Roles of the pro-apoptotic factors CaNma111 and CaYbh3 in apoptosis and virulence of Candida albicans

Abstract

Candida albicans, a commensal and opportunistic pathogen, undergoes apoptosis in response to various stimuli, including hydrogen peroxide, acetic acid, and antifungal agents. Apoptotic processes are highly conserved among mammals, plants, and fungi, but little is known about the apoptosis-regulating factors in C. albicans. In this study, C. albicans homologs of the putative apoptosis factors were identified by database screening followed by overexpression analysis. CaNma111, a homolog of the pro-apoptotic mammalian HtrA2/Omi, and CaYbh3, a homolog of BH3-only protein, yielded increased apoptotic phenotypes upon overexpression. We showed that CaNma111 and CaYbh3 functions as pro-apoptotic regulators by examining intracellular ROS accumulation, DNA end breaks (TUNEL assay), and cell survival in Canma111/Canma111 and Caybh3/Caybh3 deletion strains. We found that the protein level of CaBir1, an inhibitor-of-apoptosis (IAP) protein, was down-regulated by CaNma111. Interestingly, the Canma111/Canma111 and Caybh3/Caybh3 deletion strains showed hyperfilamentation phenotypes and increased virulence in a mouse infection model. Together, our results suggest that CaNma111 and CaYbh3 play key regulatory roles in the apoptosis and virulence of C. albicans.