Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly
Authors:Kristin Graumann1,3,#, Frieder Schaumburg1,4,#, Thomas F. Reubold2, Diana Hippe1, Susanne Eschenburg2 and Carsten G. K. Lüder1
doi: 10.15698/mic2015.05.201
Volume 2, pp. 150 to 162, published 04/05/2015.
1 Institute for Medical Microbiology, Georg-August-University, Göttingen, Germany.
2 Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany.
3 Present address: In den Brühlwiesen 12, 61352 Bad Homburg, Germany.
4 Present address: Institute for Medical Microbiology, University Hospital Münster, Domagkstraße 10, 48149 Münster, Germany.
# These authors contributed equally.
Keywords:
Toxoplasma gondii, apoptosis, pathogen-host interaction, caspase activation, intrinsic pathway, apoptosome, Apaf-1
Corresponding Author(s):
Conflict of interest statement:
The authors declare no conflict of interest.
Please cite this article as:
Kristin Graumann, Frieder Schaumburg, Thomas F. Reubold, Diana Hippe, Susanne Eschenburg and Carsten G. K. Lüder (2015). Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly. Microbial Cell 2(5): 150-162.
© 2015 Graumann et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
Inhibition of programmed cell death pathways of mammalian cells often facilitates the sustained survival of intracellular microorganisms. The apicomplexan parasite Toxoplasma gondii is a master regulator of host cell apoptotic pathways. Here, we have characterized a novel anti-apoptotic activity of T. gondii. Using a cell-free cytosolic extract model, we show that T. gondii interferes with the activities of caspase 9 and caspase 3/7 which have been induced by exogenous cytochrome c and dATP. Proteolytic cleavage of caspases 9 and 3 is also diminished suggesting inhibition of holo-apoptosome function. Parasite infection of Jurkat T cells and subsequent triggering of apoptosome formation by exogenous cytochrome c in vitro and in vivo indicated that T. gondii also interferes with caspase activation in infected cells. Importantly, parasite inhibition of cytochrome c-induced caspase activation considerably contributes to the overall anti-apoptotic activity of T. gondii as observed in staurosporine-treated cells. Co-immunoprecipitation showed that T. gondii abolishes binding of caspase 9 to Apaf-1 whereas the interaction of cytochrome c with Apaf-1 remains unchanged. Finally, T. gondii lysate mimics the effect of viable parasites and prevents holo-apoptosome functionality in a reconstituted in vitro system comprising recombinant Apaf-1 and caspase 9. Beside inhibition of cytochrome c release from host cell mitochondria, T. gondii thus also targets the holo-apoptosome assembly as a second mean to efficiently inhibit the caspase-dependent intrinsic cell death pathway.