Abstract
Depending on the environmental conditions, the pathogenic yeast Candida albicans can undergo different developmental programs, which are controlled by dedicated transcription factors and upstream signaling pathways. C. albicans strains that are homozygous at the mating type locus can switch from the normal yeast form (white) to an elongated cell type (opaque), which is the mating-competent form of this fungus. Both white and opaque cells use the Ste11-Hst7-Cek1/Cek2 MAP kinase signaling pathway to react to the presence of mating pheromone. However, while opaque cells employ the transcription factor Cph1 to induce the mating response, white cells recruit a different downstream transcription factor, Tec1, to promote the formation of a biofilm that facilitates mating of opaque cells in the population. The switch from the white to the opaque cell form is itself induced by environmental signals that result in the upregulation of the transcription factor Wor1, the master regulator of white-opaque switching. To get insight into the upstream signaling pathways controlling the switch, we expressed all C. albicans protein kinases from a tetracycline-inducible promoter in a switching-competent strain. Screening of this library of strains showed that a hyperactive form of Ste11 lacking its N-terminal domain (Ste11ΔN467) efficiently stimulated white cells to switch to the opaque phase, a behavior that did not occur in response to pheromone. Ste11ΔN467-induced switching specifically required the downstream MAP kinase Cek1 and its target transcription factor Cph1, but not Cek2 and Tec1, and forced expression of Cph1 also promoted white-opaque switching in a Wor1-dependent manner. Therefore, depending on the activation mechanism, components of the pheromone-responsive MAP kinase pathway can be reconnected to stimulate an alternative developmental program, switching of white cells to the mating-competent opaque phase.
Highlights
The yeast Candida albicans is a member of the microbiota in the gastrointestinal and genitourinary tracts of most healthy persons, but it can cause superficial as well as life-threatening systemic infections when host defenses are compromised
The pathogenic yeast Candida albicans can switch from the white yeast form to the mating-competent opaque form
We used a comprehensive protein kinase expression library to gain insight into the signaling pathways that regulate switching from the white to the opaque phase and found that a hyperactive form of the upstream kinase Ste11 induced white opaque-switching, a behavior that did not occur in response to pheromone
Summary
The yeast Candida albicans is a member of the microbiota in the gastrointestinal and genitourinary tracts of most healthy persons, but it can cause superficial as well as life-threatening systemic infections when host defenses are compromised. The switch from yeast to filamentous growth facilitates tissue invasion and is associated with the transition of C. albicans from a harmless colonizer to a pathogen that causes symptomatic infections [1]. C. albicans can switch from the normal, round-to-oval yeast morphology (white) to an elongated yeast cell type (opaque), which is the mating-competent form of this diploid fungus [2]. WOR1 is expressed at very low levels in white cells, but an increase in the amount of Wor above a threshold induces switching to the opaque phase. Additional transcription factors, including the positive regulators Wor and Czf and the negative regulator Efg, which are themselves controlled by Wor, ensure bistable expression of WOR1 (low in white and high in opaque cells) and epigenetic inheritance of the two phases [7]. In heterozygous MTLa/a strains, switching of white cells to the opaque phase is inhibited by a heterodimeric repressor consisting
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