DYRK-family kinases regulate Candida albicans morphogenesis and virulence through the Ras1/PKA pathway

Candida albicans is an opportunistic human fungal pathogen that causes common superficial mycoses in healthy populations and invasive disease in immunocompromised individuals. The fungus employs several virulence traits to cause disease in humans, including its ability to transition from yeast to filamentous morphologies. Previous work found that genetic or pharmacological inhibition of the dual-specificity tyrosine-phosphorylation regulated kinase (DYRK) Yak1 blocks C. albicans morphogenesis and biofilm formation. Here, we expand on this work to provide mechanistic insights into how Yak1 governs this important virulence trait. First, we establish that Yak1 acts either downstream or parallel to protein kinase A (PKA) to regulate filamentation in response to diverse inducing cues. Furthermore, its importance in governing filamentous growth is dependent on core transcriptional regulators, such as Efg1 and Flo8. We also report that hyperactivation of the Ras1/cAMP/PKA pathway under elevated, host-relevant concentrations of CO2 bypasses the requirement for Yak1 in the yeast-to-filament transition. Seeking to identify the factor(s) that mediates filamentation under elevated CO2, we found that in a yak1-mutant background, homozygous deletion of a predicted, but previously uncharacterized DYRK, POM1, blocks filamentation. Finally, we demonstrate that Yak1 is required for morphogenesis in a dermatitis model of C. albicans infection and that pharmacological inhibition of Yak1 with a beta-carboline also attenuates filamentation in the dermal tissue. Overall, this work characterizes the role of Yak1 in regulating C. albicans morphogenesis, identifies an undescribed role for Pom1 in the yeast-to-filament transition, and suggests that inhibition of Yak1 may serve as a therapeutic strategy to combat C. albicans dermatitis.

Automated summary

This study characterizes the role of Yak1 in regulating C. albicans morphogenesis and identifies a previously unknown role for Pom1 in the yeast-to-filament transition. Furthermore, the findings suggest that inhibition of Yak1 may serve as a therapeutic strategy to combat C. albicans dermatitis.