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Vol. 12, Issue 11, 3631-3643, November 2001
§
¶
*Eukaryotic Genetics Group, Biotechnology Research Institute,
National Research Council of Canada, Montreal, Quebec H4P 2R2, Canada;
the The human fungal pathogen Candida albicans switches
from a budding yeast form to a polarized hyphal form in response to
various external signals. This morphogenetic switching has been
implicated in the development of pathogenicity. We have cloned the
CaCDC35 gene encoding C. albicans
adenylyl cyclase by functional complementation of the conditional
growth defect of Saccharomyces cerevisiae cells with
mutations in Ras1p and Ras2p. It has previously been shown that these
Ras homologues regulate adenylyl cyclase in yeast. The C.
albicans adenylyl cyclase is highly homologous to other fungal
adenylyl cyclases but has less sequence similarity with the mammalian
enzymes. C. albicans cells deleted for both alleles of
CaCDC35 had no detectable cAMP levels, suggesting that
this gene encodes the only adenylyl cyclase in C.
albicans. The homozygous mutant cells were viable but grew more
slowly than wild-type cells and were unable to switch from the yeast to
the hyphal form under all environmental conditions that we analyzed in
vitro. Moreover, this morphogenetic switch was completely blocked in
mutant cells undergoing phagocytosis by macrophages. However,
morphogenetic switching was restored by exogenous cAMP. On the basis of
epistasis experiments, we propose that CaCdc35p acts downstream of the
Ras homologue CaRas1p. These epistasis experiments also suggest that the putative transcription factor Efg1p and components of the hyphal-inducing MAP kinase pathway depend on the function of CaCdc35p in their ability to induce morphogenetic switching. Homozygous cacdc35Institute of Clinical Microbiology, Immunology, and
Hygiene, University of Erlangen, D-91054 Erlangen, Germany; and the
Departments of Anatomy and Cell Biology,
§Biology, and Experimental Medicine, McGill
University, Montreal, Canada
cells were unable to establish vaginal
infection in a mucosal membrane mouse model and were avirulent in a
mouse model for systemic infections. These findings suggest that fungal
adenylyl cyclases and other regulators of the cAMP signaling pathway
may be useful targets for antifungal drugs.
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