Epigenetic control of pheromone MAPK signaling determines sexual fecundity in Candida albicans

Abstract

Several pathogenic species are capable of heritable and reversible switching between two epigenetic states, "white" and "opaque." In, white cells are essentially sterile, whereas opaque cells are mating-proficient. Here, we interrogate the mechanism by which the white-opaque switch regulates sexual fecundity and identify four genes in the pheromone MAPK pathway that are expressed at significantly higher levels in opaque cells than in white cells. These genes encode the β subunit of the G-protein complex (), the pheromone MAPK scaffold (), and the two terminal MAP kinases (). To define the contribution of each factor to mating, white cells were reverse-engineered to express elevated, opaque-like levels of these factors, either singly or in combination. We show that white cells co-overexpressing, , and undergo mating four orders of magnitude more efficiently than control white cells and at a frequency approaching that of opaque cells. Moreover, engineered white cells recapitulate the transcriptional and morphological responses of opaque cells to pheromone. These results therefore reveal multiple bottlenecks in pheromone MAPK signaling in white cells and that alleviation of these bottlenecks enables efficient mating by these "sterile" cell types. Taken together, our findings establish that differential expression of several MAPK factors underlies the epigenetic control of mating in We also discuss how fitness advantages could have driven the evolution of a toggle switch to regulate sexual reproduction in pathogenic species.

Unisexual reproduction promotes competition for mating partners in the global human fungal pathogenCryptococcus deneoformans

“…Elevated pheromone response pathway activation and increased response to pheromones are critical to successful courtship during mating in S. cerevisiae and C. albicans [14, 15, 18]. S. cerevisiae utilizes the α-factor protease Bar1 and a -factor barrier Afb1 to discriminate mating partners with different pheromone levels and drive evolution towards higher pheromone production for efficient mating [43–45].…”

“…Upregulation of the pheromone response pathway enhances mating efficiency; however, this upregulation can result in a fitness cost in S. cerevisiae and C. albicans [18, 48]. In yeast, a short-term experimental evolution experiment showed that mutations abrogating expression of 23 genes involved in mating conferred a fitness benefit during yeast growth when functions of these genes are not required [48].…”

“…In yeast, a short-term experimental evolution experiment showed that mutations abrogating expression of 23 genes involved in mating conferred a fitness benefit during yeast growth when functions of these genes are not required [48]. In C. albicans , cells undergo a white-opaque switch and upregulate the pheromone response pathway, which results in a fitness cost for the opaque cells [18]. Considering that the pheromone response pathway is activated at a higher level in C. deneoformans strains with more hyphal growth during bisexual reproduction, we investigated whether unisexual reproduction confers a fitness cost.…”

“…Similarly, in Schizosaccharomyces pombe , local pheromone signals and a spatially focal pheromone response dictate cell-cell pairing and fusion position during early mating processes [16, 17]. In C. albicans , overexpression of pheromone response MAP kinase pathway components can enhance mating efficiency [18]. These studies establish that the pheromone response pathway plays a critical role in promoting fungal mating efficiency.…”

Unraveling How Candida albicans Forms Sexual Biofilms

“…The activities of Cek1 and Cek2 are regulated by Cpp1, a MAP kinase phosphatase [78]. Interestingly, STE4, CST5, CEK1, and CEK2 are expressed at lower levels in white cells than opaque cells [79], and their repression contributes to the sterility of white cells as white cells engineered to express STE4, CST5, and CEK2 (CEK1 was not tested) at levels similar to opaque cells have been shown to undergo mating at frequencies approaching that of opaque cells [79]. It is also interesting to note that Cek1 (rather than Cek2) appears to play a major role in opaque cell mating; opaque cek1 mutants mate at much lower frequencies than opaque cek2 mutants [78].…”