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Published online 7 August 2006. doi:10.1083/jcb.200604044
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 4, 509-519
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Article

 The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice

Julian Pardo1, Christin Urban2, Eva M. Galvez3, Paul G. Ekert4, Uwe Müller5, June Kwon-Chung6, Mario Lobigs7, Arno Müllbacher7, Reinhard Wallich8, Christoph Borner2, and Markus M. Simon1

1 Metschnikoff Laboratory, Max-Planck-Institut für Immunbiologie, D-79108 Freiburg, Germany
2 Institute of Molecular Medicine and Cell Research, Center for Biochemistry and Molecular Research, D-79104 Freiburg, Germany
3 Institut für Physikalische Chemie, Freiburg Universität, D-79104 Freiburg, Germany
4 Children's Cancer Centre, Royal Children's Hospital, Parkville, Victoria 3052, Australia
5 Molecular Pathogenesis, Biotechnology and Biomedicine Center, University of Leipzig, D-04103 Leipzig, Germany
6 Molecular Microbiology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, MD 20892
7 John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia
8 Institut für Immunologie, Universitätsklinikum Heidelberg, D-69120 Heidelberg, Germany

Correspondence to Markus M. Simon: simon{at}immunbio.mpg.de

Aspergillus fumigatus infections cause high levels of morbidity and mortality in immunocompromised patients. Gliotoxin (GT), a secondary metabolite, is cytotoxic for mammalian cells, but the molecular basis and biological relevance of this toxicity remain speculative. We show that GT induces apoptotic cell death by activating the proapoptotic Bcl-2 family member Bak, but not Bax, to elicit the generation of reactive oxygen species, the mitochondrial release of apoptogenic factors, and caspase-3 activation. Activation of Bak by GT is direct, as GT triggers in vitro a dose-dependent release of cytochrome c from purified mitochondria isolated from wild-type and Bax- but not Bak-deficient cells. Resistance to A. fumigatus of mice lacking Bak compared to wild-type mice demonstrates the in vivo relevance of this GT-induced apoptotic pathway involving Bak and suggests a correlation between GT production and virulence. The elucidation of the molecular basis opens new strategies for the development of therapeutic regimens to combat A. fumigatus and related fungal infections.

Abbreviations used in this paper: 2-HE, 2-hydroxiethidine; AIF, apoptosis-inducing factor; ANT, adenine nucleotide transporter; FDM, factor-dependent myeloid; GT, gliotoxin; IA, invasive aspergilloses; MEF, mouse embryonic fibroblast; MnTBAP, Mn(III) tetrakis(4-benzoic acid) porphyrin chloride; MPTP, mitochondrial permeability transition pore; NAC, N-acetylcysteine; PI, propidium iodide; PS, phosphatidylserine; ROS, reactive oxygen species; wt, wild-type.


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