Genetic Analysis of Sirtuin Deacetylases in Hyphal Growth of Candida albicans

Candida albicans is a major human fungal pathogen that encountersvaried host environments during infection. In response to environmental cues, C.albicans switches between ovoid yeast and elongated hyphal growth forms, and thismorphological plasticity contributes to virulence. Environmental changes that alterthe cell’s metabolic state could be sensed by sirtuins, which are NAD1-dependentdeacetylases. Here, we studied the roles of three sirtuin deacetylases—Sir2, Hst1,and Hst2—in the hyphal growth of C. albicans. We made single, double, and triplesirtuin knockout strains and tested their ability to switch from yeast to hyphae. Wefound that true hypha formation was significantly reduced by the deletion of SIR2but not HST1 or HST2. Moreover, the expression of hypha-specific genes HWP1, ALS3,and ECE1 decreased in the sir2D/D mutant compared to the wild type. This regulationof hypha formation was likely dependent on the deacetylase activity of Sir2, asa similar defect in hypha formation was observed when an asparagine known to berequired for deacetylation was mutated. Finally, we found that Sir2 and Hst1 werelocalized to the nucleus, with Sir2 specifically focused in the nucleolus. This nuclearlocalization suggests a role for Sir2 and Hst1 in regulating gene expression. In contrast,Hst2 was localized to the cytoplasm. In conclusion, our results suggest thatSir2 plays a critical and nonredundant role in hyphal growth of C. albicans.