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Pardo J, Urban C, Galvez EM, Ekert PG, Muller U, Kwon-Chung J, Lobigs M,
Mullbacher A, Wallich R, Borner C, Simon MM
The mitochondrial protein Bak is pivotal for gliotoxin induced
apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice.
J Cell Biol. 2006 Aug 14;174(4):509-19
Metschnikoff Laboratory, Max-Planck-Institut für Immunbiologie, D-79108
Freiburg, Germany.
Aspergillus fumigatus infections cause high levels of morbidity and mortality in
immunocompromised patients. Gliotoxin, a secondary metabolite, is cytotoxic for
mammalian cells, but the molecular basis and biological relevance of this
toxicity remain speculative. We show that Gliotoxin 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 Gliotoxin is
direct, as Gliotoxin 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 Gliotoxin -induced apoptotic pathway
involving Bak and suggests a correlation between Gliotoxin 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.
PMID: 16893972 |
