mechanism of recruitment are not known. We could show, that an autophagic receptor is associated with the distal autophagosome, as well as ubiquitin. However, experiments in mutants suggested, that additional receptors are involved. Furthermore, using immunofluorescence analyses we revealed that, reminiscent to the appearance of the autophagic machinery, the ESCRT machinery is present at the distal pole. A link between autophagy and the ESCRT machinery has long been reported, but the role of ESCRT remains unclear. We put forward the hypothesis that the distal vacuole of egressing bacteria represents a stalled, usually transient stage during autophagosome closure, "frustrated autophagy". This leads to the accumulation of the "closure machinery" on the engulfing membranes. Furthermore, it would finally represent a system that allows to dissect the molecular mechanism of autophagosome closure.
Publications
- The autophagic machinery ensures nonlytic transmission of mycobacteria. Proc Natl Acad Sci USA. 2015 Feb 17;112(7):E687-92
Gerstenmaier L, Pilla R, Herrmann L, Herrmann H, Prado M, Villafano GJ, Kolonko M, Reimer R, Soldati T, King JS, Hagedorn M
(See online at https://doi.org/10.1073/pnas.1423318112) - The ESCRT and autophagy machineries cooperate to repair ESX-1-dependent damage at the Mycobacterium-containing vacuole but have opposite impact on containing the infection. PLoS Pathog. 2018 Dec 31;14(12):e1007501
López-Jiménez AT, Cardenal-Muñoz E, Leuba F, Gerstenmaier L, Barisch C, Hagedorn M, King JS, Soldati T
(See online at https://doi.org/10.1371/journal.ppat.1007501)
