The white cell pheromone response pathway in Candida albicans provides insights into the evolution of new signal transduction pathways

Candida albicans is the most common fungal pathogen that infects humans. The research described in this thesis focuses on an in-depth characterization of the regulatory pathways controlling white-opaque switching, mating and biofilm formation, and the relationships among these programs in this pathogen. It was demonstrated in 2006 that minority opaque cells of C. albicans release pheromone to signal majority white cells of the opposite mating type to form enhanced biofilms. The white cell biofilms in turn facilitate opaque cell chemotropism, an essential step in mating. The white cell pheromone response is a general characteristic of C. albicans, occuring in all tested strains and in all common lab media. By generation of deletion mutants of select genes in the opaque cell mating pathway, it was demonstrated that the pathway regulating the white cell response shares all of the components of the opaque mating pathway, from the pheromone receptor through the MAP kinase cascade with the exception of the downstream transcription factor. In addition, it was demonstrated that a C. albicans-specific region in the first intracellular loop, IC1, of the alpha-pheromone receptor is required for the white, but not the opaque, pheromone response. Furthermore, the cis-acting element in the promoters of genes induced by pheromone in white cells was identified. The white-specific pheromone response element, WPRE, is important for the regulation of the white pheromone response and induction of white-specific genes by pheromone. Finally, based on a misexpression library screening of transcription factors previously implicated in adhesion, cell wall biogenesis, filamentation or biofilm formation, the transcription factor Tec1 was identified to be the key regulator in the white pheromone response pathway. Tec1 binds to the WPRE in the promoters of genes induced by pheromone in white cells to mediate the white cell response. The white pheromone response pathway appears to be a relatively young pathway that borrowed the upstream components from the opaque mating pathway, the transcription factor from the ancestral filamentation pathway, and the downstream genes from the pathway regulating biofilm formation in a/alpha cells of C. albicans. Therefore, the configuration of the white response pathway provides a unique glimpse and possibly a paradigm for the evolution of signal transduction pathways in eukaryotes.