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

Abstract

ABSTRACT 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 CO 2 bypasses the requirement for Yak1 in the yeast-to-filament transition. Seeking to identify the factor(s) that mediates filamentation under elevated CO 2 , 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. IMPORTANCE Candida albicans is an opportunistic human fungal pathogen that frequently causes life-threatening infections in immunocompromised individuals. To cause disease, the fungus employs several virulence traits, including its ability to transition between yeast and filamentous states. Previous work identified a role for the kinase Yak1 in regulating C. albicans filamentation. Here, we demonstrate that Yak1 regulates morphogenesis through the canonical cAMP/PKA pathway and that this regulation is environmentally contingent, as host-relevant concentrations of CO 2 bypass the requirement of Yak1 for C. albicans morphogenesis. We show a related kinase, Pom1, is important for filamentation in the absence of Yak1 under these host-relevant conditions, as deletion of both genes blocked filamentous growth under all conditions tested. Finally, we demonstrate that Yak1 is required for filamentation in a mouse model of C. albicans dermatitis using genetic and pharmacological approaches. Overall, our results expand our understanding of how Yak1 regulates an important virulence trait in C. albicans .